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1.  Integrative Computational and Experimental Approaches to Establish a Post-Myocardial Infarction Knowledge Map 
PLoS Computational Biology  2014;10(3):e1003472.
Vast research efforts have been devoted to providing clinical diagnostic markers of myocardial infarction (MI), leading to over one million abstracts associated with “MI” and “Cardiovascular Diseases” in PubMed. Accumulation of the research results imposed a challenge to integrate and interpret these results. To address this problem and better understand how the left ventricle (LV) remodels post-MI at both the molecular and cellular levels, we propose here an integrative framework that couples computational methods and experimental data. We selected an initial set of MI-related proteins from published human studies and constructed an MI-specific protein-protein-interaction network (MIPIN). Structural and functional analysis of the MIPIN showed that the post-MI LV exhibited increased representation of proteins involved in transcriptional activity, inflammatory response, and extracellular matrix (ECM) remodeling. Known plasma or serum expression changes of the MIPIN proteins in patients with MI were acquired by data mining of the PubMed and UniProt knowledgebase, and served as a training set to predict unlabeled MIPIN protein changes post-MI. The predictions were validated with published results in PubMed, suggesting prognosticative capability of the MIPIN. Further, we established the first knowledge map related to the post-MI response, providing a major step towards enhancing our understanding of molecular interactions specific to MI and linking the molecular interaction, cellular responses, and biological processes to quantify LV remodeling.
Author Summary
Heart attack, known medically as myocardial infarction, often occurs as a result of partial shortage of blood supply to a portion of the heart, leading to the death of heart muscle cells. Following myocardial infarction, complications might arise, including arrhythmia, myocardial rupture, left ventricular dysfunction, and heart failure. Although myocardial infarction can be quickly diagnosed using a various number of tests, including blood tests and electrocardiography, there have been no available prognostic tests to predict the long-term outcome in response to myocardial infarction. Here, we present a framework to analyze how the left ventricle responds to myocardial infarction by combining protein interactome and experimental results retrieved from published human studies. The framework organized current understanding of molecular interactions specific to myocardial infarction, cellular responses, and biological processes to quantify left ventricular remodeling process. Specifically, our knowledge map showed that transcriptional activity, inflammatory response, and extracellular matrix remodeling are the main functional themes post myocardial infarction. In addition, text analytics of relevant abstracts revealed differentiated protein expressions in plasma or serum expressions from patients with myocardial infarction. Using this data, we predicted expression levels of other proteins following myocardial infarction.
PMCID: PMC3961365  PMID: 24651374
2.  Combining experimental and mathematical modeling to reveal mechanisms of macrophage-dependent left ventricular remodeling 
BMC Systems Biology  2011;5:60.
Progressive remodeling of the left ventricle (LV) following myocardial infarction (MI) can lead to congestive heart failure, but the underlying initiation factors remain poorly defined. The objective of this study, accordingly, was to determine the key factors and elucidate the regulatory mechanisms of LV remodeling using integrated computational and experimental approaches.
By examining the extracellular matrix (ECM) gene expression and plasma analyte levels in C57/BL6J mice LV post-MI and ECM gene responses to transforming growth factor (TGF-β1) in cultured cardiac fibroblasts, we found that key factors in LV remodeling included macrophages, fibroblasts, transforming growth factor-β1, matrix metalloproteinase-9 (MMP-9), and specific collagen subtypes. We established a mathematical model to study LV remodeling post-MI by quantifying the dynamic balance between ECM construction and destruction. The mathematical model incorporated the key factors and demonstrated that TGF-β1 stimuli and MMP-9 interventions with different strengths and intervention times lead to different LV remodeling outcomes. The predictions of the mathematical model fell within the range of experimental measurements for these interventions, providing validation for the model.
In conclusion, our results demonstrated that the balance between ECM synthesis and degradation, controlled by interactions of specific key factors, determines the LV remodeling outcomes. Our mathematical model, based on the balance between ECM construction and destruction, provides a useful tool for studying the regulatory mechanisms and for predicting LV remodeling outcomes.
PMCID: PMC3113236  PMID: 21545710
3.  Intravenous and intramyocardial injection of apoptotic white blood cell suspensions prevents ventricular remodelling by increasing elastin expression in cardiac scar tissue after myocardial infarction 
Basic Research in Cardiology  2011;106(4):645-655.
Congestive heart failure developing after acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Clinical trials of cell-based therapy after AMI evidenced only a moderate benefit. We could show previously that suspensions of apoptotic peripheral blood mononuclear cells (PBMC) are able to reduce myocardial damage in a rat model of AMI. Here we experimentally examined the biochemical mechanisms involved in preventing ventricular remodelling and preserving cardiac function after AMI. Cell suspensions of apoptotic cells were injected intravenously or intramyocardially after experimental AMI induced by coronary artery ligation in rats. Administration of cell culture medium or viable PBMC served as controls. Immunohistological analysis was performed to analyse the cellular infiltrate in the ischaemic myocardium. Cardiac function was quantified by echocardiography. Planimetry of the infarcted hearts showed a significant reduction of infarction size and an improvement of post AMI remodelling in rats treated with suspensions of apoptotic PBMC (injected either intravenously or intramoycardially). Moreover, these hearts evidenced enhanced homing of macrophages and cells staining positive for c-kit, FLK-1, IGF-I and FGF-2 as compared to controls. A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells. Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue. The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.
Electronic supplementary material
The online version of this article (doi:10.1007/s00395-011-0173-0) contains supplementary material, which is available to authorized users.
PMCID: PMC3105227  PMID: 21416207
Myocardial infarction; Apoptosis; Cytokines; Cell therapy; Elastin; Collagen
4.  Regulation of the inflammatory response in cardiac repair 
Circulation research  2012;110(1):159-173.
Myocardial necrosis triggers an inflammatory reaction that clears the wound from dead cells and matrix debris, while activating reparative pathways necessary for scar formation. A growing body of evidence suggests that accentuation, prolongation or expansion of the post-infarction inflammatory response results in worse remodeling and dysfunction following myocardial infarction. This review manuscript discusses the cellular effectors and endogenous molecular signals implicated in suppression and containment of the inflammatory response in the infarcted heart. Clearance of apoptotic neutrophils, recruitment of inhibitory monocyte subsets and regulatory T cells, macrophage differentiation and pericyte/endothelial interactions may play an active role in restraining post-infarction inflammation. Multiple molecular signals may be involved in suppressing the inflammatory cascade. Negative regulation of toll-like receptor signaling, downmodulation of cytokine responses and termination of chemokine signals may be mediated through the concerted action of multiple suppressive pathways that prevent extension of injury and protect from adverse remodeling. Expression of soluble endogenous antagonists, decoy receptors, and post-translational processing of bioactive molecules may limit cytokine and chemokine actions. Interleukin (IL)-10, members of the Transforming Growth Factor (TGF)-β family, and pro-resolving lipid mediators (such as lipoxins, resolvins and protectins) may suppress pro-inflammatory signaling. In human patients with myocardial infarction, defective suppression and impaired resolution of inflammation may be important mechanisms in the pathogenesis of remodeling and in progression to heart failure. Understanding of inhibitory and pro-resolving signals in the infarcted heart and identification of patients with uncontrolled post-infarction inflammation and defective cardiac repair is needed to design novel therapeutic strategies.
PMCID: PMC3690135  PMID: 22223212
Resolution of inflammation; Myocardial infarction; Cytokine; Chemokine; Mononuclear cells
5.  Silencing collapsin response mediator protein-2 reprograms macrophage phenotype and improves infarct healing in experimental myocardial infarction model 
Delayed M1 toward M2 macrophage phenotype transition is considered one of the major causes for the impaired healing after myocardial infarction (MI). While searching for molecules that modulate M1 and M2 macrophage polarization, we identified collapsin response mediator protein-2 (CRMP2) as a novel molecule involved in macrophage polarization to M1. In this study, we evaluated the effect of silencing CRMP2 on macrophage polarization, inflammation and fibrosis post myocardial infarction.
CRMP2 expression was assessed with Western blotting or immunohistochemistry. Macrophage phenotypes were measured with flow cytometry, quantitative real-time PCR (qPCR), Western blotting or immunohistochemistry. CRMP2 siRNA was delivered into the macrophages infiltrated in the wound of ApoE−/− mice through lipidoid nanoparticle, and fibrosis, leukocyte infiltration and inflammation parameters were measured with qPCR. Infarct size was measured with Masson’s trichrome staining. Echocardiography was performed to assess ventricular systolic dimension, left ventricular diastolic dimension, anterior wall thickness and posterior wall thickness. Student’s t-test (for 2 groups) and ANOVA (for > 2 groups) were used for statistical analyses.
CRMP2 was expressed in a higher level in M1 macrophages than M2 subsets, and CRMP2 RNA interference (RNAi) resulted in a switch of bone marrow-derived macrophages from M1 to M2 phenotype. High level of CRMP2 was also observed in the macrophages infiltrated in the infarct area 3 days post MI in both wildtype (WT) and ApoE−/− mice, and the expression of CRMP2 retained in the infiltrated macrophages of ApoE−/− mice but not in that of WT mice 10 days after MI. Nanoparticle-mediated delivery of CRMP2 siRNA to ApoE−/− mice with MI resulted in dramatic switch of wound macrophages from M1 to M2 phenotype, marked decrease in inflammation and fibrosis, and significant attenuation of post-MI heart failure and mortality.
CRMP2 is highly expressed in M1 macrophages and silencing CRMP2 reprograms macrophage phenotype and improves infarct healing in atherosclerotic mice.
PMCID: PMC4328069
Collapsin response mediator protein-2; Macrophages; Phenotypes; Inflammation; ApoE−/−; Myocardial infarction; Fibrosis
6.  Oxidized Calmodulin Kinase II Regulates Conduction Following Myocardial Infarction: A Computational Analysis 
PLoS Computational Biology  2009;5(12):e1000583.
Calmodulin kinase II (CaMKII) mediates critical signaling pathways responsible for divergent functions in the heart including calcium cycling, hypertrophy and apoptosis. Dysfunction in the CaMKII signaling pathway occurs in heart disease and is associated with increased susceptibility to life-threatening arrhythmia. Furthermore, CaMKII inhibition prevents cardiac arrhythmia and improves heart function following myocardial infarction. Recently, a novel mechanism for oxidative CaMKII activation was discovered in the heart. Here, we provide the first report of CaMKII oxidation state in a well-validated, large-animal model of heart disease. Specifically, we observe increased levels of oxidized CaMKII in the infarct border zone (BZ). These unexpected new data identify an alternative activation pathway for CaMKII in common cardiovascular disease. To study the role of oxidation-dependent CaMKII activation in creating a pro-arrhythmia substrate following myocardial infarction, we developed a new mathematical model of CaMKII activity including both oxidative and autophosphorylation activation pathways. Computer simulations using a multicellular mathematical model of the cardiac fiber demonstrate that enhanced CaMKII activity in the infarct BZ, due primarily to increased oxidation, is associated with reduced conduction velocity, increased effective refractory period, and increased susceptibility to formation of conduction block at the BZ margin, a prerequisite for reentry. Furthermore, our model predicts that CaMKII inhibition improves conduction and reduces refractoriness in the BZ, thereby reducing vulnerability to conduction block and reentry. These results identify a novel oxidation-dependent pathway for CaMKII activation in the infarct BZ that may be an effective therapeutic target for improving conduction and reducing heterogeneity in the infarcted heart.
Author Summary
Calmodulin kinase II (CaMKII) is a multifunctional serine/threonine kinase that regulates diverse functions in heart. Recently, a novel pathway for CaMKII activation was discovered where oxidation of the kinase at specific methionine residues produces persistent activity. This alternative oxidation-dependent pathway has important implications for heart disease where oxidative stress is increased (e.g., heart failure and following myocardial infarction). We hypothesized that myocardial infarction caused by occlusion of a coronary artery would increase levels of oxidized CaMKII. Moreover, we hypothesized that oxidative CaMKII activation represents an important mechanistic link between increased oxidative stress and life-threatening heart rhythm disturbances (arrhythmias) in heart disease. We report a dramatic increase in levels of oxidized CaMKII following myocardial infarction in the canine. Based on these experimental data, we developed a novel mathematical model of CaMKII activity to study the role of oxidation-dependent CaMKII activation in regulating cardiac cell excitability. Our findings identify a novel role for oxidation-dependent CaMKII activation following myocardial infarction and provide a mechanistic link between oxidative stress and lethal cardiac arrhythmias in heart disease.
PMCID: PMC2778128  PMID: 19997488
7.  Cathepsin S-mediated fibroblast trans-differentiation contributes to left ventricular remodelling after myocardial infarction 
Cardiovascular Research  2013;100(1):84-94.
Extracellular matrix (ECM) turnover plays an important role in left ventricular (LV) remodelling following myocardial infarction (MI). Cysteinyl cathepsins contribute to ECM catabolism in arterial diseases, suggesting their participation in post-MI remodelling.
Methods and results
Left anterior descending artery ligation-induced MI in mice showed increased expression and activity of cathepsin S (CatS). Administration of a non-selective cathepsin inhibitor, E64d, aggravated LV dysfunction at 7 and 28 days post-MI. Mechanistic studies showed that E64d increased post-MI inflammatory cell accumulation and cytokine expression, but did not affect apoptosis or angiogenesis in infarcted myocardium. Furthermore, E64d suppressed TGF-β1-induced Smad2 and Smad3 activation and expression of fibronectin extra domain A (ED-A), an alternatively spliced fibronectin variant, and subsequently prevented cardiac fibroblast trans-differentiation into myofibroblast, which contributed to post-MI collagen and fibronectin synthesis and deposition. Consistently, selective inhibition or genetically determined deficiency of CatS also reduced myocardial Smad2 and Smad3 activation and ED-A fibronectin expression, thus suppressing fibroblast trans-differentiation and resulting in adverse collagen turnover and impaired cardiac function—recapitulating the findings in mice treated with E64d.
Along with its established activities in ECM degradation, CatS plays novel roles in TGF-β1 signalling, myofibroblast trans-differentiation, and ECM protein synthesis, thereby regulating scar formation in the infarcted myocardium and preserving LV function after experimental MI.
PMCID: PMC3778959  PMID: 23771947
Myocardial infarction; Cathepsin S; Myofibroblast; Fibronectin; Collagen; Trans-differentiation
8.  Deleterious Effect of the IL-23/IL-17A Axis and γδT Cells on Left Ventricular Remodeling After Myocardial Infarction 
Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited.
Methods and Results
We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin (IL)–23/IL-17A axis and γδT cells that affects late-stage LV remodeling after MI. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild-type mice, a deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M1 macrophages and neutrophils were the major cellular source of IL-23, whereas >90% of IL-17A-producing T cells in infarcted heart were CD4− TCRγδ+ (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT cell recruitment into infarcted heart. IL-17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression.
The IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy.
PMCID: PMC3541626  PMID: 23316306
heart failure; immune system; inflammation; myocardial infarction; remodeling
9.  Transgenic Overexpression of Matrix Metalloproteinase-9 in Macrophages Attenuates the Inflammatory Response and Improves Left Ventricular Function Post-Myocardial Infarction 
Following myocardial infarction (MI), activated macrophages infiltrate into the necrotic myocardium as part of a robust pro-inflammatory response and secrete matrix metalloproteinase-9 (MMP-9). Macrophage activation, in turn, modulates the fibrotic response, in part by stimulating fibroblast extracellular matrix (ECM) synthesis. We hypothesized that overexpression of human MMP-9 in mouse macrophages would amplify the inflammatory and fibrotic responses to exacerbate left ventricular dysfunction. Unexpectedly, at day 5 post-MI, ejection fraction was improved in transgenic (TG) mice (25±2%) compared to the wild type (WT) mice (18±2%; p<0.05). By gene expression profiling, 23 of 84 inflammatory genes were decreased in the left ventricle infarct (LVI) region from the TG compared to WT mice (all p<0.05). Concomitantly, TG macrophages isolated from the LVI, as well as TG peritoneal macrophages stimulated with LPS, showed decreased inflammatory marker expression compared to WT macrophages. In agreement with attenuated inflammation, only 7 of 84 cell adhesion and ECM genes were increased in the TG LVI compared to WT LVI, while 43 genes were decreased (all p<0.05). These results reveal a novel role for macrophage-derived MMP-9 in blunting the inflammatory response and limiting ECM synthesis to improve left ventricular function post-MI.
PMCID: PMC3472138  PMID: 22884843
myocardial infarction; matrix metalloproteinase-9; extracellular matrix; inflammation; cardiac remodeling; mice; macrophage
10.  Interleukin-10 Is Not a Critical Regulator of Infarct Healing and Left Ventricular Remodeling 
Cardiovascular research  2006;74(2):313-322.
Interleukin-10 (IL-10) exerts potent anti-inflammatory actions and modulates matrix metalloproteinase expression. We hypothesized that endogenous IL-10 may regulate infarct healing and left ventricular remodeling by promoting resolution of the post-infarction inflammatory response and by modulating extracellular matrix metabolism.
IL-10 null and wildtype (WT) mice underwent reperfused infarction protocols. We compared the healing response and remodeling-associated parameters between IL-10 -/- and WT infarcts. In addition, we studied the effects of IL-10 on inflammatory gene synthesis by stimulated murine cardiac fibroblasts.
Infarcted IL-10 -/- mice exhibited comparable mortality rates with WT animals. Although IL-10 -/-mice had higher peak tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1/CCL2 mRNA levels in the infarcted heart than WT mice, both groups demonstrated timely repression of pro-inflammatory cytokine and chemokine mRNA synthesis after 24h of reperfusion and exhibited a similar time course of resolution of the neutrophil infiltrate. IL-10 gene disruption did not alter fibrous tissue deposition and dilative remodeling of the infarcted heart. Pre-incubation with IL-10 did not modulate the pro-inflammatory phenotype of TNF-α-stimulated cardiac fibroblasts, failing to inhibit chemokine mRNA synthesis. In contrast, transforming growth factor (TGF)-β1 pre-incubation suppressed interferon-γ-inducible protein (IP)-10/CXCL10 synthesis by cardiac fibroblasts exposed to TNF-α.
IL-10 signaling plays a non-critical role in suppression of inflammatory mediators, resolution of the inflammatory response, and fibrous tissue deposition following myocardial infarction. This may be due to the relative selectivity of IL-10-mediated anti-inflammatory actions, with respect to cell type and stimulus. Resolution of postinfarction inflammation is likely to involve multiple overlapping regulatory mechanisms controlling various pro-inflammatory pathways activated in the infarcted myocardium.
PMCID: PMC1924681  PMID: 17188669
11.  Modulation of Mononuclear Phagocyte Inflammatory Response by Liposome-Encapsulated Voltage Gated Sodium Channel Inhibitor Ameliorates Myocardial Ischemia/Reperfusion Injury in Rats 
PLoS ONE  2013;8(9):e74390.
Emerging evidence shows that anti-inflammatory strategies targeting inflammatory monocyte subset could reduce excessive inflammation and improve cardiovascular outcomes. Functional expression of voltage-gated sodium channels (VGSCs) have been demonstrated in monocytes and macrophages. We hypothesized that mononuclear phagocyte VGSCs are a target for monocyte/macrophage phenotypic switch, and liposome mediated inhibition of mononuclear phagocyte VGSC may attenuate myocardial ischemia/reperfusion (I/R) injury and improve post-infarction left ventricular remodeling.
Methodology/Principal Findings
Thin film dispersion method was used to prepare phenytoin (PHT, a non-selective VGSC inhibitor) entrapped liposomes. Pharmacokinetic study revealed that the distribution and elimination half-life of PHT entrapped liposomes were shorter than those of free PHT, indicating a rapid uptake by mononuclear phagocytes after intravenous injection. In rat peritoneal macrophages, several VGSC α subunits (NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaVX, Scn1b, Scn3b and Scn4b) and β subunits were expressed at mRNA level, and PHT could suppress lipopolysaccharide induced M1 polarization (decreased TNF-α and CCL5 expression) and facilitate interleukin-4 induced M2 polarization (increased Arg1 and TGF-β1 expression). In vivo study using rat model of myocardial I/R injury, demonstrated that PHT entrapped liposome could partially suppress I/R injury induced CD43+ inflammatory monocyte expansion, along with decreased infarct size and left ventricular fibrosis. Transthoracic echocardiography and invasive hemodynamic analysis revealed that PHT entrapped liposome treatment could attenuate left ventricular structural and functional remodeling, as shown by increased ejection fraction, reduced end-systolic and end-diastolic volume, as well as an amelioration of left ventricular systolic (+dP/dtmax) and diastolic (-dP/dtmin) functions.
Our work for the first time demonstrates the therapeutic potential of VGSC antagonism via liposome mediated monocyte/macrophage targeting in acute phase after myocardial I/R injury. These results suggest that VGSCs in mononuclear phagocyte system might be a novel target for immunomodulation and treatment of myocardial I/R injury.
PMCID: PMC3777990  PMID: 24069305
12.  Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice 
Circulation  2013;127(20):2038-2046.
Exaggerated and prolonged inflammation after myocardial infarction (MI) accelerates left ventricular remodeling. Inflammatory pathways may present a therapeutic target to prevent post-MI heart failure. However, the appropriate magnitude and timing of interventions are largely unknown, in part because noninvasive monitoring tools are lacking. We here employed nanoparticle-facilitated silencing of CCR2, the chemokine receptor that governs inflammatory Ly-6Chigh monocyte subset traffic, to reduce infarct inflammation in apoE−/− mice after MI. We used dual target PET/MRI of transglutaminase factor XIII (FXIII) and myeloperoxidase (MPO) activity to monitor how monocyte subset-targeted RNAi altered infarct inflammation and healing.
Methods and Results
Flow cytometry, gene expression analysis and histology revealed reduced monocyte numbers and enhanced resolution of inflammation in infarcted hearts of apoE−/− mice that were treated with nanoparticle-encapsulated siRNA. To follow extracellular matrix crosslinking non-invasively, we developed a fluorine-18 labeled PET agent (18F-FXIII). Recruitment of MPO-rich inflammatory leukocytes was imaged using a molecular MRI sensor of MPO activity (MPO-Gd). PET/MRI detected anti-inflammatory effects of intravenous nanoparticle-facilitated siRNA therapy (75% decrease of MPO-Gd signal, p<0.05) while 18F-FXIII PET reflected unimpeded matrix crosslinking in the infarct. Silencing of CCR2 during the first week after MI improved ejection fraction on day 21 after MI from 29 to 35% (p<0.05).
CCR2 targeted RNAi reduced recruitment of Ly-6Chigh monocytes, attenuated infarct inflammation and curbed post-MI left ventricular remodeling.
PMCID: PMC3661714  PMID: 23616627
myocardial infarction; remodeling; monocytes; RNAi; PET/MRI
13.  Pharmacological activation of the prostaglandin E2 receptor EP4 improves cardiac function after myocardial ischaemia/reperfusion injury 
Cardiovascular Research  2008;81(1):123-132.
Increased expression of several subtypes of prostaglandin E2 receptors (EP1–4) has recently been described in clinical and experimental myocardial ischaemia/reperfusion (I/R) injury. However, their pathophysiological significance in I/R remains obscure. Thus, we determined whether the activation of the prostanoid receptor, EP4, suppresses myocardial I/R injury.
Methods and results
To analyse the role of EP4, we administered an EP4 selective agonist (EP4RAG, 1 or 3 mg/kg) or vehicle to rats with myocardial I/R injury. After 7 days of reperfusion, I/R rats exhibited left ventricular (LV) dilatation and contractile dysfunction with myocyte hypertrophy and interstitial fibrosis. EP4RAG significantly reduced infarction area/ischaemic myocardium (72.4 ± 0.7 vs. 23.3 ± 0.6%; P < 0.05) and improved LV contraction and dilatation compared with that of the vehicle. EP4RAG also attenuated the recruitment of inflammatory cells, especially macrophages, and interstitial fibrosis in hearts. Monocyte chemoattractant protein (MCP)-1 and other cytokines were increased in both non-ischaemic (area not at risk, ANAR) and ischaemic (area at risk, AAR) myocardium; however, western blot analysis and RNase protection assay showed that EP4RAG suppressed these changes. Gelatin zymography revealed EP4RAG significantly reduced matrix metalloproteinase-2 and -9 activities in both ANAR and AAR. Chemoattractant assay demonstrated that EP4RAG suppressed the migration of cytokine-stimulated macrophages and decreased the level of MCP-1 production in the supernatant (587.3 ± 55.3 vs. 171.5 ± 47.5 pg/mL; P < 0.05).
The data suggest that the EP4 agonist is effective for attenuation of I/R injury by suppressing MCP-1 and the infiltration of inflammatory cells, especially macrophages.
PMCID: PMC2721641  PMID: 18805784
Prostaglandins; Inflammation; Reperfusion injury
14.  Insight into human alveolar macrophage and M. tuberculosis interactions via metabolic reconstructions 
A human alveolar macrophage genome-scale metabolic reconstruction was reconstructed from tailoring a global human metabolic network, Recon 1, by using computational algorithms and manual curation.A genome-scale host–pathogen network of the human alveolar macrophage and Mycobacterium tuberculosis is presented. This involved integrating two genome-scale network reconstructions.The reaction activity and gene essentiality predictions of the host–pathogen model represent a more accurate depiction of infection.Integration of high-throughput data into a host-pathogen model followed by systems analysis was performed in order to elucidate major metabolic differences under different types of M. tuberculosis infection.
Mycobacterium tuberculosis (M. tb) is an insidious and highly persistent pathogen that affects one-third of the world's population (WHO, 2009). Metabolism is foundational to M. tb's infection ability and the ensuing host–pathogen interactions. In addition, M. tb has a heterogeneous clinical presentation and can infect virtually every tissue. Depending on the location of the infection, different metabolic pathways are active and inactive in both the host and pathogen cells. In this study, we sought to model the host–pathogen interactions of the human alveolar macrophage and M. tb as well as detail the metabolic differences in specific infection types using genome-scale metabolic reconstructions (Figure 4A).
Genome-scale metabolic reconstructions are knowledge bases of all known metabolic reactions of a given organism. Reconstructions have been shown to elucidate the mechanistic genotype-to-phenotype relationship through the integration of high-throughput and physiological data (Oberhardt et al, 2009). Genome-scale reconstructions are converted into mathematical models under the constraints-based reconstruction and analysis (COBRA) platform (Becker et al, 2007). COBRA models use network stoichiometry and steady-state mass balances to define a solution space of potential flux states that a network can take. Thus, the COBRA approach does not require kinetic parameters.
Recently, the global human metabolic network, Recon 1, has been reconstructed (Duarte et al, 2007). To understand the metabolic host–pathogen integrations of M. tb with its human host, we first tailored the global human metabolic network into a cell-specific metabolic reconstruction of the human alveolar macrophage. This was carried out using established computational algorithms (Becker and Palsson, 2008; Shlomi et al, 2008) and manual curation to confirm the included and excluded reactions. The human alveolar macrophage reconstruction, iAB-AMØ-1410, accounts for 1410 genes, 3012 intracellular reactions, and 2572 metabolites (Figure 4C). iAB-AMØ-1410 was able to accurately predict maximum ATP and NO production rates obtained from experimental data (Griscavage et al, 1993; Newsholme et al, 1999).
The second step to studying host–pathogen interactions was integration of the human alveolar macrophage reconstruction with an existing genome-scale metabolic model of M. tb, iNJ661 (Jamshidi and Palsson, 2007). Interfacial constraints were set to create a phagosomal environment that was hypoxic, nitrosative, rich in fatty acids, and poor in carbohydrates. From the onset, it was apparent that some oxygen (<15% of in vitro uptake) was required for proper simulations. In addition, algorithmic tailoring of the M. tb biomass objective function was performed to better represent an infectious state. The integrated host–pathogen metabolic reconstruction was dubbed iAB-AMØ-1410-Mt-661.
Analysis of the integrated host–pathogen metabolic reconstruction resulted in three main findings. First, by setting interfacial constraints and tailoring the biomass objective function, the solution space better represents an infectious state. Without adding artificial constraints to the host portion of the integrated model, the iAB-AMØ-1410 solution space is greatly reduced (Figure 4B). Macrophage glycolysis and nitric oxide production are up-regulated and macrophage ATP production, nucleotide synthesis, and amino-acid metabolism are suppressed. In addition, M. tb glycolysis is suppressed and isocitrate lyase is up-regulated for generation of acetyl-CoA. Fatty acid oxidation pathways and production of mycolic acids are increased, while production of nucleotides, peptidoglycans, and phenolic glycolipids are reduced. The modified solution space of the alveolar macrophage and M. tb better represents the infectious state.
Second, the host-pathogen model more accurately predicts M. tb gene deletion tests than the current in vitro model, iNJ661. The host-pathogen model predicted 11 essential genes and 37 unessential genes differently than iNJ661. A total of 22 of the differentially predicted genes have been experimentally characterized (Sassetti and Rubin, 2003; Sohaskey, 2008). The host-pathogen model correctly predicted 18 of the 22 genes. Thus, iAB-AMØ-1410-Mt-661 is a more accurate platform for studying infectious states of M. tb.
Finally, we sought to determine metabolic differences in both the macrophage and M. tb between three different types of infection: latent, pulmonary, and meningeal. Transcription profiling data of the macrophage for the three infections (Thuong et al, 2008) were integrated in the context of the host–pathogen network to elucidate the reaction activity of the three infections. There was wide heterogeneity in the three infection states; some of these differences are highlighted. Macrophage hyaluronan synthase and export were only active in the pulmonary infection. This is potentially interesting from a pharmaceutical viewpoint as hyaluronan has been implicated as a potential carbon source for extracellular M. tb (Hirayama et al, 2009). In addition, we detected metabolic activity differences in M. tb pathways that have been previously discussed as potential drug targets (Eoh et al, 2007; Boshoff et al, 2008). Polyprenyl metabolic reactions were only active in the latent state infection, while de novo synthesis of nicotinamide cofactors was only active in latent and meningeal M. tb infections.
Host-pathogen modeling represents a novel approach for studying metabolic interactions during infection. iAB-AMØ-1410-Mt-661 is a more accurate platform for understanding the biology and pathophysiology of M. tb infection. Most importantly, genome-scale metabolic reconstructions can act as scaffolds for integrating high-throughput data. Particularly, in this study we were able to discern reaction activity differences between different infection types.
Metabolic coupling of Mycobacterium tuberculosis to its host is foundational to its pathogenesis. Computational genome-scale metabolic models have shown utility in integrating -omic as well as physiologic data for systemic, mechanistic analysis of metabolism. To date, integrative analysis of host–pathogen interactions using in silico mass-balanced, genome-scale models has not been performed. We, therefore, constructed a cell-specific alveolar macrophage model, iAB-AMØ-1410, from the global human metabolic reconstruction, Recon 1. The model successfully predicted experimentally verified ATP and nitric oxide production rates in macrophages. This model was then integrated with an M. tuberculosis H37Rv model, iNJ661, to build an integrated host–pathogen genome-scale reconstruction, iAB-AMØ-1410-Mt-661. The integrated host–pathogen network enables simulation of the metabolic changes during infection. The resulting reaction activity and gene essentiality targets of the integrated model represent an altered infectious state. High-throughput data from infected macrophages were mapped onto the host–pathogen network and were able to describe three distinct pathological states. Integrated host–pathogen reconstructions thus form a foundation upon which understanding the biology and pathophysiology of infections can be developed.
PMCID: PMC2990636  PMID: 20959820
computational biology; host–pathogen; Mycobacterium tuberculosis; systems biology; macrophage
15.  Mast cell tryptase may modulate endothelial cell phenotype in healing myocardial infarcts 
The Journal of pathology  2005;205(1):102-111.
Mast cells and macrophages infiltrate healing myocardial infarcts and may play an important role in regulating fibrous tissue deposition and extracellular matrix remodelling. This study examined the time-course of macrophage and mast cell accumulation in healing infarcts and studied the histological characteristics and protease expression profile of mast cells in a canine model of experimental infarction. Although macrophages were more numerous than mast cells in infarct granulation tissue, macrophage density decreased during maturation of the scar, whereas mast cell numbers remained persistently elevated. During the inflammatory phase of infarction, newly recruited leucocytes infiltrated the injured myocardium and appeared to be clustered in close proximity to degranulating cardiac mast cells. During the proliferative phase of healing, mast cells had decreased granular content and were localized close to infarct neovessels. In contrast, macrophages showed no selective localization. Mast cells in healing canine infarcts were alcian blue/safranin-positive cells that expressed both tryptase and chymase. In order to explain the pro-inflammatory and angiogenic actions of tryptase — the major secretory protein of mast cells — its effects on endothelial chemokine expression were examined. Chemokines are chemotactic cytokines that play an important role in leucocyte trafficking and angiogenesis and are highly induced in infarcts. Tryptase, a proteinase-activated receptor (PAR)-2 agonist, induced endothelial expression of the angiogenic chemokines CCL2/MCP-1 and CXCL8/IL-8, but not the angiostatic chemokine CXCL10/IP-10. Endothelial PAR-2 stimulation with the agonist peptide SLIGKV induced a similar chemokine expression profile. Mast cell tryptase may exert its angiogenic effects in part through selective stimulation of angiogenic chemokines.
PMCID: PMC2275298  PMID: 15586361
mast cell; infarction; myocardial ischaemia/reperfusion; macrophage; chemokine; tryptase; chymase; inflammation
16.  Myocardial Connective Tissue Growth Factor (CCN2/CTGF) Attenuates Left Ventricular Remodeling after Myocardial Infarction 
PLoS ONE  2012;7(12):e52120.
Myocardial CCN2/CTGF is induced in heart failure of various etiologies. However, its role in the pathophysiology of left ventricular (LV) remodeling after myocardial infarction (MI) remains unresolved. The current study explores the role of CTGF in infarct healing and LV remodeling in an animal model and in patients admitted for acute ST-elevation MI.
Methods and Results
Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate controls (NLC) were subjected to permanent ligation of the left anterior descending coronary artery. Despite similar infarct size (area of infarction relative to area at risk) 24 hours after ligation of the coronary artery in Tg-CTGF and NLC mice, Tg-CTGF mice disclosed smaller area of scar tissue, smaller increase of cardiac hypertrophy, and less LV dilatation and deterioration of LV function 4 weeks after MI. Tg-CTGF mice also revealed substantially reduced mortality after MI. Remote/peri-infarct tissue of Tg-CTGF mice contained reduced numbers of leucocytes, macrophages, and cells undergoing apoptosis as compared with NLC mice. In a cohort of patients with acute ST-elevation MI (n = 42) admitted to hospital for percutaneous coronary intervention (PCI) serum-CTGF levels (s-CTGF) were monitored and related to infarct size and LV function assessed by cardiac MRI. Increase in s-CTGF levels after MI was associated with reduced infarct size and improved LV ejection fraction one year after MI, as well as attenuated levels of CRP and GDF-15.
Increased myocardial CTGF activities after MI are associated with attenuation of LV remodeling and improved LV function mediated by attenuation of inflammatory responses and inhibition of apoptosis.
PMCID: PMC3527406  PMID: 23284892
17.  Anti-Thymocyte Globulin Induces Neoangiogenesis and Preserves Cardiac Function after Experimental Myocardial Infarction 
PLoS ONE  2012;7(12):e52101.
Acute myocardial infarction (AMI) followed by ventricular remodeling is the major cause of congestive heart failure and death in western world countries.
Of relevance are reports showing that infusion of apoptotic leucocytes or anti-lymphocyte serum after AMI reduces myocardial necrosis and preserves cardiac function. In order to corroborate this therapeutic mechanism, the utilization of an immunosuppressive agent with a comparable mechanism, such as anti-thymocyte globulin (ATG) was evaluated in this study.
Methods and Results
AMI was induced in rats by ligation of the left anterior descending artery. Initially after the onset of ischemia, rabbit ATG (10 mg/rat) was injected intravenously. In vitro and in vivo experiments showed that ATG induced a pronounced release of pro-angiogenic and chemotactic factors. Moreover, paracrine factors released from ATG co-incubated cell cultures conferred a down-regulation of p53 in cardiac myocytes. Rats that were injected with ATG evidenced higher numbers of CD68+ macrophages in the ischemic myocardium. Animals injected with ATG evidenced less myocardial necrosis, showed a significant reduction of infarct dimension and an improvement of post-AMI remodeling after six weeks (infarct dimension 24.9% vs. 11.4%, p<0.01). Moreover, a higher vessel density in the peri-infarct region indicated a better collateralization in rats that were injected with ATG.
These data indicate that ATG, a therapeutic agent successfully applied in clinical transplant immunology, triggered cardioprotective effects after AMI that salvaged ischemic myocardium by down-regulation of p53. This might have raised the resistance against apoptotic cell death during ischemia. The combination of these mechanisms seems to be causative for improved cardiac function and less ventricular remodeling after experimental AMI.
PMCID: PMC3527351  PMID: 23284885
18.  Infarct Restraint to Limit Adverse Ventricular Remodeling 
The left ventricular response to a myocardial infarction is a complex biomechanical process that is only beginning to be understood. Infarct expansion (stretching) is an immediate and progressive phenomenon that is known to initiate and sustain the ventricular dilatation and global loss of contractile function that leads to symptomatic heart failure. Limitation of infarct expansion has, therefore, been identified as a potential therapeutic goal that could reduce the morbidity and cost associated with adverse infarction-induced ventricular remodeling and the symptomatic heart failure that results from it. This review will present experimental work that demonstrates the central importance of infarct expansion to the remodeling process as well as proof-of-concept studies that establish the efficacy of early mechanical infarct restraint for limiting ventricular remodeling after myocardial infarction (MI). Ventricular restraint with polymeric mesh materials (wraps) placed early after MI will be discussed. Data supporting the use of injected acellular biomaterials to alter infarct material properties (stiffness) and geometry (thickness) will also be presented. This approach has been shown to be effective in our laboratory and others in limiting post-infarction remodeling and represents a potential means for limiting infarct expansion early after MI via minimally invasive catheter-based technology.
PMCID: PMC3021244  PMID: 21161462
Myocardial infarction; Ventricular remodeling; Heart failure; Biomaterials
19.  Matrix Metalloproteinase-28 Deletion Exacerbates Cardiac Dysfunction and Rupture Following Myocardial Infarction in Mice by Inhibiting M2 Macrophage Activation 
Circulation research  2012;112(4):675-688.
Matrix metalloproteinase (MMP)-28 regulates the inflammatory and extracellular matrix (ECM) responses in cardiac aging, but the roles of MMP-28 after myocardial infarction (MI) have not been explored.
To determine the impact of MMP-28 deletion on post-MI remodeling of the left ventricle (LV)
Methods and Results
Adult C57BL/6J wild type (WT, n=76) and MMP null (MMP-28−/−, n=86) mice of both sexes were subjected to permanent coronary artery ligation to create MI. MMP-28 expression decreased post-MI, and its cell source shifted from myocytes to macrophages. MMP-28 deletion increased day 7 mortality as a result of increased cardiac rupture post-MI. MMP-28−/− mice exhibited larger LV volumes, worse LV dysfunction, a worse LV remodeling index, and increased lung edema. Plasma MMP-9 levels were unchanged in the MMP-28−/− mice but increased in WT mice at day 7 post-MI. The mRNA levels of inflammatory and ECM proteins were attenuated in the infarct regions of MMP-28−/− mice, indicating reduced inflammatory and ECM responses. M2 macrophage activation was impaired when MMP-28 was absent. MMP-28 deletion also led to decreased collagen deposition and fewer myofibroblasts. Collagen cross-linking was impaired, due to decreased expression and activation of lysyl oxidase in the infarcts of MMP-28−/− mice. The LV tensile strength at day 3 post-MI, however, was similar between the two genotypes
MMP-28 deletion aggravated MI induced LV dysfunction and rupture, due to defective inflammatory response and scar formation by suppressing M2 macrophage activation.
PMCID: PMC3597388  PMID: 23261783
Myocardial infarction; MMP-28; fibroblast; macrophage phenotype; inflammation
20.  Safety and efficacy of an injectable extracellular matrix hydrogel for treating myocardial infarction 
Science translational medicine  2013;5(173):10.1126/scitranslmed.3005503.
New therapies are needed to prevent heart failure after myocardial infarction (MI). As experimental treatment strategies for MI approach translation, safety and efficacy must be established in relevant animal models that mimic the clinical situation. We have developed an injectable hydrogel derived from porcine myocardial extracellular matrix (ECM) as a scaffold for cardiac repair post-MI. In this study, we establish the safety and efficacy of this injectable biomaterial in large-and small-animal studies that simulate the clinical setting. Infarcted pigs were treated with percutaneous transendocardial injections of the myocardial matrix hydrogel two weeks post-MI and evaluated after three months. Echocardiography indicated improvement in cardiac function, ventricular volumes, and global wall motion scores. Furthermore, a significantly larger zone of cardiac muscle was found at the endocardium in matrix-injected pigs compared to controls. In rats, we establish the safety of this biomaterial and explore the host response via direct injection into the left ventricular lumen and in an inflammation study, both of which support the biocompatibility of this material. Hemocompatibility studies with human blood indicate that exposure to the material at relevant concentrations does not affect clotting times or platelet activation. This work therefore provides a strong platform to move forward in clinical studies with this cardiac-specific biomaterial that can be delivered by catheter.
PMCID: PMC3848875  PMID: 23427245
21.  Factor XIII Deficiency Causes Cardiac Rupture, Impairs Wound Healing, and Aggravates Cardiac Remodeling in Mice With Myocardial Infarction 
Circulation  2006;113(9):1196-1202.
Identification of key molecular players in myocardial healing could lead to improved therapies, reduction of scar formation, and heart failure after myocardial infarction (MI). We hypothesized that clotting factor XIII (FXIII), a transglutaminase involved in wound healing, may play an important role in MI given prior clinical and mouse model data.
Methods and Results
To determine whether a truly causative relationship existed between FXIII activity and myocardial healing, we prospectively studied myocardial repair in FXIII-deficient mice. All FXIII−/− and FXIII−/+ (FXIII activity <5% and 70%) mice died within 5 days after MI from left ventricular rupture. In contradistinction, FXIII−/− mice that received 5 days of intravenous FXIII replacement therapy had normal survival rates; however, cardiac MRI demonstrated worse left ventricular remodeling in these reconstituted FXIII−/− mice. Using a FXIII-sensitive molecular imaging agent, we found significantly greater FXIII activity in wild-type mice and FXIII−/− mice receiving supplemental FXIII than in FXIII−/− mice (P<0.05). In FXIII−/− but not in reconstituted FXIII−/− mice, histology revealed diminished neutrophil migration into the MI. Reverse transcriptase–polymerase chain reaction studies suggested that the impaired inflammatory response in FXIII−/− mice was independent of intercellular adhesion molecule and lipopolysaccharide-induced CXC chemokine, both important for cell migration. After MI, expression of matrix metalloproteinase-9 was 650% higher and collagen-1 was 53% lower in FXIII−/− mice, establishing an imbalance in extracellular matrix turnover and providing a possible mechanism for the observed cardiac rupture in the FXIII−/− mice.
These data suggest that FXIII has an important role in murine myocardial healing after infarction.
PMCID: PMC4066325  PMID: 16505171
factor XIII; healing; heart failure; myocardial infarction; remodeling
22.  Donepezil, Anti-Alzheimer's Disease Drug, Prevents Cardiac Rupture during Acute Phase of Myocardial Infarction in Mice 
PLoS ONE  2011;6(7):e20629.
We have previously demonstrated that the chronic intervention in the cholinergic system by donepezil, an acetylcholinesterase inhibitor, plays a beneficial role in suppressing long-term cardiac remodeling after myocardial infarction (MI). In comparison with such a chronic effect, however, the acute effect of donepezil during an acute phase of MI remains unclear. Noticing recent findings of a cholinergic mechanism for anti-inflammatory actions, we tested the hypothesis that donepezil attenuates an acute inflammatory tissue injury following MI.
Methods and Results
In isolated and activated macrophages, donepezil significantly reduced intra- and extracellular matrix metalloproteinase-9 (MMP-9). In mice with MI, despite the comparable values of heart rate and blood pressure, the donepezil-treated group showed a significantly lower incidence of cardiac rupture than the untreated group during the acute phase of MI. Immunohistochemistry revealed that MMP-9 was localized at the infarct area where a large number of inflammatory cells including macrophages infiltrated, and the expression and the enzymatic activity of MMP-9 at the left ventricular infarct area was significantly reduced in the donepezil-treated group.
The present study suggests that donepezil inhibits the MMP-9-related acute inflammatory tissue injury in the infarcted myocardium, thereby reduces the risk of left ventricular free wall rupture during the acute phase of MI.
PMCID: PMC3130031  PMID: 21750701
23.  Targeted Imaging of the Spatial and Temporal Variation of Matrix Metalloproteinase Activity in Porcine Model of Post-Infarct Remodeling: Relationship to Myocardial Dysfunction 
Matrix metalloproteinases (MMPs) are known to modulate left ventricular (LV) remodeling after a myocardial infarction (MI). However, the temporal and spatial variation of MMP activation and their relationship to mechanical dysfunction post MI remains undefined.
Methods and Results
MI was surgically induced in pigs (n=23) and cine MR and dual isotope hybrid SPECT/CT imaging obtained using thallium-201 (201Tl) and a technetium-99m labeled MMP targeted tracer (99mTc-RP805) at 1, 2 and 4 weeks post MI along with controls (n=5). Regional myocardial strain was computed from MR images and related to MMP zymography and ex vivo myocardial 99mTc-RP805 retention. MMP activation as assessed by in vivo and ex vivo 99mTc-RP805 imaging/retention studies was increased nearly 5-fold within the infarct region at 1 week post-MI and remained elevated up to 1 month post-MI. The post-MI change in LV end-diastolic volumes was correlated with MMP activity (y=31.34e0.48x, p=0.04). MMP activity was increased within the border and remote regions early post-MI, but declined over 1 month. There was a high concordance between regional 99mTc-RP805 uptake and ex vivo MMP-2 activity.
A novel, multimodality non-invasive hybrid SPECT/CT imaging approach was validated and applied for in vivo evaluation of MMP activation in combination with cine MR analysis of LV deformation. Increased 99mTc-RP805 retention was seen throughout the heart early post-MI and was not purely a reciprocal of 201Tl perfusion. 99mTc-RP805 SPECT/CT imaging may provide unique information regarding regional myocardial MMP activation and predict late post-MI LV remodeling.
PMCID: PMC3140564  PMID: 21505092
MMP; LV remodeling; spatiotemporal imaging
24.  Serum MMP-8: A Novel Indicator of Left Ventricular Remodeling and Cardiac Outcome in Patients after Acute Myocardial Infarction 
PLoS ONE  2013;8(8):e71280.
Left ventricular (LV) remodeling following myocardial infarction (MI) is characterized by progressive alterations of structure and function, named LV remodeling. Although several risk factors such as infarct size have been identified, LV remodeling remains difficult to predict in clinical practice. Changes within the extracellular matrix, involving matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), are an integral part of left ventricular (LV) remodeling after myocardial infarction (MI). We investigated the temporal profile of circulating MMPs and TIMPs and their relations with LV remodeling at 1 year and clinical outcome at 3 years in post-MI patients.
This prospective multicentre study included 246 patients with a first anterior MI. Serial echocardiographic studies were performed at hospital discharge, 3 months, and 1 year after MI, and analysed at a core laboratory. LV remodeling was defined as the percent change in LV end-diastolic volume (EDV) from baseline to 1 year. Serum samples were obtained at hospital discharge, 1, 3, and 12 months. Multiplex technology was used for analysis of MMP-1, -2, -3, -8, -9, -13, and TIMP-1, -2, -3, -4 serum levels.
Baseline levels of MMP-8 and MMP-9 were positively associated with changes in LVEDV (P = 0.01 and 0.02, respectively). When adjusted for major baseline characteristics, MMP-8 levels remained an independent predictor LV remodeling (P = 0.025). By univariate analysis, there were positive relations between cardiovascular death or hospitalization for heart failure during the 3-year follow-up and the baseline levels of MMP-2 (P = 0.03), MMP-8 (P = 0.002), and MMP-9 (P = 0.03). By multivariate analysis, MMP-8 was the only MMP remaining significantly associated with clinical outcome (P = 0.02).
Baseline serum MMP-8 is a significant predictor of LV remodeling and cardiovascular outcome after MI and may help to improve risk stratification.
PMCID: PMC3743841  PMID: 23967183
25.  Endogenous IRAK-M Attenuates Post-infarction Remodeling through Effects on Macrophages and Fibroblasts 
Effective post-infarction repair requires timely suppression of innate immune signals to prevent the catastrophic consequences of uncontrolled inflammation on cardiac geometry and function. In macrophages, Interleukin Receptor-Associated Kinase (IRAK)-M acts as a functional decoy preventing uncontrolled TLR/Interleukin-1-mediated responses. Our study investigates the role of IRAK-M as a negative regulator of the post-infarction inflammatory response and as a modulator of cardiac remodeling.
Methods and results
In WT mouse infarcts IRAK-M was upregulated in infiltrating macrophages and fibroblasts exhibiting a biphasic response. When compared to wildtype animals, infarcted IRAK-M −/− mice had enhanced adverse remodeling and worse systolic dysfunction; however, acute infarct size was comparable between groups. Adverse remodeling in IRAK-M −/− animals was associated with enhanced myocardial inflammation and protease activation. The protective actions of IRAK-M involved phenotypic modulation of macrophages and fibroblasts. IRAK-M −/− infarcts showed increased infiltration with pro-inflammatory CD11b+/Ly6Chi monocytes; leukocytes harvested from IRAK-M null infarcts exhibited accentuated cytokine expression. In vitro, IRAK-M expression was upregulated in cytokine-stimulated murine cardiac fibroblasts and suppressed their matrix-degrading properties without affecting their inflammatory activity.
Endogenous IRAK-M attenuates adverse post-infarction remodeling suppressing leukocyte inflammatory activity, while inhibiting fibroblast-mediated matrix degradation.
PMCID: PMC3510666  PMID: 22995519
cardiac remodeling; cytokines; macrophages; metalloproteinases; immune system

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