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1.  Plasma Glycoproteomics Reveals Sepsis Outcomes Linked to Distinct Proteins in Common Pathways 
Critical care medicine  2015;43(10):2049-2058.
Objective
Sepsis remains a predominant cause of mortality in the ICU, yet strategies to increase survival have proved largely unsuccessful. This study aimed to identify proteins linked to sepsis outcomes using a glycoproteomic approach to target extracellular proteins that trigger downstream pathways and direct patient outcomes.
Design
Plasma was obtained from the LacTATEs cohort. N-linked plasma glycopeptides were quantified by solid-phase extraction coupled with mass spectrometry. Glycopeptides were assigned to proteins using RefSeq and visualized in a heat map. Protein differences were validated by immunoblotting, and proteins were mapped for biological processes using Database for Annotation, Visualization and Integrated Discovery and for functional pathways using Kyoto Encyclopedia of Genes and Genomes databases.
Setting
Hospitalized care.
Measurements and Main Results
A total of 501 glycopeptides corresponding to 234 proteins were identified. Of these, 66 glycopeptides were unique to the survivor group and corresponded to 54 proteins, 60 were unique to the nonsurvivor group and corresponded to 43 proteins, and 375 were common responses between groups and corresponded to 137 proteins. Immunoblotting showed that nonsurvivors had increased total kininogen; decreased total cathepsin-L1, vascular cell adhesion molecule, periostin, and neutrophil gelatinase–associated lipocalin; and a two-fold decrease in glycosylated clusterin (all p < 0.05). Kyoto Encyclopedia of Genes and Genomes analysis identified six enriched pathways. Interestingly, survivors relied on the extrinsic pathway of the complement and coagulation cascade, whereas nonsurvivors relied on the intrinsic pathway.
Conclusion
This study identifies proteins linked to patient outcomes and provides insight into unexplored mechanisms that can be investigated for the identification of novel therapeutic targets. (Crit Care Med 2015; XX:00–00)
doi:10.1097/CCM.0000000000001134
PMCID: PMC4573827  PMID: 26086942
blood coagulation factors; complement system proteins; computational biology; glycoproteins; proteomics; sepsis
2.  A Novel Collagen Matricryptin Reduces Left Ventricular Dilation Post-myocardial Infarction by Promoting Scar Formation and Angiogenesis 
Background
Proteolytically-released extracellular matrix (ECM) fragments, matricryptins, are biologically active and play important roles in wound healing. Following myocardial infarction (MI), collagen I, a major component of cardiac ECM, is cleaved by matrix metalloproteinases (MMPs).
Objectives
We identified novel collagen-derived matricryptins generated post-MI that mediate remodeling of the left ventricle (LV).
Results
In situ, MMP-2 and -9 generate a collagen Iα1 C-1158/59 fragment, and MMP-9 can further degrade it. The C-1158/59 fragment was identified post-MI both in human plasma and mouse LV at levels that inversely correlated to MMP-9 levels. We synthesized a peptide beginning at the cleavage site (p1158/59, amino acids 1159 to 1173) to investigate its biological functions. In vitro, p1158/59 stimulated fibroblast wound healing and robustly promoted angiogenesis. In vivo, early post-MI treatment with p1158/59 reduced LV dilation at day 7 post-MI by preserving LV structure (p < 0.05 versus control). The p1158/59 stimulated both in vitro and in vivo wound healing by enhancing basement membrane proteins, granulation tissue components, and angiogenic factors.
Conclusions
Collagen Iα1 matricryptin p1158/59 facilitates LV remodeling post-MI by regulating scar formation through targeted ECM generation and stimulation of angiogenesis.
doi:10.1016/j.jacc.2015.07.035
PMCID: PMC4575409  PMID: 26383724
extracellular matrix; MMP; proteomics; remodeling
3.  State feedback control design for Boolean networks 
BMC Systems Biology  2016;10(Suppl 3):70.
Background
Driving Boolean networks to desired states is of paramount significance toward our ultimate goal of controlling the progression of biological pathways and regulatory networks. Despite recent computational development of controllability of general complex networks and structural controllability of Boolean networks, there is still a lack of bridging the mathematical condition on controllability to real boolean operations in a network. Further, no realtime control strategy has been proposed to drive a Boolean network.
Results
In this study, we applied semi-tensor product to represent boolean functions in a network and explored controllability of a boolean network based on the transition matrix and time transition diagram. We determined the necessary and sufficient condition for a controllable Boolean network and mapped this requirement in transition matrix to real boolean functions and structure property of a network. An efficient tool is offered to assess controllability of an arbitrary Boolean network and to determine all reachable and non-reachable states. We found six simplest forms of controllable 2-node Boolean networks and explored the consistency of transition matrices while extending these six forms to controllable networks with more nodes. Importantly, we proposed the first state feedback control strategy to drive the network based on the status of all nodes in the network. Finally, we applied our reachability condition to the major switch of P53 pathway to predict the progression of the pathway and validate the prediction with published experimental results.
Conclusions
This control strategy allowed us to apply realtime control to drive Boolean networks, which could not be achieved by the current control strategy for Boolean networks. Our results enabled a more comprehensive understanding of the evolution of Boolean networks and might be extended to output feedback control design.
doi:10.1186/s12918-016-0314-z
PMCID: PMC5009829  PMID: 27586140
Boolean network; State feedback control; Controllability
4.  Using systems biology approaches to understand cardiac inflammation and extracellular matrix remodeling in the setting of myocardial infarction 
Inflammation and extracellular matrix (ECM) remodeling are important components regulating the response of the left ventricle (LV) to myocardial infarction (MI). Significant cellular and molecular level contributors can be identified by analyzing data acquired through high-throughput genomic and proteomic technologies that provide expression levels for thousands of genes and proteins. Large scale data provide both temporal and spatial information that need to be analyzed and interpreted using systems biology approaches in order to integrate this information into dynamic models that predict and explain mechanisms of cardiac healing post-MI. In this review, we summarize the systems biology approaches needed to computationally simulate post-MI remodeling, including data acquisition, data analysis for biomarker classification and identification, data integration to build dynamic models, and data interpretation for biological functions. An example for applying a systems biology approach to ECM remodeling is presented as a reference illustration.
PMCID: PMC3990867  PMID: 24741709
mathematical modeling; differential equations; biclustering; myocardial infarction; matrix metalloproteinase; LV remodeling; review
5.  Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence 
Cardiovascular Research  2015;106(3):421-431.
Aims
Cardiac ageing involves the progressive development of cardiac fibrosis and diastolic dysfunction coordinated by MMP-9. Here, we report a cardiac ageing signature that encompasses macrophage pro-inflammatory signalling in the left ventricle (LV) and distinguishes biological from chronological ageing.
Methods and results
Young (6–9 months), middle-aged (12–15 months), old (18–24 months), and senescent (26–34 months) mice of both C57BL/6J wild type (WT) and MMP-9 null were evaluated. Using an identified inflammatory pattern, we were able to define individual mice based on their biological, rather than chronological, age. Bcl6, Ccl24, and Il4 were the strongest inflammatory markers of the cardiac ageing signature. The decline in early-to-late LV filling ratio was most strongly predicted by Bcl6, Il1r1, Ccl24, Crp, and Cxcl13 patterns, whereas LV wall thickness was most predicted by Abcf1, Tollip, Scye1, and Mif patterns. With age, there was a linear increase in cardiac M1 macrophages and a decrease in cardiac M2 macrophages in WT mice; of which, both were prevented by MMP-9 deletion. In vitro, MMP-9 directly activated young macrophage polarization to an M1/M2 mid-transition state.
Conclusion
Our results define the cardiac ageing inflammatory signature and assign MMP-9 roles in mediating the inflammaging profile by indirectly and directly modifying macrophage polarization. Our results explain early mechanisms that stimulate ageing-induced cardiac fibrosis and diastolic dysfunction.
doi:10.1093/cvr/cvv128
PMCID: PMC4498140  PMID: 25883218
Cardiac ageing; Inflammation; Macrophage polarization; MMP-9; Proteomics
6.  Multi-analyte Profiling Reveals MMP-9 and MCP-1 as Plasma Biomarkers of Cardiac Aging 
Background
We have previously shown that cardiac sarcopenia occurs with age in C57/BL6J mice. However, underlying mechanisms and plasma biomarkers of cardiac aging have not been identified. Accordingly, the objective of this study was to identify and evaluate plasma biomarkers that reflect cardiac aging phenotypes.
Methods and Results
Plasma from adult (7.5±0.5 months old, n=27) and senescent (31.7±0.5 months old, n=25) C57/BL6J mice was collected and levels of 69 markers were measured by multi-analyte profiling. Of these, 26 analytes were significantly increased and 3 were significantly decreased in the senescent group compared to the adult group. The majority of analytes that increased in the senescent group were inflammatory markers associated with macrophage functions, including matrix metalloproteinase-9 (MMP-9) and monocyte chemotactic protein-1 (MCP-1/CCL-2). Immunoblotting (n=12/ group) showed higher MMP-9 and MCP-1 levels in the left ventricle (LV) of senescent mice (p<0.05), and their expression levels in the LV correlated with plasma levels (rho=0.50 for MMP-9 and rho=0.62 for MCP1, p<0.05). Further, increased plasma MCP-1 and MMP-9 levels correlated with the increase in end diastolic dimensions that occurs with senescence. Immunohistochemistry (n=3/ group) for Mac-3, a macrophage marker, showed increased macrophage densities in the senescent LV; and dual labeling immunohistochemistry of Mac-3 and MMP-9 revealed robust co-localization of MMP-9 to the macrophages in the senescent LV sections, indicating that the macrophage is a major contributor of MMP-9 in the senescent LV.
Conclusions
Our results suggest that MCP-1 and MMP-9 are potential plasma markers for cardiac aging and that augmented MCP-1 and MMP-9 levels and macrophage content in the LV could provide an underlying inflammatory mechanism of cardiac aging.
doi:10.1161/CIRCGENETICS.111.959981
PMCID: PMC3158732  PMID: 21685172
aging; biomarker; macrophage; metalloproteinase; myocardium
7.  P. gingivalis lipopolysaccharide intensifies inflammation post-myocardial infarction through matrix metalloproteinase-9 
Rationale
Periodontal disease (PD) strongly correlates with increased mortality post-myocardial infarction (MI); however, the underlying mechanisms are unknown. Matrix metalloproteinase (MMP)-9 levels directly correlate with dysfunction and remodeling of the left ventricle (LV) post-MI. Post-MI, MMP-9 is produced by leukocytes and modulates inflammation. We have shown that exposure to Porphyromonas gingivalis lipopolysaccharide (PgLPS), an immunomodulatory molecule identified in PD patients, increases LV MMP-9 levels in mice and leads to cardiac inflammation and dysfunction.
Aims
To determine if circulating PgLPS exacerbates the LV inflammatory response post-MI through MMP-9 dependent mechanisms.
Methods and Results
We exposed wild type C57BL/6J and MMP-9−/− mice to PgLPS (ATCC 33277) for a period of 28 days before performing MI, and continued to deliver PgLPS for up to 7 days post-MI. We found systemic levels of PgLPS 1) increased MMP-9 levels in both plasma and infarcted LV resulting in reduced wall thickness and increased incidence of LV rupture post-MI and 2) increased systemic and local macrophage chemotaxis leading to accelerated M1 macrophage infiltration post-MI and decreased LV function. MMP-9 deletion played a protective role by attenuating the inflammation induced by systemic delivery of PgLPS.
Conclusion
In conclusion, MMP-9 deletion has a cardioprotective role against PgLPS exposure, by attenuating macrophage mediated inflammation.
doi:10.1016/j.yjmcc.2014.09.007
PMCID: PMC4250428  PMID: 25240641
Matrix metalloproteinase-9; myocardial infarction; periodontal disease; Porphyromonas gingivalis;; proteomics; cardiac function
8.  Aliskiren and Valsartan Mediate Left Ventricular Remodeling Post-Myocardial Infarction in Mice through MMP-9 Effects 
Background
We evaluated whether aliskiren, valsartan, or the combination was protective following myocardial infarction (MI) through effects on matrix metalloproteinase (MMP)-9.
Methods and Results
C57BL/6J wild type (WT, n=94) and MMP-9 null (null, n=85) mice were divided into 4 groups at 3 h post-MI: saline (S), aliskiren (A; 50 mg/kg/d), valsartan (V; 40 mg/kg/d), or A+V and compared to no MI controls at 28 d post-MI. All groups had similar infarct areas, and survival rates were higher in the null mice. The treatments influenced systolic function and hypertrophy index, as well as extracellular matrix (ECM) and inflammatory genes in the remote region, indicating that primary effects were on the viable myocardium. Saline treated WT mice showed increased end systolic and diastolic volumes and hypertrophy index, along with reduced ejection fraction. MMP-9 deletion improved LV function post-MI. Aliskiren attenuated the increase in end systolic volume and hypertrophy index, while valsartan improved end diastolic volumes and aliskiren + valsartan improved the hypertrophy index only when MMP-9 was absent. Extracellular matrix and inflammatory gene expression showed distinct patterns among the treatment groups, indicating a divergence in mechanisms of remodeling.
Conclusions
This study shows that MMP-9 regulates aliskiren and valsartan effects in mice. These results in mice provide mechanistic insight to help translate these findings to post-MI patients.
doi:10.1016/j.yjmcc.2014.04.007
PMCID: PMC4095995  PMID: 24768766
myocardial infarction; matrix metalloproteinase; proteomics; remodeling; inflammation; extracellular matrix; MMP-9; aliskiren; valsartan
9.  Systems analysis of gene ontology and biological pathways involved in post-myocardial infarction responses 
BMC Genomics  2015;16(Suppl 7):S18.
Background
Pathway analysis has been widely used to gain insight into essential mechanisms of the response to myocardial infarction (MI). Currently, there exist multiple pathway databases that organize molecular datasets and manually curate pathway maps for biological interpretation at varying forms of organization. However, inconsistencies among different databases in pathway descriptions, frequently due to conflicting results in the literature, can generate incorrect interpretations. Furthermore, although pathway analysis software provides detailed images of interactions among molecules, it does not exhibit how pathways interact with one another or with other biological processes under specific conditions.
Methods
We propose a novel method to standardize descriptions of enriched pathways for a set of genes/proteins using Gene Ontology terms. We used this method to examine the relationships among pathways and biological processes for a set of condition-specific genes/proteins, represented as a functional biological pathway-process network. We applied this algorithm to a set of 613 MI-specific proteins we previously identified.
Results
A total of 96 pathways from Biocarta, KEGG, and Reactome, and 448 Gene Ontology Biological Processes were enriched with these 613 proteins. The pathways were represented as Boolean functions of biological processes, delivering an interactive scheme to organize enriched information with an emphasis on involvement of biological processes in pathways. We extracted a network focusing on MI to demonstrate that tyrosine phosphorylation of Signal Transducer and Activator of Transcription (STAT) protein, positive regulation of collagen metabolic process, coagulation, and positive/negative regulation of blood coagulation have immediate impacts on the MI response.
Conclusions
Our method organized biological processes and pathways in an unbiased approach to provide an intuitive way to identify biological properties of pathways under specific conditions. Pathways from different databases have similar descriptions yet diverse biological processes, indicating variation in their ability to share similar functional characteristics. The coverages of pathways can be expanded with the incorporation of more biological processes, predicting involvement of protein members in pathways. Further, detailed analyses of the functional biological pathway-process network will allow researchers and scientists to explore critical routes in biological systems in the progression of disease.
doi:10.1186/1471-2164-16-S7-S18
PMCID: PMC4474415  PMID: 26100218
10.  Translating Koch’s Postulates to Identify Matrix Metalloproteinase Roles in Post-Myocardial Infarction Remodeling: The Cardiac Metalloproteinase Actions (CarMA) Postulates 
Circulation research  2014;114(5):860-871.
The first matrix metalloproteinase (MMP) was described in 1962; and since the 1990’s, cardiovascular research has focused on understanding how MMPs regulate many aspects of cardiovascular pathology from atherosclerosis formation to myocardial infarction and stroke. While much information has been gleaned by these past reports, to a large degree MMP cardiovascular biology remains observational, with few studies homing in on cause and effect relationships. Koch’s postulates were first developed in the 19th century as a way to establish microorganism function and were modified in the 20th century to include methods to establish molecular causality. In this review, we outline the concept for establishing a similar approach to determine causality in terms of MMP functions. We use left ventricular remodeling post-myocardial infarction as an example, but this approach will have broad applicability across both the cardiovascular and MMP fields.
doi:10.1161/CIRCRESAHA.114.301673
PMCID: PMC3972011  PMID: 24577966
matrix metalloproteinases; remodeling; left ventricle; inflammation; fibrosis; extracellular matrix; Koch’s postulates
11.  Matrix Metalloproteinase (MMP)-9: a proximal biomarker for cardiac remodeling and a distal biomarker for inflammation 
Pharmacology & therapeutics  2013;139(1):32-40.
Adverse cardiac remodeling following myocardial infarction (MI) remains a significant cause of congestive heart failure. Additional and novel strategies that improve our ability to predict, diagnose, or treat remodeling are needed. Numerous groups have explored single and multiple biomarker strategies to identify diagnostic prognosticators of remodeling progression, which will improve our ability to promptly and accurately identify high-risk individuals. The identification of better clinical indicators should further lead to more effective prediction and timely treatment.
Matrix metalloproteinase (MMP-9) is one potential biomarker for cardiac remodeling, as demonstrated by both animal models and clinical studies. In animal MI models, MMP-9 expression significantly increases and is linked with inflammation, diabetic microvascular complications, extracellular matrix degradation and synthesis, and cardiac dysfunction. Clinical studies have also established a relationship between MMP-9 and post-MI remodeling and mortality, making MMP-9 a viable candidate to add to the multiple biomarker list.
By definition, a proximal biomarker shows a close relationship with its target disease, whereas a distal biomarker exhibits non-targeted disease modifying outcomes. In this review, we explore the ability of MMP-9 to serve as a proximal biomarker for cardiac remodeling and a distal biomarker for inflammation. We summarize the current molecular basis and clinical platform that allow us to include MMP-9 as a biomarker in both categories.
doi:10.1016/j.pharmthera.2013.03.009
PMCID: PMC3660444  PMID: 23562601
biomarker; cardiovascular; congestive heart failure; inflammation; MMP-9; myocardial infarction
12.  Matrix Metalloproteinase-28 Deletion Amplifies Inflammatory and Extracellular Matrix Responses to Cardiac Aging 
To determine if matrix metalloproteinase (MMP)-28 mediates cardiac aging, wild-type (WT) and MMP-28−/− young (7 ± 1 months, n = 9 each) and old (20 ± 2 months, n = 7 each) female mice were evaluated. MMP-28 expression in the left ventricle (LV) increased 42% in old WT mice compared to young controls (p < 0.05). By Doppler echocardiography, LV function declined at 20 ± 2 months of age for both groups. However, dobutamine stress responses were similar, indicating that cardiac reserve was maintained. Plasma proteomic profiling revealed that macrophage inflammatory protein (MIP)-1 α, MIP-1β and MMP-9 plasma levels did not change in WT old mice but were significantly elevated in MMP-28−/− old mice (all p < 0.05), suggestive of a higher inflammatory status when MMP-28 is deleted. RT2-PCR gene array and immunoblotting analyses demonstrated that MIP-1α and MMP-9 gene and protein levels in the LV were also higher in MMP-28−/− old mice (all p < 0.05). Macrophage numbers in the LV increased similarly in WT and MMP-28−/− old mice, compared to respective young controls (both p < 0.05). Collagen content was not different among the WT and MMP-28−/− young and old mice. In conclusion, LV inflammation increases with age, and MMP-28 deletion further elevates inflammation and extracellular matrix responses, without altering macrophage numbers or collagen content.
doi:10.1017/S1431927611012220
PMCID: PMC3972008  PMID: 22153350
MMP-28; cardiac aging; extracellular matrix; inflammation; macrophage; collagen; left ventricle; mice
13.  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.
doi:10.1371/journal.pcbi.1003472
PMCID: PMC3961365  PMID: 24651374
14.  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.
Rationale
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.
Objective
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
Conclusions
MMP-28 deletion aggravated MI induced LV dysfunction and rupture, due to defective inflammatory response and scar formation by suppressing M2 macrophage activation.
doi:10.1161/CIRCRESAHA.111.300502
PMCID: PMC3597388  PMID: 23261783
Myocardial infarction; MMP-28; fibroblast; macrophage phenotype; inflammation
15.  Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice 
Cardiovascular Research  2012;96(3):444-455.
Aims
Age-related diastolic dysfunction has been attributed to an increased passive stiffness, which is regulated by extracellular matrix (ECM). We recently showed that matrix metalloproteinase (MMP)-9, an ECM mediator, increases in the left ventricle (LV) with age. The aim of this study, accordingly, was to determine the role of MMP-9 in cardiac ageing.
Methods and results
We compared LV function in young (6–9 months), middle-aged (12–15 months), old (18–24 months) and senescent (26–34 months) wild-type (WT) and MMP-9 null mice (n ≥ 12/group). All groups had similar fractional shortenings and aortic peak velocities, indicating that systolic function was not altered by ageing or MMP-9 deletion. The mitral ratios of early to late diastolic filling velocities were reduced in old and senescent WT compared with young controls, and this reduction was attenuated in MMP-9 null mice. Concomitantly, the increase in LV collagen content was reduced in MMP-9 null mice (n = 5-6/group). To dissect the mechanisms of these changes, we evaluated the mRNA expression levels of 84 ECM and adhesion molecules by real-time qPCR (n = 6/group). The expression of pro-fibrotic periostin and connective tissue growth factor (CTGF) increased with senescence, as did transforming growth factor-β (TGF-β)-induced protein levels and Smad signalling, and these increases were blunted by MMP-9 deletion. In senescence, MMP-9 deletion also resulted in a compensatory increase in MMP-8.
Conclusion
MMP-9 deletion attenuates the age-related decline in diastolic function, in part by reducing TGF-β signalling-induced periostin and CTGF expression and increasing MMP-8 expression to regulate myocardial collagen turnover and deposition.
doi:10.1093/cvr/cvs275
PMCID: PMC3500048  PMID: 22918978
Ageing; Collagen; Diastolic function; Matrix metalloproteinase; Extracellular matrix
16.  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.
doi:10.1016/j.yjmcc.2012.07.017
PMCID: PMC3472138  PMID: 22884843
myocardial infarction; matrix metalloproteinase-9; extracellular matrix; inflammation; cardiac remodeling; mice; macrophage
18.  Mathematical modeling of left ventricular dimensional changes in mice during aging 
BMC Systems Biology  2012;6(Suppl 3):S10.
Cardiac aging is characterized by diastolic dysfunction of the left ventricle (LV), which is due in part to increased LV wall stiffness. In the diastolic phase, myocytes are relaxed and extracellular matrix (ECM) is a critical determinant to the changes of LV wall stiffness. To evaluate the effects of ECM composition on cardiac aging, we developed a mathematical model to predict LV dimension and wall stiffness changes in aging mice by integrating mechanical laws and our experimental results. We measured LV dimension, wall thickness, LV mass, and collagen content for wild type (WT) C57/BL6J mice of ages ranging from 7.3 months to those of 34.0 months. The model was established using the thick wall theory and stretch-induced tissue growth to an isotropic and homogeneous elastic composite with mixed constituents. The initial conditions of the simulation were set based on the data from the young mice. Matlab simulations of this mathematical model demonstrated that the model captured the major features of LV remodeling with age and closely approximated experimental results. Specifically, the temporal progression of the LV interior and exterior dimensions demonstrated the same trend and order-of-magnitude change as our experimental results. In conclusion, we present here a validated mathematical model of cardiac aging that applies the thick-wall theory and stretch-induced tissue growth to LV remodeling with age.
doi:10.1186/1752-0509-6-S3-S10
PMCID: PMC3524011  PMID: 23281647
19.  Mathematical modeling and stability analysis of macrophage activation in left ventricular remodeling post-myocardial infarction 
BMC Genomics  2012;13(Suppl 6):S21.
Background
About 6 million Americans suffer from heart failure and 70% of heart failure cases are caused by myocardial infarction (MI). Following myocardial infarction, increased cytokines induce two major types of macrophages: classically activated macrophages which contribute to extracellular matrix destruction and alternatively activated macrophages which contribute to extracellular matrix construction. Though experimental results have shown the transitions between these two types of macrophages, little is known about the dynamic progression of macrophages activation. Therefore, the objective of this study is to analyze macrophage activation patterns post-MI.
Results
We have collected experimental data from adult C57 mice and built a framework to represent the regulatory relationships among cytokines and macrophages. A set of differential equations were established to characterize the regulatory relationships for macrophage activation in the left ventricle post-MI based on the physical chemistry laws. We further validated the mathematical model by comparing our computational results with experimental results reported in the literature. By applying Lyaponuv stability analysis, the established mathematical model demonstrated global stability in homeostasis situation and bounded response to myocardial infarction.
Conclusions
We have established and validated a mathematical model for macrophage activation post-MI. The stability analysis provided a possible strategy to intervene the balance of classically and alternatively activated macrophages in this study. The results will lay a strong foundation to understand the mechanisms of left ventricular remodelling post-MI.
doi:10.1186/1471-2164-13-S6-S21
PMCID: PMC3481436  PMID: 23134700
20.  Bayesian parameter estimation for nonlinear modelling of biological pathways 
BMC Systems Biology  2011;5(Suppl 3):S9.
Background
The availability of temporal measurements on biological experiments has significantly promoted research areas in systems biology. To gain insight into the interaction and regulation of biological systems, mathematical frameworks such as ordinary differential equations have been widely applied to model biological pathways and interpret the temporal data. Hill equations are the preferred formats to represent the reaction rate in differential equation frameworks, due to their simple structures and their capabilities for easy fitting to saturated experimental measurements. However, Hill equations are highly nonlinearly parameterized functions, and parameters in these functions cannot be measured easily. Additionally, because of its high nonlinearity, adaptive parameter estimation algorithms developed for linear parameterized differential equations cannot be applied. Therefore, parameter estimation in nonlinearly parameterized differential equation models for biological pathways is both challenging and rewarding. In this study, we propose a Bayesian parameter estimation algorithm to estimate parameters in nonlinear mathematical models for biological pathways using time series data.
Results
We used the Runge-Kutta method to transform differential equations to difference equations assuming a known structure of the differential equations. This transformation allowed us to generate predictions dependent on previous states and to apply a Bayesian approach, namely, the Markov chain Monte Carlo (MCMC) method. We applied this approach to the biological pathways involved in the left ventricle (LV) response to myocardial infarction (MI) and verified our algorithm by estimating two parameters in a Hill equation embedded in the nonlinear model. We further evaluated our estimation performance with different parameter settings and signal to noise ratios. Our results demonstrated the effectiveness of the algorithm for both linearly and nonlinearly parameterized dynamic systems.
Conclusions
Our proposed Bayesian algorithm successfully estimated parameters in nonlinear mathematical models for biological pathways. This method can be further extended to high order systems and thus provides a useful tool to analyze biological dynamics and extract information using temporal data.
doi:10.1186/1752-0509-5-S3-S9
PMCID: PMC3287577  PMID: 22784628
22.  Combining experimental and mathematical modeling to reveal mechanisms of macrophage-dependent left ventricular remodeling 
BMC Systems Biology  2011;5:60.
Background
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.
Results
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.
Conclusions
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.
doi:10.1186/1752-0509-5-60
PMCID: PMC3113236  PMID: 21545710
23.  Novel Ciprofloxacin-Resistant, Nalidixic Acid-Susceptible Mutant of Staphylococcus aureus 
A ciprofloxacin-resistant, nalidixic acid-susceptible mutant of Staphylococcus aureus (F145) contained no mutations within gyrA, gyrB, grlA, and grlB or within norA or its promoter region. MICs and accumulation studies suggest the role of a novel multidrug efflux pump.
doi:10.1128/AAC.46.7.2276-2278.2002
PMCID: PMC127307  PMID: 12069989

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