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1.  Dichloroacetate prevents restenosis in preclinical animal models of vessel injury 
Nature  2014;509(7502):641-644.
Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States1. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation2,3 and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.
doi:10.1038/nature13232
PMCID: PMC4323184  PMID: 24747400
3.  Clinical and Angiographic Risk Stratification and Differential Impact on Treatment Outcomes in the BARI 2D Trial 
Circulation  2012;126(17):2115-2124.
Background
The BARI 2D trial assigned patients with type 2 diabetes to prompt coronary revascularization (REV) plus intensive medical therapy versus intensive medical therapy (MED) alone and reported no significant difference in mortality. Among patients selected for CABG, REV was associated with a significant reduction in death/MI/stroke compared with MED. We hypothesized that clinical and angiographic risk stratification would impact the effectiveness of the treatments overall and within revascularization strata.
Methods and Results
An angiographic risk score was developed from variables assessed at randomization; independent prognostic factors were myocardial jeopardy index, total number of coronary lesions, prior coronary revascularization, and left ventricular ejection fraction. The Framingham risk score for patients with coronary disease was used to summarize clinical risk. Cardiovascular event rates were compared by assigned treatment within high-risk and low-risk subgroups.
No overall MED versus REV outcome differences were seen in any risk stratum. The five-year risk of death/MI/stroke was 36.8% for MED compared with 24.8% for REV among the 381 CABG-selected patients in the highest angiographic risk tertile (p=0.005); this treatment effect was amplified in patients with both high angiographic and high Framingham risk (47.3% MED versus 27.1% REV, p=0.010; Hazard Ratio=2.10, p=0.009). Treatment group differences were not significant in other clinical-angiographic risk groups within the CABG stratum nor any subgroups within the PCI stratum.
Conclusions
Among patients with diabetes and stable ischemic heart disease, a strategy of prompt CABG significantly reduces the rate of death/MI/stroke in those with extensive coronary artery disease or impaired left ventricular function.
Clinical Trial Registration: ClinicalTrials.gov NCT00006305
doi:10.1161/CIRCULATIONAHA.112.092973
PMCID: PMC4104411  PMID: 23008442
Diabetes mellitus; coronary revascularization; coronary artery disease
4.  The Role of Large Animal Studies in Cardiac Regenerative Therapy Concise Review of Translational Stem Cell Research 
Korean Circulation Journal  2013;43(8):511-518.
Animal models have long been developed for cardiovascular research. These animal models have been helpful in understanding disease, discovering potential therapeutics, and predicting efficacy. Despite many efforts, however, translational study has been underestimated. Recently, investigations have identified stem cell treatment as a potentially promising cell therapy for regenerative medicine, largely because of the stem cell's ability to differentiate into many functional cell types. Stem cells promise a new era of cell-based therapy for salvaging the heart. However, stem cells have the potential risk of tumor formation. These properties of stem cells are considered a major concern over the efficacy of cell therapy. The translational/preclinical study of stem cells is essential but only at the beginning stages. What types of heart disease are indicated for stem cell therapy, what type of stem cell, what type of animal model, how do we deliver stem cells, and how do we improve heart function? These may be the key issues that the settlement of which would facilitate the transition of stem cell research from bench to bedside. In this review article, we discuss state-of-the-art technology in stem cell therapies for cardiovascular diseases.
doi:10.4070/kcj.2013.43.8.511
PMCID: PMC3772295  PMID: 24044009
Translational research; Clinical trial; Stem cells; Heart diseases; Regenerative medicine
6.  Dual Manganese-Enhanced and Delayed Gadolinium-Enhanced MRI Detects Myocardial Border Zone Injury in a Pig Ischemia-Reperfusion Model 
Background
Delayed gadolinium (Gd) enhancement MRI (DEMRI) identifies non-viable myocardium, but is non-specific and may overestimate nonviable territory. Manganese (Mn2+)-enhanced MRI (MEMRI) denotes specific Mn2+ uptake into viable cardiomyocytes. We performed a dual-contrast myocardial assessment in a porcine ischemia-reperfusion (IR) model to test the hypothesis that combined DEMRI and MEMRI will identify viable infarct border zone (BZ) myocardium in vivo.
Methods and Results
Sixty-minute LAD ischemia-reperfusion injury (IR) was induced in 13 adult swine. Twenty-one days post-IR, 3T cardiac MRI was performed. MEMRI was obtained after injection (0.7 cc/kg) of Mn2+ contrast agent (EVP1001-1, Eagle Vision Pharmaceutical Corp.). DEMRI was then acquired after 0.2mmol/kg Gd injection. Left ventricular (LV) mass, infarct, and function were analyzed. Subtraction of MEMRI defect from DEMRI signal identified injured border zone myocardium. Explanted hearts were analyzed by 2,3,5-triphenyltetrazolium chloride (TTC) stain and tissue electron microscopy (TEM) to compare infarct, BZ, and remote myocardium. Average LV ejection fraction was reduced (30±7%). MEMRI and DEMRI infarct volumes correlated with TTC (MEMRI: r=0.78; DEMRI: r=0.75; p<0.004). MEMRI infarct volume percentage was significantly lower than DEMRI (14±4%* vs. 23±4%; *p<0.05). BZ MEMRI SNR was intermediate to remote and core infarct SNR (7.5±2.8* vs. 13.2±3.4 and 2.9±1.6; *p<0.0001), and DEMRI BZ SNR tended to be intermediate to remote and core infarct (8.4±5.4 vs. 3.3±0.6 and 14.3±6.6; p>0.05). TEM analysis exhibited preserved cell structure in BZ cardiomyocytes despite transmural DEMRI enhancement.
Conclusions
Dual-contrast MEMRI-DEMRI detects BZ viability within DEMRI infarct zones. This approach may identify injured, at-risk myocardium in ischemic cardiomyopathy.
doi:10.1161/CIRCIMAGING.110.960591
PMCID: PMC3178667  PMID: 21719779
ischemia-reperfusion; magnetic resonance imaging; delayed enhancement MRI; manganese-enhanced MRI; viability imaging
8.  BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways 
The Journal of Cell Biology  2011;192(1):171-188.
Vascular smooth muscle cell motility relies on interdependent activation of canonical and noncanonical Wnt signal transduction pathways; fibronectin, produced in response to BMP-2–mediated activation of β-catenin, promotes motility by activating an integrin-linked kinase via α4-integrin.
We present a novel cell-signaling paradigm in which bone morphogenetic protein 2 (BMP-2) consecutively and interdependently activates the wingless (Wnt)–β-catenin (βC) and Wnt–planar cell polarity (PCP) signaling pathways to facilitate vascular smooth muscle motility while simultaneously suppressing growth. We show that BMP-2, in a phospho-Akt–dependent manner, induces βC transcriptional activity to produce fibronectin, which then activates integrin-linked kinase 1 (ILK-1) via α4-integrins. ILK-1 then induces the Wnt–PCP pathway by binding a proline-rich motif in disheveled (Dvl) and consequently activating RhoA-Rac1–mediated motility. Transfection of a Dvl mutant that binds βC without activating RhoA-Rac1 not only prevents BMP-2–mediated vascular smooth muscle cell motility but promotes proliferation in association with persistent βC activity. Interfering with the Dvl-dependent Wnt–PCP activation in a murine stented aortic graft injury model promotes extensive neointima formation, as shown by optical coherence tomography and histopathology. We speculate that, in response to injury, factors that subvert BMP-2–mediated tandem activation of Wnt–βC and Wnt–PCP pathways contribute to obliterative vascular disease in both the systemic and pulmonary circulations.
doi:10.1083/jcb.201008060
PMCID: PMC3019546  PMID: 21220513
9.  The Representative Porcine Model for Human Cardiovascular Disease 
To improve human health, scientific discoveries must be translated into practical applications. Inherent in the development of these technologies is the role of preclinical testing using animal models. Although significant insight into the molecular and cellular basis has come from small animal models, significant differences exist with regard to cardiovascular characteristics between these models and humans. Therefore, large animal models are essential to develop the discoveries from murine models into clinical therapies and interventions. This paper will provide an overview of the more frequently used large animal models, especially porcine models for preclinical studies.
doi:10.1155/2011/195483
PMCID: PMC3022214  PMID: 21253493
11.  Preserved Coronary Endothelial Function by Inhibition of δ Protein Kinase C in a Porcine Acute Myocardial Infarction Model 
International journal of cardiology  2008;133(2):256-259.
Background
Previous studies demonstrate impairment of endothelial-dependent vasodilation after ischemia/reperfusion (I/R). Though we have demonstrated that inhibition of δ protein kinase C (δPKC) at reperfusion reduces myocyte damage and improves cardiac function in a porcine acute myocardial infarction (AMI) model, impact of the selective δPKC inhibitor on epicardial coronary endothelial function remains unknown.
Methods
Either δPKC inhibitor (δV1-1, n=5) or saline (n=5) was infused into the left anterior descending artery at the last 1 minute of the 30-minute ischemia by balloon occlusion. In vivo responses to bradykinin (endothelium-dependent vasodilator) or nitroglycerin (endothelium-independent vasodilator) were analyzed at 24 h after I/R using intravascular ultrasound. Vascular responses were calculated as the ratio of vessel area at each time point (30, 60, 90 and 120 seconds after the infusion), divided by values at baseline (before the infusion).
Results
In control pigs, endothelial-dependent vasodilation following bradykinin infusion in infarct-related epicardial coronary artery was impaired, whereas in δPKC inhibitor treated-pigs the endothelial-dependent vasodilation was preserved. Nitroglycerin infusion caused similar vasodilatory responses in the both groups.
Conclusions
This is the first demonstration that a δPKC inhibitor preserves vasodilator capacity in epicardial coronary arteries in an in vivo porcine AMI model. Because endothelial dysfunction correlates with worse outcome in patients with AMI, this preserved endothelial function in epicardial coronary arteries might result in a better clinical outcome.
doi:10.1016/j.ijcard.2007.11.021
PMCID: PMC2688394  PMID: 18242734
ultrasonography; angioplasty; myocardial infarction; protein kinases; endothelium
12.  Imaging In-Stent Restenosis: An Inexpensive, Reliable, and Rapid Preclinical Model 
Preclinical models of restenosis are essential to unravel the pathophysiological processes that lead to in-stent restenosis and to optimize existing and future drug-eluting stents.
A variety of antibodies and transgenic and knockout strains are available in rats. Consequently, a model for in-stent restenosis in the rat would be convenient for pathobiological and pathophysiological studies.
In this video, we present the full procedure and pit-falls of a rat stent model suitable for high throughput stent research. We will show the surgical procedure of stent deployment, and the assessment of in-stent restenosis using the most elegant technique of OCT (Optical Coherence Tomography). This technique provides high accuracy in assessing plaque CSAs (cross section areas) and correlates well with histological sections, which require special and time consuming embedding and sectioning techniques. OCT imaging further allows longitudinal monitoring of the development of in-stent restenosis within the same animal compared to one-time snapshots using histology.
doi:10.3791/1346
PMCID: PMC3129662  PMID: 19752856
13.  Impaired perfusion after myocardial infarction is due to reperfusion-induced δPKC-mediated myocardial damage 
Cardiovascular research  2006;73(4):699-709.
Objective
To improve myocardial flow during reperfusion after acute myocardial infarction and to elucidate the molecular and cellular basis that impedes it. According to the AHA/ACC recommendation, an ideal reperfusion treatment in patients with acute myocardial infarction (AMI) should not only focus on restoring flow in the occluded artery, but should aim to reduce microvascular damage to improve blood flow in the infarcted myocardium.
Methods
Transgenic mouse hearts expressing the δPKC (protein kinase C) inhibitor, δV1-1, in their myocytes only were treated with or without the δPKC inhibitor after ischemia in an ex vivo AMI model. δV1-1 or vehicle was also delivered at reperfusion in an in vivo porcine model of AMI. Microvascular dysfunction was assessed by physiological and histological measurements.
Results
δPKC inhibition in the endothelial cells improved myocardial perfusion in the transgenic mice. In the porcine in vivo AMI model, coronary flow reserve (CFR), which is impaired for 6 days following infarction, was improved immediately following a one-minute treatment at the end of the ischemic period with the δPKC-selective inhibitor, δV1-1 (∼250 ng/Kg), and was completely corrected by 24 hrs. Myocardial contrast echocardiography, electron microscopy studies, and TUNEL staining demonstrated δPKC-mediated microvascular damage. δPKC-induced preconditioning, which also reduces infarct size by >60%, did not improve microvascular function.
Conclusions
These data suggest that δPKC activation in the microvasculature impairs blood flow in the infarcted tissue after restoring flow in the occluded artery and that AMI patients with no-reflow may therefore benefit from treatment with a δPKC inhibitor given in conjunction with removal of the coronary occlusion.
doi:10.1016/j.cardiores.2006.12.011
PMCID: PMC2180159  PMID: 17234167

Results 1-13 (13)