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Mayorga M.E.,Skirball Laboratory for Cardiovascular Cellular Therapeutics | Mayorga M.E.,Northeast Ohio Medical University | Penn M.S.,Skirball Laboratory for Cardiovascular Cellular Therapeutics | Penn M.S.,Northeast Ohio Medical University | Penn M.S.,Summa Cardiovascular Institute
Journal of Cellular and Molecular Medicine | Year: 2012

The effect of wnt/β-catenin signalling in the response to acute myocardial infarction (AMI) remains controversial. The membrane receptor adaptor protein Disabled-2 (Dab2) is a tumour suppressor protein and has a critical role in stem cell specification. We recently demonstrated that down-regulation of Dab2 regulates cardiac protein expression and wnt/β-catenin activity in mesenchymal stem cells (MSC) in response to transforming growth factor-β1 (TGF-β1). Although Dab2 expression has been shown to have effects in stem cells and tumour suppression, the molecular mechanisms regulating this expression are still undefined. We identified putative binding sites for miR-145 in the 3′-UTR of Dab2. In MSC in culture, we observed that TGF-β1 treatment led to rapid and sustained up-regulation of pri-miR-145. Through gain and loss of function studies we demonstrate that miR-145 up-regulation was required for the down-regulation of Dab2 and increased β-catenin activity in response to TGF-β1. To begin to define how Dab2 might regulate wnt/β-catenin in the heart following AMI, we quantified myocardial Dab2 as a function of time after left anterior descending ligation. There was no significant Dab2 expression in sham-operated myocardium. Following AMI, Dab2 levels were rapidly up-regulated in cardiac myocytes in the infarct border zone. The increase in cardiac myocyte Dab2 expression correlated with the rapid and sustained down-regulation of myocardial pri-miR-145 expression following AMI. Our data demonstrate a novel and critical role for miR-145 expression as a regulator of Dab2 expression and β-catenin activity in response to TGF-β1 and hypoxia. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. Source

Penn M.S.,Northeast Ohio Medical University | Penn M.S.,Summa Cardiovascular Institute | Dong F.,Northeast Ohio Medical University | Klein S.,Northeast Ohio Medical University | Mayorga M.E.,Northeast Ohio Medical University
Clinical Pharmacology and Therapeutics | Year: 2011

The field of cardiovascular regenerative medicine has made significant strides over the past decade. Clinical trials have demonstrated benefit in acute myocardial infarction (AMI) and chronic heart failure (CHF). As the field has matured, it has defined novel biology and invented an array of therapeutic strategies that are currently under development. In this brief review, we attempt to conceptualize the knowledge to date as well as examine how this knowledge has been translated to various therapeutic strategies. © 2011 American Society for clinical Pharmacology and therapeutics. Source

Penn M.S.,Summa Cardiovascular Institute | Penn M.S.,Northeast Ohio Medical University | Penn M.S.,Juventas Therapeutics Inc. | Pastore J.,Juventas Therapeutics Inc. | And 2 more authors.
Gene Therapy | Year: 2012

Stem cell therapy for the prevention and treatment of cardiac dysfunction holds significant promise for patients with ischemic heart disease. Excitingly early clinical studies have demonstrated safety and some clinical feasibility, while at the same time studies in the laboratory have investigated mechanisms of action and strategies to optimize the effects of regenerative cardiac therapies. One of the key pathways that has been demonstrated critical in stem cell-based cardiac repair is (stromal cell-derived factor-1) SDF-1:CXCR4. SDF-1:CXCR4 has been shown to affect stem cell homing, cardiac myocyte survival and ventricular remodeling in animal studies of acute myocardial infarction and chronic heart failure. Recently released clinical data suggest that SDF-1 alone is sufficient to induce cardiac repair. Most importantly, studies like those on the SDF-1:CXCR4 axis have suggested mechanisms critical for cardiac regenerative therapies that if clinical investigators continue to ignore will result in poorly designed studies that will continue to yield negative results. © 2012 Macmillan Publishers Limited All rights reserved. Source

Penn M.S.,Summa Cardiovascular Institute | Penn M.S.,Northeast Ohio Medical University | Mendelsohn F.O.,Center for Therapeutic Angiogenesis | Schaer G.L.,Rush University Medical Center | And 8 more authors.
Circulation Research | Year: 2013

RATIONALE:: Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. OBJECTIVE:: We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. METHODS AND RESULTS:: Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ≤40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-Terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mg: median [range]: 41 minutes [3-61 minutes]; 30 mg: 31 minutes [22-74 minutes]) and quality of life (15 mg: -16 points [+1 to -32 points]; 30 mg: -24 points [+17 to -38 points]) over baseline. At 12 months, improvements in symptoms were maintained. CONCLUSIONS:: These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy. © 2013 American Heart Association, Inc. Source

Penn M.S.,Cleveland Heart Laboratory | Penn M.S.,Summa Cardiovascular Institute | Klemes A.B.,MDVIP
Future Cardiology | Year: 2013

The widespread use of lipids to define risk has been a success based on the dramatic decrease in the incidence of transmural myocardial infarctions. This success and the fact that many patients with normal lipid levels go on to have acute coronary syndrome have led to investigations on the use of nonlipid-based inflammatory biomarkers to predict risk. Interestingly, as the physiology reflected by distinct biomarkers is better understood, there is increasing interest in multimarker approaches to determine risk and where a given patient may be on a spectrum of risk. In this perspective, we review data from over 95,000 patients who had a multimarker annual wellness panel to demonstrate the utility of multiple markers in defining those patients at risk. We discuss a novel multimarker panel for cardiovascular risk, define the differences between a multimarker approach and expensive amalgamations of multiple markers, and discuss how the field may develop in the future. © 2013 Future Medicine Ltd. Source

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