Statins Enhance Clonal Growth of Late Outgrowth Endothelial Progenitors and Increase Myocardial Capillary Density in the Chronically Ischemic Heart

Wen Wang,Gen Suzuki,Thomas Cimato,John M Canty,Jennifer K Lang,Gangjian Qin Gangjian Qin

doi:10.1371/journal.pone.0024868

Abstract

BackgroundCoronary artery disease and ischemic heart disease are leading causes of heart failure and death. Reduced blood flow to heart tissue leads to decreased heart function and symptoms of heart failure. Therapies to improve heart function in chronic coronary artery disease are important to identify. HMG-CoA reductase inhibitors (statins) are an important therapy for prevention of coronary artery disease, but also have non-cholesterol lowering effects. Our prior work showed that pravastatin improves contractile function in the chronically ischemic heart in pigs. Endothelial progenitor cells are a potential source of new blood vessels in ischemic tissues. While statins are known to increase the number of early outgrowth endothelial progenitor cells, their effects on late outgrowth endothelial progenitor cells (LOEPCs) and capillary density in ischemic heart tissue are not known. We hypothesized that statins exert positive effects on the mobilization and growth of late outgrowth EPCs, and capillary density in ischemic heart tissue.Methodology/Principal FindingsWe determined the effects of statins on the mobilization and growth of late outgrowth endothelial progenitor cells from pigs. We also determined the density of capillaries in myocardial tissue in pigs with chronic myocardial ischemia with or without treatment with pravastatin. Pravastatin therapy resulted in greater than two-fold increase in CD31+ LOEPCs versus untreated animals. Addition of pravastatin or simvastatin to blood mononuclear cells increased the number of LOEPCs greater than three fold in culture. Finally, in animals with chronic myocardial ischemia, pravastatin increased capillary density 46%.ConclusionsStatins promote the derivation, mobilization, and clonal growth of LOEPCs. Pravastatin therapy in vivo increases myocardial capillary density in chronically ischemic myocardium, providing an in vivo correlate for the effects of statins on LOEPC growth in vitro. Our findings provide evidence that statin therapy can increase the density of capillaries in the chronically ischemic heart.

Highlights

Coronary artery disease is the leading cause of heart failure in the United States [1]
Porcine late outgrowth endothelial progenitor cells (LOEPCs) expressed antigens found in endothelial cells, and described in LOEPCs from human blood [7] including PECAM (CD31), VE-Cadherin (CD144), VEGFR2, c-kit (CD117), endothelial specific nitric oxide synthase, and Tie 2 (Figure 1B)
Pravastatin Mobilizes LOEPCs into the Blood Stream Given the positive effects of statins on the quantity and activity of early outgrowth Endothelial progenitor cells (EPCs) shown previously, we hypothesized that statin therapy mobilizes LOEPCs into the bloodstream when given to animals in vivo [12]

Summary

Introduction

Coronary artery disease is the leading cause of heart failure in the United States [1]. In some patients coronary artery disease persists unidentified, or cannot be revascularized, resulting in chronically ischemic myocardium, with regional contractile dysfunction These clinical findings can result in heart failure manifesting as shortness of breath with exertion, weight gain, and retention of fluid. Therapy with HMG-CoA reductase inhibitors (statins) is an important component of medical treatment for coronary artery disease primarily for their cholesterol lowering benefits to prevent the progression and recurrence of disease in the heart. We found that therapy with the HMG-CoA reductase inhibitor pravastatin mobilized c-kit+ bone marrow cells to the heart in animals with chronic myocardial ischemia with regional myocardial dysfunction, leading to improved contractile function without significantly affecting myocardial blood flow [2]. HMG-CoA reductase inhibitors (statins) are an important therapy for prevention of coronary artery disease, and have non-cholesterol lowering effects. We hypothesized that statins exert positive effects on the mobilization and growth of late outgrowth EPCs, and capillary density in ischemic heart tissue

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