HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway

TLDR

Statins are lipid‑lowering drugs that reduce coronary artery disease morbidity and mortality, and the angiogenic factor VEGF also requires Akt to increase endothelial progenitor cell numbers, underscoring Akt’s role in progenitor differentiation. Statins promote EPC differentiation through the PI3K/Akt pathway, as shown by inhibition with PI3K blockers or dominant‑negative Akt overexpression. Statins potently increase endothelial progenitor cell differentiation in human peripheral blood mononuclear and CD34+ stem cells, raise bone‑marrow c‑kit+/Sca‑1+ stem cells and differentiated EPCs in mice, and are as effective as VEGF, implying that EPC augmentation may underlie their cardiovascular benefits.

Abstract

HMG-CoA reductase inhibitors (statins) have been developed as lipid-lowering drugs and are well established to reduce morbidity and mortality from coronary artery disease. Here we demonstrate that statins potently augment endothelial progenitor cell differentiation in mononuclear cells and CD34-positive hematopoietic stem cells isolated from peripheral blood. Moreover, treatment of mice with statins increased c-kit+/Sca-1+–positive hematopoietic stem cells in the bone marrow and further elevated the number of differentiated endothelial progenitor cells (EPCs). Statins induce EPC differentiation via the PI 3-kinase/Akt (PI3K/Akt) pathway as demonstrated by the inhibitory effect of pharmacological PI3K blockers or overexpression of a dominant negative Akt construct. Similarly, the potent angiogenic growth factor VEGF requires Akt to augment EPC numbers, suggesting an essential role for Akt in regulating hematopoietic progenitor cell differentiation. Given that statins are at least as potent as VEGF in increasing EPC differentiation, augmentation of circulating EPC might importantly contribute to the well-established beneficial effects of statins in patients with coronary artery disease.