Synergistic effects of telmisartan and simvastatin on endothelial progenitor cells

Abstract

Circulating endothelial progenitor cells (EPC) contribute to endothelial replenishment. Telmisartan is an angiotensin-receptor blocker with PPARγ-agonistic properties. PPARγ-agonists and HMG-CoA reductase inhibitors have been shown to enhance EPC number and function. We focused on the effects of telmisartan alone or in combination with simvastatin on EPC. EPC were isolated from healthy human volunteers, cultured and stimulated with telmisartan, simvastatin, or the combination of telmisartan and simvastatin. Telmisartan significantly increased the number of acLDL/lectin double-positive early EPC, the number of colony forming units (EC-CFU) as well as EPC migratory capacity, inhibited TNFα-induced EPC apoptosis and reduced glucose-induced oxidative stress. The telmisartan effect was dose-dependent and could be inhibited by GW9662, indicating a PPARγ-dependent mechanism. The combination of telmisartan and simvastatin led to a significant additive increase in EPC count and function. In wild-type mice, systemic treatment with either telmisartan or simvastatin elevated the number of sca-1/flk-1-positive EPC in bone marrow and peripheral blood, spleen-derived acLDL/lectin double-positive EPC, EPC migration and EC-CFU. Consistent with the in vitro findings, the combination of telmisartan and simvastatin resulted in a further enhancement of EPC counts. Re-endothelialization after carotid injury was significantly enhanced by telmisartan, simvastatin and the combination. Telmisartan increases EPC number and function mediated by a PPARγ-dependent mechanism. This effect is further enhanced by combination with simvastatin, suggesting a synergistic activation of potentially diverse intracellular pathways.