Enalapril increases ischemia-induced endothelial progenitor cell mobilization through manipulation of the CD26 system.
Enalapril, an angiotensin-converting enzyme (ACE) inhibitor, reduces cardiovascular events in patients with acute myocardial infarction. However, whether the beneficial effect of enalapril is mediated in part through endothelial progenitor cells (EPCs) has yet to be elucidated. This study investigated the role of the CD26/dipeptidylpeptidase IV (DPP IV) system in enalapril-modulated EPC mobilization. C57 BL/6 mice were divided into control and enalapril-treated groups. Peripheral EPCs were enumerated before and after ischemic stress. CD26/DPP IV activity and stroma-derived factor-1alpha (SDF-1alpha) levels were measured in the blood and the bone marrow. In response to ischemic stress, the enalapril group displayed a significant increase in circulating EPCs (with a 3.6-fold increase of sca-1+KDR+ cells and a 2.2-fold increase of c-kit+CD31+ cells versus controls at 12 h). Enalapril also caused a sixfold increase in the contribution of bone marrow-derived EPCs to the ischemia-induced neovascularization. In the bone marrow, enalapril did not alter CD26+ cell numbers; however, it did amplify DPP IV activity. In the blood, through the anti-inflammatory effect, enalapril significantly decreased CD26+ cell numbers, leading to a decrease in total DPP IV activity. These phenomena were associated with a lower SDF-1alpha concentration in the bone marrow but higher in the blood in the enalapril group, compared to the controls. All these findings were not demonstrated without ischemic stress. The effect of enalapril on EPC mobilization could be substantially blocked by Diprotin-A, a DDP IV antagonist. This study demonstrates that one of the pleiotropic effects of enalapril on the cardiovascular system involves the modulation of circulating EPC numbers via the CD26/DPP IV system, which may serve as a potential target for mobilizing EPCs for therapeutic purposes.
Wang
Chao-Hung
CH
Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Chang Gung University College of Medicine, 222, Mai-Chin Road, Keelung, Taiwan. bearty@adm.cgmh.org.tw
Verma
Subodh
S
Hsieh
I-Chang
IC
Chen
Yeung-Jen
YJ
Kuo
Li-Tang
LT
Yang
Ning-I
NI
Wang
Shin-Yi
SY
Wu
Mei-Yun
MY
Hsu
Chia-Ming
CM
Cheng
Chi-Wen
CW
Cherng
Wen-Jin
WJ