Differences in the Effect of Angiotensin-converting Enzyme Inhibitors on the Rate of Endothelial Cell Apoptosis: In Vitro and In Vivo Studies
- 242 Downloads
An imbalance between endothelial apoptosis and regeneration is one of the initiating events in atherosclerosis. Angiotensin-converting enzyme (ACE) inhibition corrects the endothelial dysfunction observed in coronary artery disease, and this could be the consequence of a reduction in the rate of endothelial apoptosis. The aim of this study was to investigate the effect of different ACE inhibitors on endothelial apoptosis.
We examined the effect of five ACE inhibitors (enalapril, perindopril, quinapril, ramipril, and trandolapril) on the rate of endothelial apoptosis, either in vitro in human umbilical vein endothelial cells (HUVECs), using a serum deprivation method to induce apoptosis, or in vivo in rats, inducing apoptosis via endotoxic shock with Escherichia coli lipopolysaccharides (LPS).
We were unable to detect any significant effect of ACE inhibition on the rate of in vitro endothelial apoptosis at concentrations ranging from 5 × 10−8 to 10−6 M. In contrast, chronic in vivo administration of ACE inhibitors to rats at dosages that had similar hypotensive effects reduced the rate of LPS-induced apoptosis significantly for perindopril (P < 0.001) and nonsignificantly for the other ACE inhibitors. The order of potency of the ACE inhibitors tested was perindopril > ramipril ≫ quinapril = trandolapril = enalapril, with significant differences between perindopril and quinapril (P < 0.01), trandolapril (P < 0.001), and enalapril (P < 0.001). The difference between perindopril and ramipril did not reach significance.
Our experiments suggest differences between ACE inhibitors in terms of inhibition of endothelial apoptosis in vivo.
Key wordsACE inhibition endothelial apoptosis HUVEC perindopril RAEC
endothelial nitric oxide synthase
human umbilical vein endothelial cell
pooled human serum
rat aortic endothelial cell
systolic blood pressure
The study was supported by an unrestricted grant from Servier, France.
- 3.The European Reduction Of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782–8.CrossRefGoogle Scholar
- 31.Remme WJ. Prevention of cardiovascular events by perindopril in patients with stable coronary disease does not depend on blood pressure and its reduction—results from the EUROPA study. Circulation. 2004;110:III628Abstract.Google Scholar
- 48.Ceconi C, Francolini G, Olivares A, Comini L, Bachetti T, Ferrari R. Angiotensin-converting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic ACE. Eur J Pharmacol 2007 DOI 10.1016/j.ejphar.2007.07.061