ACE inhibition actively promotes cell survival by altering gene expression.
We tested the effect of ACE inhibition on the survival of bovine retinal (REC) and choroidal (CEC) endothelial cells (EC) in culture. The ACE inhibitor captopril delayed the apoptotic tube collapse of REC on Matrigel for >15 days. Captopril treatment of confluent monolayers (2-8 weeks) followed by slow starvation (2-4 weeks) increased EC viability by approximately 200%. Two-week captopril exposures were sufficient to confer maximal protection. Only vehicle-treated EC demonstrated apoptotic features such as membrane blebbing and DNA laddering. By RT-PCR, the starvation marker p202 was upregulated only in starved cells. In REC, captopril upregulated the pro-survival proteins mortalin-2, uPA, and uPAR while downregulating the anti-growth sprouty-4 and tPA. In CEC, captopril also upregulated tPA and its inhibitor PAI-1. Amiloride (uPA inhibitor) blocked the captopril-induced increase in EC survival, secondary sprouting, and invasion in Matrigel. The pro-survival effects of captopril involve the reprogramming of genes involved in cell survival and immortalization.
Hamdi
Hamdi K
HK
Department of Ophthalmology, University of California-Irvine, Irvine, CA, USA. hhamdi@uci.edu
Castellon
Raquel
R
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002216:Captopril / Q000494:pharmacology*; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D015854:Up-Regulation
D000806:Angiotensin-Converting Enzyme Inhibitors; D017931:DNA Primers; D002216:Captopril