Losartan-induced apoptosis as a novel mechanism for the prevention of vascular lesion formation after injury.
Smooth muscle cell (SMC) apoptosis is transiently increased at the onset of the regression of aortic hypertrophy in spontaneously hypertensive rats (SHR) treated with the angiotensin II AT(1) antagonist losartan. We postulated that losartan induction of SMC apoptosis contributes to suppression of neointimal hyperplasia after vascular injury. Losartan or placebo treatment was initiated two days before balloon injury in the SHR aorta. Compared with time-matched placebo, losartan decreased neointimal cross-sectional area at Days 5 and 10 after injury by 50% and 64% respectively, without affecting medial mass. At Day 10, losartan significantly decreased SMC number (by 56%) in the neointima, but not in the media. DNA synthesis was significantly inhibited at Day 5 but not at Day 10. Losartan significantly increased aortic DNA fragmentation by 2.6- and 4.1-fold, at Days 5 and 10, respectively. In situ labeling of SMC with terminal deoxynucleotidyltransferase revealed significant 61% and 68% increases in apoptotic SMC at Days 5 and 10 with losartan treatment, predominantly in the neointima. Thus, losartan suppressed neointima formation in part by the induction of SMC apoptosis, which may be dissociated from the inhibition of DNA synthesis. Therefore, losartan-induced SMC apoptosis may be a potential therapeutic approach to control occlusive vascular disorders.
Lemay
J
J
University of Montreal Hospital, Montreal, Quebec, Canada.
Hamet
P
P
deBlois
D
D
D000818:Animals; D001013:Aorta, Thoracic / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis; D002404:Catheterization / Q000009:adverse effects*; D053938:DNA Fragmentation; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D006965:Hyperplasia; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D012038:Regeneration; D014652:Vascular Diseases / Q000209:etiology* / Q000517:prevention & control*; D014947:Wounds and Injuries / Q000150:complications* / Q000209:etiology / Q000235:genetics / Q000473:pathology
D019808:Losartan