Neointimal-specific induction of apoptosis by losartan results in regression of vascular lesion in rat aorta.
We previously reported that initiating treatment with the angiotensin II receptor antagonist losartan, prior to and immediately after balloon injury, attenuates neointimal hyperplasia via induction of smooth muscle cell (SMC) apoptosis in the aorta of spontaneously hypertensive rats (SHR). The present study examines whether losartan can induce regression of an established neointima. Balloon angioplasty was performed in the aorta of 1 1 week-old SHR. Five weeks were allowed for neointima formation before rats received placebo or losartan (30 mg/kg/day) for 1 to 4 weeks. Blood pressure was measured by tail cuff plethysmography. Losartan significantly reduced blood pressure (16%) versus placebo within 2 weeks of treatment. In situ labeling with terminal deoxynucleotidyl transferase among neointimal SMC was transiently increased with losartan (10-fold at 2 weeks; P=0.004) in correlation with internucleosomal fragmentation of vascular DNA. Accordingly, losartan reversed neointimal hyperplasia by 43% (P=0.002) and 61% (P=0.007) at weeks 2 and 4, respectively, and neointimal mass by 63% (P<0.001) and 75% (P<0.001) at weeks 2 and 4, respectively, as compared to pre-treatment values. No change in aortic medial hyperplasia or mass was observed during losartan treatment. Taken together, endothelial denudation rendered the underlying media resistant to drug-induced remodeling, while losartan treatment induced vascular lesion regression by inducing apoptosis selectively in neointimal SMC, an effect that may contribute to the reduction of cardiovascular complications in hypertension.
Lemay
Jacinthe
J
Department of Pharmacology, University of Montreal, Canada.
Hale
Taben M
TM
deBlois
Denis
D
D000800:Angioplasty, Balloon / Q000009:adverse effects; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D053938:DNA Fragmentation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051020:bcl-X Protein / Q000378:metabolism
D057912:Angiotensin II Type 2 Receptor Blockers; D000959:Antihypertensive Agents; D051020:bcl-X Protein; D051057:Proto-Oncogene Proteins c-akt; D019808:Losartan