期刊
HYPERTENSION
卷 36, 期 5, 页码 747-754出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.HYP.36.5.747
关键词
hypertension, experimental; hypertrophy; transforming growth factors; fibrosis
Angiotensin TI recruits transforming growth factor beta (1) (TGF beta (1)) and is related to left ventricular fibrosis, However, it is unclear whether chronic in vivo reduction in left ventricular TGF beta (1), expression blunts fibrosis and improves outcome in angiotensin II-dependent hypertension. Four week-old male hypertensive TGR(mRen2)27 (Ren2) rats received either normal food, low-dose losartan (0.5 mg.kg(-1).d(-1)), or tranilast (a nonspecific TGF beta inhibitor; 400 mg.kg(-1).d(-1)) (n = 10 For each group) for 12 weeks and were compared with Sprague-Dawley control rats. The effect of tranilast on survival was evaluated in 34 additional untreated homozygous Ren2 rats. Tranilast or low-dose losartan did not lower blood pressure. However, the increase in left ventricular weight (Ren2 versus SD 3.1 +/- 0.16 versus 2.1 +/- 0.06 mg/g body wt; P < 0,05) was significantly (P < 0,05) blunted by both tranilast (2.7 +/- 0.05) and losartan (2,7 +/- 0.07), Both drugs prevented the increase in left ventricular TGF beta (1), mRNA and fibronectin mRNA and blunted the increase in hydroxyproline content and the increase in perivascular fibrosis, The perivascular fibrosis score correlated significantly with the level of expression of TGF beta (1), (r = 0.62; P = 0,019), In situ hybridization demonstrated increases in TGF beta (1), mRNA, predominantly in perivascular and nonmyocyte areas. Both drugs did not prevent the decrease in systolic or diastolic dP/dt, but tranilast significantly improved the survival of untreated Ren2 rats (P = 0,029). In conclusion, TGF beta (1), mRNA expression is increased predominantly in nonmyocyte regions in the hypertrophied left ventricle in this angiotensin II-dependent model of hypertension. This increase is probably due to high angiotensin II levels rather than to hypertension. This is the first study to suggest that chronic inhibition of TGF beta (1), expression attenuates left ventricular hypertrophy and fibrosis, even without lowering blood pressure.
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