Reduction in left ventricular messenger RNA for transforming growth factorbeta(1) attenuates left ventricular fibrosis and improves survival withoutlowering blood pressure in the hypertensive TGR(mRen2)27 rat

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 blu nts fibrosis and improves outcome in angiotensin II-dependent hypertension. Four week-old male hypertensive TGR(mRen2)27 (Ren2) rats received either n ormal food, low-dose losartan (0.5 mg.kg(-1).d(-1)), or tranilast (a nonspe cific 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 R en2 rats. Tranilast or low-dose losartan did not lower blood pressure. Howe ver, the increase in left ventricular weight (Ren2 versus SD 3.1 +/- 0.16 v ersus 2.1 +/- 0.06 mg/g body wt; P < 0,05) was significantly (P < 0,05) blu nted by both tranilast (2.7 +/- 0.05) and losartan (2,7 +/- 0.07), Both dru gs prevented the increase in left ventricular TGF beta (1), mRNA and fibron ectin mRNA and blunted the increase in hydroxyproline content and the incre ase in perivascular fibrosis, The perivascular fibrosis score correlated si gnificantly 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, p redominantly in perivascular and nonmyocyte areas. Both drugs did not preve nt the decrease in systolic or diastolic dP/dt, but tranilast significantly improved the survival of untreated Ren2 rats (P = 0,029). In conclusion, T GF beta (1), mRNA expression is increased predominantly in nonmyocyte regio ns in the hypertrophied left ventricle in this angiotensin II-dependent mod el of hypertension. This increase is probably due to high angiotensin II le vels rather than to hypertension. This is the first study to suggest that c hronic inhibition of TGF beta (1), expression attenuates left ventricular h ypertrophy and fibrosis, even without lowering blood pressure.