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(Hypertension. 2000;36:747.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Reduction in Left Ventricular Messenger RNA for Transforming Growth Factor ß₁ Attenuates Left Ventricular Fibrosis and Improves Survival Without Lowering Blood Pressure in the Hypertensive TGR(mRen2)27 Rat

Yigal M. Pinto; Sara-Joan Pinto-Sietsma; Tobias Philipp; Sonja Engler; Peter Koßmehl; Berthold Hocher; Heike Marquardt; Svenja Sethmann; Roland Lauster; Hans-Joachim Merker; Martin Paul

From the Department of Clinical Pharmacology and Toxicology (Y.M.P., S.-J.P.-S., T.P., S.E., P.K., H.M., H.-J.M., M.P.), Benjamin Franklin Medical Center, Freie Universität Berlin, Berlin, Germany; Deutsches Rheumaforschungszentrum Berlin (S.S., R.L.), Berlin, Germany; and Department of Internal Medicine (B.H.), Humboldt University, Berlin, Germany.

Correspondence to Yigal M. Pinto, MD, PhD, and Martin Paul, MD, Department of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Garystrasse 5, Berlin, 14195 Germany. E-mail y.m.pinto{at}thorax.azg.nl

Abstract—Angiotensin II recruits transforming growth factor ß₁ (TGFß₁) and is related to left ventricular fibrosis. However, it is unclear whether chronic in vivo reduction in left ventricular TGFß₁ 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 TGFß 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 TGFß₁ 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 TGFß₁ (r=0.62; P=0.019). In situ hybridization demonstrated increases in TGFß₁ 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, TGFß₁ 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 TGFß₁ expression attenuates left ventricular hypertrophy and fibrosis, even without lowering blood pressure.

Key Words: hypertension, experimental • hypertrophy • transforming growth factors • fibrosis

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