Angiotensin II recruits
transforming growth factor beta(1) (
TGFbeta(1)) and is related to left ventricular
fibrosis. However, it is unclear whether chronic in vivo reduction in left ventricular
TGFbeta(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
TGFbeta 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
TGFbeta(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
TGFbeta(1) (r=0.62; P=0.019). In situ hybridization demonstrated increases in
TGFbeta(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,
TGFbeta(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
TGFbeta(1) expression attenuates
left ventricular hypertrophy and
fibrosis, even without lowering blood pressure.