title: Reduction in left ventricular messenger RNA for transforming growth factor beta(1) attenuates left ventricular fibrosis and improves survival without lowering blood pressure in the hypertensive TGR(mRen2)27 Rat.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Freie Universität Berlin, Berlin, Germany. y.m.pinto@thorax.azg.nl
authors.forename: Y M
authors.initials: YM
authors.lastname: Pinto
authors.forename: S J
authors.initials: SJ
authors.lastname: Pinto-Sietsma
authors.forename: T
authors.initials: T
authors.lastname: Philipp
authors.forename: S
authors.initials: S
authors.lastname: Engler
authors.forename: P
authors.initials: P
authors.lastname: Kossamehl
authors.forename: B
authors.initials: B
authors.lastname: Hocher
authors.forename: H
authors.initials: H
authors.lastname: Marquardt
authors.forename: S
authors.initials: S
authors.lastname: Sethmann
authors.forename: R
authors.initials: R
authors.lastname: Lauster
authors.forename: H J
authors.initials: HJ
authors.lastname: Merker
authors.forename: M
authors.initials: M
authors.lastname: Paul
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000378:metabolism; D006331:Heart Diseases / Q000378:metabolism*; D006352:Heart Ventricles / Q000737:chemistry* / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D012333:RNA, Messenger / Q000032:analysis* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis* / Q000187:drug effects / Q000378:metabolism; D016019:Survival Analysis; D015291:Transforming Growth Factors / Q000032:analysis* / Q000187:drug effects / Q000378:metabolism; D016276:Ventricular Function; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D062367:ortho-Aminobenzoates; D015291:Transforming Growth Factors; C012293:tranilast; D019808:Losartan