title: Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma.
abstract: Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) leads to cardiac dysfunction. We examined whether Telmisartan, an angiotensin (Ang) II type I receptor blocker (ARB), could improve the recovery of LV function in a rat model of MI. The effect of Telmisartan as a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist was also investigated. After 28 days of MI, a significant improvement of survival was observed in the Telmisartan-treated rat group compared with the vehicle control rat group, non-PPAR-γ agonistic ARB (Losartan)-treated rat group, and Telmisartan plus specific PPAR-γ antagonist (GW9662)-treated rat group. Although no significant differences of blood pressure or infarct size were observed among these four groups, the Telmisartan group had better systolic and diastolic LV function. There was a significant reduction of the plasma brain natriuretic peptide level, cardiac fibrosis area, infiltration of macrophages, size of cardiomyocytes, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive myocytes, activation of matrix metalloproteinases-2 and -9 (MMPs-2/9), and expression of transforming growth factor β-1 (TGF-β1), connective tissue growth factor (CTGF), and osteopontin (OPN), while expression of PPAR-γ and activation of tissue inhibitor of metalloproteinase-1 (TIMP-1) was enhanced, in the noninfarcted myocardium of rats from the Telmisartan group compared with the other three groups. To mimic ischemic conditions in vitro, neonatal rat cardiomyocytes and cardiac fibroblasts were incubated in hypoxic condition for 24 h. Increased transcriptional activation of PPAR-γ and TIMP-1, and inhibition of TGF-β1 expression were observed in cardiomyocytes, while decreased activation of MMPs-2/9 and decrease in CTGF and OPN expression was seen in cardiac fibroblasts cultured with Telmisartan. In conclusion, Telmisartan prevented unfavorable cardiac remodeling through a reduction of cardiac hypertrophy and fibrosis. An anti-inflammatory effect and PPAR-γ activation were suggested to be important in addition to suppression of Ang II activity.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okada
authors.forename: Go
authors.initials: G
authors.lastname: Haraguchi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Onai
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kosuge
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004452:Echocardiography; D004789:Enzyme Activation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000097:blood; D053495:Osteopontin / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D000077333:Telmisartan; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; C526316:CCN2 protein, rat; D047495:PPAR gamma; C506897:Spp1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D020097:Natriuretic Peptide, Brain; D055513:Connective Tissue Growth Factor; D045726:Metalloproteases; D000077333:Telmisartan