Document Detail


Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma.
MedLine Citation:
PMID:  21403641     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Yasuhiro Maejima; Hiroyuki Okada; Go Haraguchi; Yasuyuki Onai; Hisanori Kosuge; Jun-Ichi Suzuki; Mitsuaki Isobe
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-03-14
Journal Detail:
Title:  Laboratory investigation; a journal of technical methods and pathology     Volume:  91     ISSN:  1530-0307     ISO Abbreviation:  Lab. Invest.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-05-27     Completed Date:  2011-08-09     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  0376617     Medline TA:  Lab Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  932-44     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Angiotensin II Type 1 Receptor Blockers / pharmacology*,  therapeutic use
Animals
Benzimidazoles / pharmacology*,  therapeutic use
Benzoates / pharmacology*,  therapeutic use
Connective Tissue Growth Factor / metabolism
Echocardiography
Enzyme Activation / drug effects
Macrophages / metabolism
Male
Metalloproteases / metabolism
Myocardial Infarction / drug therapy*,  pathology
Natriuretic Peptide, Brain / blood
Osteopontin / metabolism
PPAR gamma / agonists*
Rats
Rats, Sprague-Dawley
Survival Analysis
Tissue Inhibitor of Metalloproteinase-1 / metabolism
Transforming Growth Factor beta1 / metabolism
Ventricular Remodeling / drug effects*
Chemical
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Benzimidazoles; 0/Benzoates; 0/Ctgf protein, rat; 0/PPAR gamma; 0/Spp1 protein, rat; 0/Tissue Inhibitor of Metalloproteinase-1; 0/Transforming Growth Factor beta1; 106441-73-0/Osteopontin; 114471-18-0/Natriuretic Peptide, Brain; 139568-91-5/Connective Tissue Growth Factor; EC 3.4.-/Metalloproteases; U5SYW473RQ/telmisartan

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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