Divergent effects of losartan and metoprolol on cardiac remodeling, c-kit+ cells, proliferation and apoptosis in the left ventricle after myocardial infarction.
There is strong evidence for the use of angiotensin converting enzyme inhibitors and beta-blockers to reduce morbidity and mortality in patients with myocardial infarction (MI), whereas the effect of angiotensin receptor blockers is less clear. We evaluated the effects of an angiotensin receptor blocker losartan and a beta-blocker metoprolol on left ventricular (LV) remodeling, c-kit+ cells, proliferation, fibrosis, apoptosis, and angiogenesis using a model of coronary ligation in rats. Metoprolol treatment for 2 weeks improved LV systolic function. In contrast, losartan triggered deleterious structural remodeling and functional deterioration of LV systolic function, ejection fraction being 41% and fractional shortening 47% lower in losartan group than in controls 2 weeks after MI. The number of c-kit+ cells as well as expression of Ki-67 was increased by metoprolol. Losartan-induced thinning of the anterior wall and ventricular dilation were associated with increased apoptosis and fibrosis, while losartan had no effect on the expression of c-kit or Ki-67. Metoprolol or losartan had no effect on microvessel density. These results demonstrate that beta-blocker treatment attenuated adverse remodeling via c-kit+ cells and proliferation, whereas angiotensin receptor blocker-induced worsening of LV systolic function was associated with increased apoptosis and fibrosis in the peri-infarct region.
Serpi
Raisa
R
Institute of Biomedicine, Department of Pharmacology and Toxicology, Biocenter, Oulu, Finland.
Tolonen
Anna-Maria
AM
Tenhunen
Olli
O
Pieviläinen
Oskari
O
Kubin
Anna-Maria
AM
Vaskivuo
Tommi
T
Soini
Ylermi
Y
Kerkelä
Risto
R
Leskinen
Hanna
H
Ruskoaho
Heikki
H
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008790:Metoprolol / Q000494:pharmacology* / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000150:complications / Q000503:physiopathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D051381:Rats; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
D000959:Antihypertensive Agents; D053583:Interleukin-1beta; D019009:Proto-Oncogene Proteins c-kit; D008790:Metoprolol; D019808:Losartan