title: Inhibition of endogenous Mst1 prevents apoptosis and cardiac dysfunction without affecting cardiac hypertrophy after myocardial infarction.
abstract: Mammalian sterile 20-like kinase-1 (Mst1) plays an important role in mediating cardiac myocyte apoptosis in response to ischemia/reperfusion. Whether or not Mst1 is also involved in the long-term development of heart failure after myocardial infarction (MI) is unknown. We addressed this issue using transgenic mice with cardiac specific overexpression of dominant negative Mst1 (Tg-DN-Mst1). The left coronary artery was permanently ligated, and the size of MI was similar between Tg-DN-Mst1 and nontransgenic controls (NTg). After 4 weeks, Mst1 was significantly activated in the remodeling area in NTg, but not in Tg-DN-Mst1. Although left ventricular (LV) enlargement was significantly attenuated in Tg-DN-Mst1 compared with NTg, neither LV weight/body weight nor myocyte cross sectional area was statistically different between Tg-DN-Mst1 and NTg. LV ejection fraction was significantly greater in Tg-DN-Mst1 than in NTg (53 versus 38%, P<0.01), whereas LV end-diastolic pressure (6 versus 12 mm Hg, P<0.05) and lung weight/body weight (9.8 versus 12.2 P<0.05) were significantly smaller in Tg-DN-Mst1 than in NTg. The number of TUNEL-positive myocytes (0.17 versus 0.28%, P<0.05) and amount of interstitial fibrosis (5.0 versus 7.1%, P<0.05) in the remodeling area were significantly less in Tg-DN-Mst1 than in NTg. Upregulation of matrix metalloproteinase 2 and proinflammatory cytokines was significantly attenuated in Tg-DN-Mst1. These results indicate that endogenous Mst1 plays an important role in mediating cardiac dilation, apoptosis, fibrosis, and cardiac dysfunction, but not cardiac hypertrophy, after MI. Inhibition of Mst1 improves cardiac function without attenuating cardiac hypertrophy. Thus, Mst1 may be an important target of heart failure treatment.
authors: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA.
authors: Mari
authors: M
authors: Odashima
authors: Soichiro
authors: S
authors: Usui
authors: Hiromitsu
authors: H
authors: Takagi
authors: Chull
authors: C
authors: Hong
authors: Jing
authors: J
authors: Liu
authors: Mitsuhiro
authors: M
authors: Yokota
authors: Junichi
authors: J
authors: Sadoshima
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000209:etiology*; D016207:Cytokines / Q000502:physiology; D005355:Fibrosis; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000150:complications*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control*; D020257:Ventricular Remodeling
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor