This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 100/9/1344    most recent 01.RES.0000265846.23485.7av1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Odashima, M. Articles by Sadoshima, J. Search for Related Content PubMed PubMed Citation Articles by Odashima, M. Articles by Sadoshima, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Heart Attack Related Collections Chronic ischemic heart disease Congestive Apoptosis

(Circulation Research. 2007;100:1344.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Inhibition of Endogenous Mst1 Prevents Apoptosis and Cardiac Dysfunction Without Affecting Cardiac Hypertrophy After Myocardial Infarction

Mari Odashima^*, Soichiro Usui^*, Hiromitsu Takagi, Chull Hong, Jing Liu, Mitsuhiro Yokota, Junichi Sadoshima

From the Cardiovascular Research Institute (M.O., S.U., H.T., C.H., J.L., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark; and Department of Genome Science (M.Y.), Aichi-Gakuin University, Nagoya Japan.

Correspondence to Junichi Sadoshima, MD, PhD, Cardiovascular Research Institute, University of Medicine of Dentistry of New Jersey, New Jersey Medical School, 185 S Orange Ave, MSB G609, Newark, New Jersey 07103. E-mail sadoshju{at}umdnj.edu

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.

Key Words: apoptosis • hypertrophy • myocardial infarction • signal transduction

This article has been cited by other articles:

				P. Zhai, S. Gao, E. Holle, X. Yu, A. Yatani, T. Wagner, and J. Sadoshima Glycogen Synthase Kinase-3{alpha} Reduces Cardiac Growth and Pressure Overload-induced Cardiac Hypertrophy by Inhibition of Extracellular Signal-regulated Kinases J. Biol. Chem., November 9, 2007; 282(45): 33181 - 33191. [Abstract] [Full Text] [PDF]

				D. K. Singla, G. E. Lyon, and T. J. Kamp Reply to "Letter to the editor: Infarct size measurements are critically important when comparing interventions affecting ventricular remodeling" Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3222 - H3222. [Full Text] [PDF]