Cardiomyocyte hypertrophy increases the risk of adverse clinical events and is a common prelude to cardiac dilatation and heart failure. However, little is known about the counter-regulatory mechanisms controlling cardiomyocyte hypertrophy or the mechanisms mediating the transition to heart failure. ? Using microarray analysis of hypertrophic hearts from Akt transgenic mice, we have recently identified dramatic induction of myostatin, a highly conserved negative regulator of skeletal muscle growth, not previously known to play a role in the heart. Preliminary in vitro data suggest myostatin expression exerts a potent anti-hypertrophic effect in cardiomyocytes. However, the long-term effects of inhibiting cardiomyocyte hypertrophy in this way are unknown. The goals of the current proposal are to examine the role of myostatin in both in vitro and in vivo models of cardiac hypertrophy and failure. ? This proposal is based on three hypotheses: 1) that myostatin is an endogenous negative regulator of cardiac hypertrophy, 2) that cardiac myostatin activity is induced by cardiac hypertrophy in vivo, and that 3) myostatin expression ultimately contributes to the transition from hypertrophy to dilatation and heart failure by enhancing cardiomyocyte apoptosis. To test these hypotheses, we will study the effects of myostatin inhibition or deletion, as well as cardiac expression of myostatin, in both in vitro and in vivo models of cardiomyocyte hypertrophy, apoptosis, and failure.
In Specific Aim 1, we will examine the effects of myostatin expression in vitro on cardiomyocyte hypertrophy and apoptosis.
In Specific Aim 2, we will define the downstream signaling pathways involved.
In Specific Aim 3, we will evaluate the long-term effects of myostatin deletion on the heart both at baseline and in models of cardiac hypertrophy and failure in vivo.
In Specific Aim 4, we will examine the effects of transgenic cardiac expression of myostatin or the inhibitory myostatin propeptide, at baseline and in models of cardiac hypertrophy. ? Understanding the role of specific pathways in cardiomyocyte hypertrophy may provide novel therapeutic approaches for the management of cardiac hypertrophy and heart failure. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL061557-06
Application #
6682019
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Reinlib, Leslie
Project Start
1998-09-21
Project End
2007-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
6
Fiscal Year
2003
Total Cost
$427,230
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Rosenberg, Michael A; Das, Saumya; Pinzon, Pablo Quintero et al. (2012) A Novel Transgenic Mouse Model of Cardiac Hypertrophy and Atrial Fibrillation. J Atr Fibrillation 2:1-15
Bezzerides, Vassilios; Rosenzweig, Anthony (2011) Saying yes to exercise and NO to cardiac injury. Circ Res 108:1414-6
Morissette, Michael R; Stricker, Janelle C; Rosenberg, Michael A et al. (2009) Effects of myostatin deletion in aging mice. Aging Cell 8:573-83
Matsui, Takashi; Nagoshi, Tomohisa; Hong, Eun-Gyoung et al. (2006) Effects of chronic Akt activation on glucose uptake in the heart. Am J Physiol Endocrinol Metab 290:E789-97
Morissette, Michael R; Cook, Stuart A; Foo, ShiYin et al. (2006) Myostatin regulates cardiomyocyte growth through modulation of Akt signaling. Circ Res 99:15-24
Chao, Wei; Shen, Yan; Zhu, Xinsheng et al. (2005) Lipopolysaccharide improves cardiomyocyte survival and function after serum deprivation. J Biol Chem 280:21997-2005
Matsui, Takashi; Rosenzweig, Anthony (2005) Convergent signal transduction pathways controlling cardiomyocyte survival and function: the role of PI 3-kinase and Akt. J Mol Cell Cardiol 38:63-71
Aoyama, Takuma; Matsui, Takashi; Novikov, Mikhail et al. (2005) Serum and glucocorticoid-responsive kinase-1 regulates cardiomyocyte survival and hypertrophic response. Circulation 111:1652-9
Grazette, Luanda P; Rosenzweig, Anthony (2005) Role of apoptosis in heart failure. Heart Fail Clin 1:251-61
Grazette, Luanda P; Boecker, Wolfgang; Matsui, Takashi et al. (2004) Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J Am Coll Cardiol 44:2231-8

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