Myocardial ischemia negatively impacts cardiac function through: 1) Immediate post-ischemic contractile dysfunction of non-infarcted, reperfused myocardium (stunning);2) Myocardial infarction and infarct extension;and 3) Delayed left ventricular remodeling. Since cardiac ischemia and infarction are associated with increased free cytosolic calcium, activation of calpains (calcium-activated cystein proteases) is thought to contribute to ischemic cardiac injury. Limb-Girdle Muscular Dystrophy 2A (or """"""""calpainopathy"""""""") in patients with loss of function mutations in the calpain-3 gene result reveals an essential function for calpains in skeletal muscle health. We have created a myocardial calpain loss-of-function mouse (transgenic overexpression of calpain-inhibitory calpastatin) which develops a cardiomyopathy with many of the histologic features of skeletal calpainopathy. Based on these observations, our GENERAL HYPOTHESIS is that calpains 1 and 2 have unique functions in normal cardiac health, and due to differential activation by calcium and differential mRNA regulation after infarction, play distinct roles in mediating post-ischemic injury. To test this hypothesis we created cardiac-specific calpain 1 and 2 knockout and conditional overexpression mice, and will pursue these SPECIFIC AIMS: SA #1 -Define the normal functions of myocardial calpain 1 and calpain 2 in studies of cardiac structure, function, and cell signaling. SA#2-Delineate the pathophysiological consequences and relevant cellular mechanisms of calpain 1 and calpain 2 activation after myocardial infarction and ischemia-reperfusion injury by defining the relative roles of apoptotic and necrotic cardiomyocyte death. SA#3-Determine the biochemical mechanisms for calpain-mediated caspase activation and stimulation of apoptosis in studies of calpain 1 and 2-modulated cultured neonatal and adult cardiac myocytes. Collectively, these studies will apply state-of-the-art techniques for in vivo genetic manipulation, microphysiologic analysis, and biochemical assessment to achieve insight into the roles of myocardial calpains in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080008-06
Application #
7903365
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2006-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
6
Fiscal Year
2010
Total Cost
$368,980
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Matkovich, Scot J; Van Booven, Derek J; Eschenbacher, William H et al. (2011) RISC RNA sequencing for context-specific identification of in vivo microRNA targets. Circ Res 108:18-26
Dorn 2nd, Gerald W (2011) Nix Nought Nothing: fairy tale or real deal. J Mol Cell Cardiol 51:497-500
Zhang, Yan; Matkovich, Scot J; Duan, Xiujun et al. (2011) Receptor-independent protein kinase C alpha (PKCalpha) signaling by calpain-generated free catalytic domains induces HDAC5 nuclear export and regulates cardiac transcription. J Biol Chem 286:26943-51
Dorn 2nd, Gerald W (2011) MicroRNAs in cardiac disease. Transl Res 157:226-35
Dorn 2nd, Gerald W; Scorrano, Luca (2010) Two close, too close: sarcoplasmic reticulum-mitochondrial crosstalk and cardiomyocyte fate. Circ Res 107:689-99
Eijkelkamp, Niels; Heijnen, Cobi J; Willemen, Hanneke L D M et al. (2010) GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain. J Neurosci 30:2138-49
Dorn 2nd, Gerald W (2010) MicroRNAs: redefining mechanisms in cardiac disease. J Cardiovasc Pharmacol 56:589-95
Nijboer, Cora H; Heijnen, Cobi J; Willemen, Hanneke L D M et al. (2010) Cell-specific roles of GRK2 in onset and severity of hypoxic-ischemic brain damage in neonatal mice. Brain Behav Immun 24:420-6
Kang, Min-Young; Zhang, Yan; Matkovich, Scot J et al. (2010) Receptor-independent cardiac protein kinase Calpha activation by calpain-mediated truncation of regulatory domains. Circ Res 107:903-12
Cappola, Thomas P; Li, Mingyao; He, Jing et al. (2010) Common variants in HSPB7 and FRMD4B associated with advanced heart failure. Circ Cardiovasc Genet 3:147-54

Showing the most recent 10 out of 25 publications