Remodeling of the left ventricle (LV), which includes dilatation, reduced contractile function, and, typically, increased fibrosis, is a major problem following myocardial infarction (MI) or severe pressure stress as one sees in advanced hypertension or valvular disease. Remodeling typically culminates in heart failure. Current therapeutics are inadequate, and while they can slow the progression of remodeling, the remodeling does inexorably progress. It is very clear that prevention of remodeling is an unmet need in cardiovascular disease. We have recently employed novel mouse models to identify critical roles for the GSK-3 family of protein kinases in remodeling post-MI and post-thoracic aortic constriction (TAC). In brief, deletion of the gene encoding GSK-3b is protective in the post-MI state. In stark contrast, deletion of the gene encoding GSK-3a leads to profound heart failure following either MI or TAC, due at least in part to markedly impaired b-adrenergic responsiveness. It is the purpose of this competing renewal application to extend our studies examining the role of the GSK-3 family in pathologic disease states in the heart. We plan to examine a very poorly understood issue: the role of the GSK-3 family in post-injury fibrosis, utilizing mouse models in which GSK-3a vs. GSK-3b is selectively knocked out in cardiomyocytes vs. fibroblasts. Our preliminary studies suggest that GSK-3a functions as a critical break on fibrosis. We will also identify the molecular mechanism by which GSK-3a regulates b-adrenergic responsiveness. The latter studies could lead to alternative strategies to traditional b-blockade, with the additional advantage that deletion (or inhibition) of GSK- 3a, unlike b-blockers, leads to improved glucose tolerance and insulin sensitivity.

Public Health Relevance

Is this competing renewal we propose to extend our studies on the many roles played by GSK-3 family members in pathologic processes in the heart. Specifically, we will examine remodeling in the post-MI and post aortic-banded heart. We will also examine the role played by GSK-3 in regulating post-injury fibrosis, utilizing mice deleted for GSK-3a vs. -3b, in cardiomyocytes vs. fibroblasts. Finally, we have found that GSK-3a positively regulates the b1-adrenergic system, and in the absence of GSK-3a, the stressed heart rapidly fails.
In Aim 3 we will identify the molecular mechanism by which GSK-3a regulates this critically important system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL061688-16
Application #
8257514
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
1999-09-20
Project End
2015-04-30
Budget Start
2012-05-15
Budget End
2013-04-30
Support Year
16
Fiscal Year
2012
Total Cost
$382,500
Indirect Cost
$132,500
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Zhou, Jibin; Ahmad, Firdos; Parikh, Shan et al. (2016) Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy. Circ Res 118:1208-22
Lal, Hind; Ahmad, Firdos; Woodgett, James et al. (2015) The GSK-3 family as therapeutic target for myocardial diseases. Circ Res 116:138-49
Lal, Hind; Ahmad, Firdos; Parikh, Shan et al. (2014) Troponin I-interacting protein kinase: a novel cardiac-specific kinase, emerging as a molecular target for the treatment of cardiac disease. Circ J 78:1514-9
Ahmad, Firdos; Lal, Hind; Zhou, Jibin et al. (2014) Cardiomyocyte-specific deletion of Gsk3α mitigates post-myocardial infarction remodeling, contractile dysfunction, and heart failure. J Am Coll Cardiol 64:696-706
Lal, Hind; Ahmad, Firdos; Zhou, Jibin et al. (2014) Cardiac fibroblast glycogen synthase kinase-3β regulates ventricular remodeling and dysfunction in ischemic heart. Circulation 130:419-30
Lal, Hind; Kolaja, Kyle L; Force, Thomas (2013) Cancer genetics and the cardiotoxicity of the therapeutics. J Am Coll Cardiol 61:267-74
Vagnozzi, Ronald J; Gatto Jr, Gregory J; Kallander, Lara S et al. (2013) Inhibition of the cardiomyocyte-specific kinase TNNI3K limits oxidative stress, injury, and adverse remodeling in the ischemic heart. Sci Transl Med 5:207ra141
Force, Thomas; Wang, Yibin (2013) Mechanism-based engineering against anthracycline cardiotoxicity. Circulation 128:98-100
Zhou, Jibin; Freeman, Theresa A; Ahmad, Firdos et al. (2013) GSK-3α is a central regulator of age-related pathologies in mice. J Clin Invest 123:1821-32
Ky, Bonnie; Vejpongsa, Pimprapa; Yeh, Edward T H et al. (2013) Emerging paradigms in cardiomyopathies associated with cancer therapies. Circ Res 113:754-64

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