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 #
7R01HL061688-19
Application #
8902309
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
2014-08-15
Budget End
2015-04-30
Support Year
19
Fiscal Year
2014
Total Cost
$325,099
Indirect Cost
$118,029
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
Zhou, Jibin; Ahmad, Firdos; Lal, Hind et al. (2016) Response by Zhou et al to Letter Regarding Article, ""Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy"". Circ Res 119:e29-e30
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
Lal, Hind; Ahmad, Firdos; Zhou, Jibin et al. (2014) Cardiac fibroblast glycogen synthase kinase-3? regulates ventricular remodeling and dysfunction in ischemic heart. Circulation 130:419-30
Ahmad, Firdos; Lal, Hind; Zhou, Jibin et al. (2014) Cardiomyocyte-specific deletion of Gsk3? mitigates post-myocardial infarction remodeling, contractile dysfunction, and heart failure. J Am Coll Cardiol 64:696-706
Zhou, Jibin; Freeman, Theresa A; Ahmad, Firdos et al. (2013) GSK-3? 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
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

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