This competitive renewal application is designed to test three new hypotheses about the role of excessive oxidative stress and calmodulin kinase II (CaMKII) in pathological responses to myocardial infarction (MI) and aldosterone (Aldo). These studies will use new genetic mouse models developed by us where the activity of mitochondrial CaMKII, oxidized CaMKII (ox-CaMKII) and methionine sulfoxide reductase A (MsrA), the enzyme that reduces and inactivates ox-CaMKII, are controlled. Each of the inter-related, but independent aims is backed by strong preliminary data.
Aim 1 Determine how Aldo and ox-CaMKII promote cardiac rupture after MI. We will determine if Aldo increases the frequency of post-MI rupture by enhancing NADPH oxidase and ox-CaMKII, and unravel a previously unknown pathway where ox-CaMKII drives myocardial matrix metalloproteinase 9 (MMP9) expression by HDAC4/5 phosphorylation and MEF2 derepression.
Aim 2 Determine the role of ox-CaMKII in myocardial hypertrophy. CaMKII contributes to myocardial hypertrophy, but the potential role of the ox-CaMKII pathway in myocardial hypertrophy is unknown. We will test the novel concept that myocardial ox-CaMKII coherently promotes transcription of matrix remodeling (in Aim 1) and hypertrophic gene programs (in Aim 2) by HDAC4/5 phosphorylation and MEF2 derepression.
Aim 3 Determine the role of ox-CaMKII in the transition from hypertrophy to heart failure. Our preliminary studies indicate that CaMKII is resident in mitochondria and that mitochondrial ox-CaMKII plays a decisive role in mitochondria membrane permeability transition pore (mPTP) opening and cell death. We predict that mitochondrial-targeted CaMKII inhibition will significantly delay and mitochondrial-targeted CaMKII over-expression will significantly hasten development of heart failure.

Public Health Relevance

Myocardial infarction (MI) is a major cause of death and suffering in the United States. Patients may die soon after MI from rupture of the heart muscle (myocardium). At present there are no highly effective treatments for myocardial rupture. Patients who survive the initial MI event are at risk developing heart failure later. Heart failure is a major cause of hospitalization and confers a high mortality that is comparable to many cancers. Our studies will test the idea that calmodulin kinase II (CaMKII) is a critical signal for causing post-MI myocardial rupture and heart failure. The goal of this work is to determine how CaMKII contributes to pathological responses to MI and explore the potential for therapeutic manipulation of the CaMKII pathway in mouse models to improve outcomes in patients who suffer MI.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL079031-05
Application #
8039499
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Lathrop, David A
Project Start
2004-12-01
Project End
2015-11-30
Budget Start
2010-12-15
Budget End
2011-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$376,042
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Manotheepan, Ravinea; Danielsen, Tore K; Sadredini, Mani et al. (2016) Exercise training prevents ventricular tachycardia in CPVT1 due to reduced CaMKII-dependent arrhythmogenic Ca2+ release. Cardiovasc Res 111:295-306

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