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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Lathrop, David A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
Zip Code
Chakraborty, Asima; Pasek, Daniel A; Huang, Tai-Qin et al. (2014) Inhibition of CaMKII does not attenuate cardiac hypertrophy in mice with dysfunctional ryanodine receptor. PLoS One 9:e104338
Zhu, Linda J; Klutho, Paula J; Scott, Jason A et al. (2014) Oxidative activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) regulates vascular smooth muscle migration and apoptosis. Vascul Pharmacol 60:75-83
Luczak, Elizabeth D; Anderson, Mark E (2014) CaMKII oxidative activation and the pathogenesis of cardiac disease. J Mol Cell Cardiol 73:112-6
Hund, Thomas J; Snyder, Jedidiah S; Wu, Xiangqiong et al. (2014) ?(IV)-Spectrin regulates TREK-1 membrane targeting in the heart. Cardiovasc Res 102:166-75
Zhu, Zhiyong; Sierra, Ana; Burnett, Colin M-L et al. (2014) Sarcolemmal ATP-sensitive potassium channels modulate skeletal muscle function under low-intensity workloads. J Gen Physiol 143:119-34
Viatchenko-Karpinski, Serge; Kornyeyev, Dmytro; El-Bizri, Nesrine et al. (2014) Intracellular Na+ overload causes oxidation of CaMKII and leads to Ca2+ mishandling in isolated ventricular myocytes. J Mol Cell Cardiol 76:247-56
Anderson, Mark E (2014) Three ways to die suddenly: do they all require calcium calmodulin-dependent protein kinase II? Trans Am Clin Climatol Assoc 125:173-85
Lai, Michael H; Wu, Yuejin; Gao, Zhan et al. (2014) BK channels regulate sinoatrial node firing rate and cardiac pacing in vivo. Am J Physiol Heart Circ Physiol 307:H1327-38
Scott, Jason A; Klutho, Paula J; El Accaoui, Ramzi et al. (2013) The multifunctional Caýýýýý/calmodulin-dependent kinase IIýý (CaMKIIýý) regulates arteriogenesis in a mouse model of flow-mediated remodeling. PLoS One 8:e71550
Sierra, Ana; Zhu, Zhiyong; Sapay, Nicolas et al. (2013) Regulation of cardiac ATP-sensitive potassium channel surface expression by calcium/calmodulin-dependent protein kinase II. J Biol Chem 288:1568-81

Showing the most recent 10 out of 73 publications