Heart failure is the number one reason for discharge for Veterans treated in VA health care system. Heart failure, measured at the organ level, is the result of cellular failure due to impairment of cardiac excitation-contraction (E-C) coupling. One key structural component of E-C coupling is the myocyte transverse (T)-tubule system. T-tubules play essential roles in membrane excitation, coordinated and synchronized activation of sarcoplasmic reticulum (SR) Ca2+ release, and muscle contraction. In failing myocytes from animal models and human patients, we and others have shown that the regularly arrayed T-tubule system undergoes disruptive remodeling, leading to aberrant intracellular Ca2+ release and compromised myocyte contractility. Our recently published data strongly suggest that T-tubule structural integrity is a critical structural determinant of myocardial contractile function. Moreover, we found that loss of protein expression of junctophilin-2 (JP2), a structural protein spanning T-tubules and the SR membrane, is a causative factor in T-tubule deformation in heart disease. Substantial evidence demonstrates that E-C coupling is impaired by oxidative stress, which is elevated in cardiomyocytes in heart disease. Despite the clear role for oxidative stress in cardiomyopathies, antioxidant trials in humans have failed to provide a therapeutic benefit, suggesting an incomplete understanding of oxidative stress-mediated pathways in heart disease or possibly wrong antioxidant strategy used in previous clinical trials. Previous reports have provided solid evidence that protein kinase C (PKC) is activated by oxidative stress. At the cellular level, PKC has been shown to impair E-C coupling. In pilot studies, activation of PKC resulted in alterations in cardiomyocyte structure and function. However, in order to identify new treatment strategies for heart disease that preserve cardiac contractility, there is a critical need to determine the mechanism by which PKC activation by oxidative stress induces E-C coupling dysfunction. The objective/goal of this application is to determine the mechanistic link between excessive oxidative stress, PKC signaling, and development and progression of heart failure. We will combine multidisciplinary approaches including in situ confocal imaging, electrophysiology, molecular biology, pathological mouse models and novel transgenic mouse models to test our hypothesis. Accomplishment of our studies will advance our understanding and provide new insights into the mechanisms of oxidative stress-mediated PKC activation and T-tubule remodeling in heart failure pathophysiology and is expected to have an important positive impact by revealing new targets for heart failure therapeutics. Given that over the last decade the number of resources used to treat heart failure within the VA health care system has grown steadily, new treatments that both improve patient outcomes and reduce the cost of care associated with heart failure will provide significant benefit to the VA health care system.

Public Health Relevance

Heart failure is associated with high mortality and poor quality of life, currently affecting 5.7 million Americans. Heart failure is the number one reason for discharge for Veterans treated within the VA healthcare system. Over the last decade the number of resources used to treat heart failure within the VA healthcare system has grown steadily. New treatments that both improve patient outcomes and reduce the cost of care associated with heart failure will provide significant benefit to the VA healthcare system. Accomplishment of our studies will advance our understanding and provide new insights into the mechanisms of oxidative stress and activation of protein kinase C in heart failure pathophysiology and is expected to have an important positive impact for veterans by revealing new targets for heart failure therapeutics.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX002334-01A2
Application #
9029006
Study Section
Cardiovascular Studies A (CARA)
Project Start
2016-04-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Iowa City VA Medical Center
Department
Type
DUNS #
028084333
City
Iowa City
State
IA
Country
United States
Zip Code
52246