It is well established that cardiac contractile reserve declines while the incidence of heart failure increases dramatically with age. According to the """"""""free radical theory of aging,"""""""" cardiac dysfunction may be the result of oxidative stress-induced myocardial remodeling. Our long-term goal is to elucidate signal transduction and cellular and molecular mechanisms by which post-translational modifications of myofilament proteins, lead to alterations in cardiac muscle function and ultimately to heart failure. The hypothesis underlying this work is that oxidative stress-induced modifications of cardiac contractile proteins are exacerbated with age and cardiac disease progression, and lead to impaired myofilament function. To test this hypothesis we propose a comprehensive and versatile set of experiments using a mixture of mechano-energetic and biochemical/biophysical approaches. The proposed research will utilize the spontaneously hypertensive rat model, regarded for years as a good model for human systemic hypertension, recently demonstrated as an excellent model to study oxidative stress-associated contractile dysfunction.
Our aims seek to: 1) Elucidate the oxidative stress-induced modifications of myofilament proteins in young, adult and old spontaneously hypertensive rats, compared with age matched normotensive Wistar-Kyoto rats. Experiments proposed here test the hypothesis that oxidative stress induces detectable modifications of myofilament proteins, and that aging and hemodynamic stress (hypertension) lead to distinctive levels of modifications, which may differentially modulate myofilament function. 2) Investigate the functional effects of oxidative stress with age and heart disease progression in WKY and SHR myocardium. Experiments proposed here test the hypothesis that oxidative stress-induced modifications of sarcomeric proteins alter myofilament activation and might be key determinants of cardiac dysfunction. Functional significance of oxidative stress-induced modifications will be evaluated in skinned papillary muscle fiber bundles and intact myocytes from SHR and WKY animals. Overall, these experiments will result in a better understanding of the timing and the hierarchy of cellular events leading to cardiac dysfunction during the normal myocardial senescence, and during the development of heart failure in the rat. This research could prove of paramount importance in unraveling mechanisms leading to heart failure and identifying new targets or target areas for rational drug design.

Public Health Relevance

Heart failure the leading cause of death in the U.S. increases dramatically with age due of oxidative stress. We propose to study how age and oxidative stress modify the structure of heart muscle proteins and change function. We hope to prevent this by the use of antioxidants.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
1R03AG032009-01A2
Application #
7660269
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Finkelstein, David B
Project Start
2009-05-15
Project End
2011-04-30
Budget Start
2009-05-15
Budget End
2010-04-30
Support Year
1
Fiscal Year
2009
Total Cost
$60,817
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Dong, Xintong; Sumandea, C Amelia; Chen, Yi-Chen et al. (2012) Augmented phosphorylation of cardiac troponin I in hypertensive heart failure. J Biol Chem 287:848-57
Sumandea, Marius P; Steinberg, Susan F (2011) Redox signaling and cardiac sarcomeres. J Biol Chem 286:9921-7
Sumandea, C Amelia; Garcia-Cazarin, Mary L; Bozio, Catherine H et al. (2011) Cardiac troponin T, a sarcomeric AKAP, tethers protein kinase A at the myofilaments. J Biol Chem 286:530-41
Gilliam, Laura A A; Moylan, Jennifer S; Ann Callahan, Leigh et al. (2011) Doxorubicin causes diaphragm weakness in murine models of cancer chemotherapy. Muscle Nerve 43:94-102
Belin, Rashad J; Sumandea, Marius P; Sievert, Gail A et al. (2011) Interventricular differences in myofilament function in experimental congestive heart failure. Pflugers Arch 462:795-809
Sfichi-Duke, Liliana; Garcia-Cazarin, Mary L; Sumandea, C Amelia et al. (2010) Cardiomyopathy-causing deletion K210 in cardiac troponin T alters phosphorylation propensity of sarcomeric proteins. J Mol Cell Cardiol 48:934-42
Sumandea, Marius P; Vahebi, Susan; Sumandea, C Amelia et al. (2009) Impact of cardiac troponin T N-terminal deletion and phosphorylation on myofilament function. Biochemistry 48:7722-31