This is a proposal from a multidisciplinary team with expertise in cardiac physiology, mitochondrial biology, advanced proteomics technologies, biostatistics and bioinformatics to work together to improve understanding of the role of cardiomyocyte mitochondrial dysfunction and adaptation in cardiac aging and failure. This proposal builds upon our novel observations that overexpression of mitochondrial catalase (mCAT) can delay cardiac aging and prevent cardiac hypertrophy and failure and that mitochondrial targeted peptide antioxidants can be cardioprotective. We will study the mechanisms responsible for cardioprotection conferred by mCAT and we will test the translational potential of newly developed mitochondrially targeted antioxidant and protective peptide drugs.
Aim 1 (Mechanism) will determine the mechanism(s) of this protection and will elucidate how the changes in the mitochondrial proteome contribute to the functional and biochemical causes of cardiac hypertrophy and failure. To do this we will combine state-of-the art quantitative label-free differential proteomics to measure differences in abundance of the cardiac mitochondrial proteome with in vivo heavy labeling to measure proteome-wide differences in cardiac mitochondrial protein syntheses and turnover rates. The proposed proteomic approach will provide a unique insight into the relationship between mitochondrial function, biology and protein turnover, and abundance.
Aim 2 (Translation) will test whether and how newly developed mitochondrially targeted antioxidant and protective drugs have the potential to translate mitochondrial protection into a clinical intervention. This comprehensive approach will provide an integrated assessment of the role of mitochondria in cardiac health, disease and disease-resistance.

Public Health Relevance

This multidisciplinary proposal combines molecular, physiologic and proteomics approaches with biostatistical and bioinformatic analyses to provide an integrated assessment of in vivo cardiac function, mitochondrial energetics and changes in the mitochondrial proteome. Important insights will be gained from study of the mechanisms of cardioprotection conferred by mitochondrial targeted catalase and the ability of mitochondrially targeted antioxidant and protective drugs to provide similar cardioprotective effects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL101186-03
Application #
8244481
Study Section
Special Emphasis Panel (ZHL1-CSR-N (F1))
Program Officer
Wong, Renee P
Project Start
2010-05-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$636,539
Indirect Cost
$186,394
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wang, Ying; Wang, Gary Z; Rabinovitch, Peter S et al. (2014) Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-*B-mediated inflammation in macrophages. Circ Res 114:421-33
Szeto, H H; Birk, A V (2014) Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther 96:672-83
Dai, Dao-Fu; Karunadharma, Pabalu P; Chiao, Ying A et al. (2014) Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 13:529-39
Dai, Dao-Fu; Hsieh, Edward J; Chen, Tony et al. (2013) Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail 6:1067-76
Birk, Alexander V; Liu, Shaoyi; Soong, Yi et al. (2013) The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol 24:1250-61
Dai, Dao-Fu; Rabinovitch, Peter S; Ungvari, Zoltan (2012) Mitochondria and cardiovascular aging. Circ Res 110:1109-24
Dai, Dao-Fu; Chen, Tony; Johnson, Simon C et al. (2012) Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal 16:1492-526
Dai, Dao-Fu; Hsieh, Edward J; Liu, Yonggang et al. (2012) Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress. Cardiovasc Res 93:79-88
Dai, Dao-Fu; Johnson, Simon C; Villarin, Jason J et al. (2011) Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res 108:837-46
Dai, Dao-Fu; Chen, Tony; Szeto, Hazel et al. (2011) Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol 58:73-82

Showing the most recent 10 out of 13 publications