Despite recent advances in the prevention and treatment of cardiovascular disease, the prevalence of heart failure, a worldwide health threat, continues to grow. Current therapeutic strategies for heart failure are largely directed at disturbances in the neurohormonal axis rather than targeting the myocyte. Evidence is emerging that alterations in myocyte energy metabolism contributes to the pathogenesis of heart failure. Previous work linked to this RO1-funded project has shown that a gene regulatory cascade, under the influence of the transcriptional coactivators, PPAR3 transcriptional coactivator-11 and 2 (PGC-11 and PGC-12), controls the expression of genes involved in a wide array of mitochondrial energy transduction and ATP-generating processes in the cardiac myocyte. The results of our recent studies conducted in mice deficient for the PGC-1 coactivators have shown that the PGC-1 regulatory cascade is required for postnatal mitochondrial biogenic maturation. We have also found that the expression and activity of the PGC-1 coactivators are downregulated in pathologic forms of cardiac hypertrophy and in the failing heart. These findings have led to the central hypothesis of this renewal proposal that chronic deactivation of PGC-1 signaling in the adult heart contributes to the progressive pathologic metabolic and functional remodeling that leads to end-stage heart failure. To test this hypothesis we will: (1) conduct mitochondrial functional and proteomic studies in the hearts of adult mice in which the cardiac PGC-1 gene regulatory cascade has been deactivated;(2) define mitochondrial functional and proteomic derangements in hearts of wild-type mice subjected to pressure overload and ischemic insult and compare the results with the dataset generated in the PGC-1-deficient hearts in order to identify shared signatures;(3) explore the potential role of PGC-1 coactivators in the control of mitochondrial dynamics (fusion, fission, biogenesis);and (4) devise and implement proof-of-concept """"""""rescue"""""""" studies in which PGC-1 coactivators or relevant downstream targets are reactivated in heart failure models in wild-type mice. In the long-term, we seek to identify and validate novel targets aimed at modulating cardiac metabolism as a novel approach to prevent or treat heart failure in its early stages. )

Public Health Relevance

Heart failure is a growing worldwide health threat. This project seeks to understand how changes in the metabolism of the heart contribute to the development of heart failure. This work should identify new approaches to treat heart failure by boosting its energy supply.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058493-16
Application #
8495386
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
1998-04-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
16
Fiscal Year
2013
Total Cost
$459,459
Indirect Cost
$223,839
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Gan, Zhenji; Fu, Tingting; Kelly, Daniel P et al. (2018) Skeletal muscle mitochondrial remodeling in exercise and diseases. Cell Res 28:969-980
Vega, Rick B; Kelly, Daniel P (2017) Cardiac nuclear receptors: architects of mitochondrial structure and function. J Clin Invest 127:1155-1164
Vega, Rick B; Konhilas, John P; Kelly, Daniel P et al. (2017) Molecular Mechanisms Underlying Cardiac Adaptation to Exercise. Cell Metab 25:1012-1026
Horton, Julie L; Martin, Ola J; Lai, Ling et al. (2016) Mitochondrial protein hyperacetylation in the failing heart. JCI Insight 2:
Liang, Xijun; Liu, Lin; Fu, Tingting et al. (2016) Exercise Inducible Lactate Dehydrogenase B Regulates Mitochondrial Function in Skeletal Muscle. J Biol Chem 291:25306-25318
Liu, Jing; Liang, Xijun; Zhou, Danxia et al. (2016) Coupling of mitochondrial function and skeletal muscle fiber type by a miR-499/Fnip1/AMPK circuit. EMBO Mol Med 8:1212-1228
Aubert, Gregory; Martin, Ola J; Horton, Julie L et al. (2016) The Failing Heart Relies on Ketone Bodies as a Fuel. Circulation 133:698-705
Weinheimer, Carla J; Lai, Ling; Kelly, Daniel P et al. (2015) Novel mouse model of left ventricular pressure overload and infarction causing predictable ventricular remodelling and progression to heart failure. Clin Exp Pharmacol Physiol 42:33-40
Ping, Peipei; Gustafsson, Åsa B; Bers, Don M et al. (2015) Harnessing the Power of Integrated Mitochondrial Biology and Physiology: A Special Report on the NHLBI Mitochondria in Heart Diseases Initiative. Circ Res 117:234-8
Gong, Guohua; Song, Moshi; Csordas, Gyorgy et al. (2015) Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 350:aad2459

Showing the most recent 10 out of 63 publications