Heart failure remains a major public health problem and effective therapies are limited. Recent work by our group and others has suggested that caveolins, structured proteins involved in numerous cell functions including cell growth and hypertrophy may be novel targets for heart failure therapy. Work in our laboratory has shown that the muscle specific subtype of caveolin, Caveolin-3 (Cav-3) is a critical molecule in protecting the myocardium from myocardial stress. In addition, we have shown recently that cardiac myocyte-specific overexpression of Cav-3 (Cav-3 OE) produces increased survival and enhanced cardiac function in the transverse aortic constriction (TAC) model of heart failure. The precise mechanisms involved in the attenuation of heart failure by Cav-3 remain to be elucidated and are the focus of the current unit. Caveolae are a specialized subset of lipid rafts enriched in cholesterol, sphingolipids and caveolins. Caveolae and caveolins are now known to produce critical interactions between the sarcolemmal membrane and cytoplasmic organelles including mitochondria in cardiac myocytes. Mitochondrial dysfunction is a critical element of heart failure progression. Caveolins have been found in mitochondrial membranes, however the role of caveolins and their effects on mitochondrial function have not been investigated. We have developed exciting novel preliminary data that show 1) an intimate relationship between caveolae and mitochondria that is increased by myocardial stress, 2) the presence of Cav-3 within the inner mitochondrial membrane of mitochondria, 3) the overexpression of Cav-3 in cardiac myocytes increases Cav-3 within mitochondria and improves mitochondrial function, and 4) targeting Cav-3 specifically to mitochondria produces improved mitochondrial function and reduced oxidative stress in cardiac myocj1:es. Based on these compelling preliminary data we will test the hypothesis that Cav-3 can alter the progression of heart failure via modulation of mitochondrial function. We will use state of the art molecular biology, imaging technology, electron paramagnetic resonance technology and physiological techniques in cardiac myocytes and clinically relevant models of heart failure to focus on mechanism and produce important preclinical data to support the potential use of caveolins as novel therapeutics for heart failure patients.

Public Health Relevance

Heart failure is a major cause of death and disability in the United States. This project is designed to test the hypothesis that caveolins can potentially alter the progression of heart failure via modulation of mitochondrial function. The work has potential to lead to novel therapies for heart failure patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL066941-11A1
Application #
8647151
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-09-26
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$403,867
Indirect Cost
$113,733
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Pandey, Amit K; Penny, William F; Bhargava, Valmik et al. (2016) Clinical Evaluation of Heart Failure: Agreement among Tests. PLoS One 11:e0161536
Gao, Mei Hua; Giamouridis, Dimosthenis; Lai, N Chin et al. (2016) One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance. JCI Insight 1:e88322
Schilling, Jan M; Horikawa, Yousuke T; Zemljic-Harpf, Alice E et al. (2016) Electrophysiology and metabolism of caveolin-3-overexpressing mice. Basic Res Cardiol 111:28
Cividini, Federico; Scott, Brian T; Dai, Anzhi et al. (2016) O-GlcNAcylation of 8-Oxoguanine DNA Glycosylase (Ogg1) Impairs Oxidative Mitochondrial DNA Lesion Repair in Diabetic Hearts. J Biol Chem 291:26515-26528
See Hoe, Louise E; Schilling, Jan M; Busija, Anna R et al. (2016) Chronic β1-adrenoceptor blockade impairs ischaemic tolerance and preconditioning in murine myocardium. Eur J Pharmacol 789:1-7
Tran, Chinh; Stary, Creed M; Schilling, Jan M et al. (2015) Role of caveolin-3 in lymphocyte activation. Life Sci 121:35-9
Lai, N Chin; Gao, Mei Hua; Giamouridis, Dimosthenis et al. (2015) Intravenous AAV8 Encoding Urocortin-2 Increases Function of the Failing Heart in Mice. Hum Gene Ther 26:347-56
Schilling, Jan M; Roth, David M; Patel, Hemal H (2015) Caveolins in cardioprotection - translatability and mechanisms. Br J Pharmacol 172:2114-25
Sun, Junhui; Nguyen, Tiffany; Aponte, Angel M et al. (2015) Ischaemic preconditioning preferentially increases protein S-nitrosylation in subsarcolemmal mitochondria. Cardiovasc Res 106:227-36
Markandeya, Yogananda S; Phelan, Laura J; Woon, Marites T et al. (2015) Caveolin-3 Overexpression Attenuates Cardiac Hypertrophy via Inhibition of T-type Ca2+ Current Modulated by Protein Kinase Cα in Cardiomyocytes. J Biol Chem 290:22085-100

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