With the aging of the United States population, it is estimated that the elderly (>65 years of age) will increase from 13-14% to 25% by 2035. If this trend continues, >50% of the United States population and >2 billion people worldwide will be "aged" in the next 50 years. Aged individuals face formidable challenges to their health, as aging is associated with a myriad of diseases. Cardiovascular disease is the leading cause of morbidity and mortality in the United States with >50% of mortality attributed to coronary artery disease and >80% of these deaths occurring in those age 65 and older. Aged hearts are more sensitive than young hearts to ischemic insults. Several theories have been proposed to account for this aging deficit. These theories either invoke a genetic, a biochemical, a catabolic, or a physiologic component. Though the mechanisms that underlie an age-related deficit in ischemic tolerance are not clear, they likely involve abnormalities in cellular signaling and mitochondria that are a combined result of genetic, biochemical, catabolic, and physiologic deficiencies. Therapeutics that target these mechanisms have potential to rescue the aged myocardium. Our preliminary studies show that caveolin is localized to motochondria and can modulate mitochondrial function/dynamics. We propose the following hypotheses: 1) targeted cellular trafficking of caveolin to key regulatory junctions (i.e., sarcolemmal membrane and mitochondria) is a critical response to ischemic stress;2) cellular trafficking of caveolin to mitochondria is disrupted in the aged myocardium due to loss of membrane-localized caveolin;3) restoration of caveolin in distinct cellular compartments via membrane and mitochondrial targeting in aged animals may provide a means to restore tolerance to myocardial ischemia. The following specific objectives will be addressed:
Specific Aim 1 : Determine if loss of membrane-localized caveolin leads to loss of caveolin expression/caveolae formation thus limiting trafficking of caveolin to mitochondria and if membrane-targeted expression of caveolin in aged myocardium restores trafficking to mitochondria.
Specific Aim 2 : Determine if aging results in reduced mitochondria-localized caveolin to alter mitochondrial function (i.e., reactive oxygen species generation and regulation of mPTP) and mitochondrial dynamics (i.e., fusion-fission to regulate mitochondrial turnover and mitophagy) and if mitochondria-targeted caveolin expression is necessary and sufficient to restore mitochondrial function/dynamics.
Specific Aim 3 : Determine if targeted expression of caveolin in membrane or mitochondria is necessary and sufficient to restore ischemic tolerance in aged hearts.

Public Health Relevance

The current proposal aims to unravel the molecular mechanism of cardiac injury and utilize re- expression strategies to restore ischemic tolerance in the aged heart. We will assess the role of caveolins in keeping the heart young. The work described in this proposal focuses on elucidating mechanisms to support the use of caveolin proteins as novel therapeutic targets for patients at risk of myocardial ischemia and heart attacks.)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107200-02
Application #
8280244
Study Section
Special Emphasis Panel (ZRG1-CVRS-B (02))
Program Officer
Schwartz, Lisa
Project Start
2011-06-15
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$539,148
Indirect Cost
$172,877
Name
University of California San Diego
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
See Hoe, Louise E; Schilling, Jan M; Tarbit, Emiri et al. (2014) Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection. Am J Physiol Heart Circ Physiol 307:H895-903
Pfeiffer, E R; Wright, A T; Edwards, A G et al. (2014) Caveolae in ventricular myocytes are required for stretch-dependent conduction slowing. J Mol Cell Cardiol 76:265-74
Wang, Jiawan; Schilling, Jan M; Niesman, Ingrid R et al. (2014) Cardioprotective trafficking of caveolin to mitochondria is Gi-protein dependent. Anesthesiology 121:538-48
Head, Brian P; Patel, Hemal H; Insel, Paul A (2014) Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim Biophys Acta 1838:532-45
Peart, Jason N; Pepe, Salvatore; Reichelt, Melissa E et al. (2014) Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium. Exp Gerontol 50:72-81
Yang, Kai-Chien; Rutledge, Cody A; Mao, Mao et al. (2014) Caveolin-1 modulates cardiac gap junction homeostasis and arrhythmogenecity by regulating cSrc tyrosine kinase. Circ Arrhythm Electrophysiol 7:701-10
Niesman, Ingrid R; Schilling, Jan M; Shapiro, Lee A et al. (2014) Traumatic brain injury enhances neuroinflammation and lesion volume in caveolin deficient mice. J Neuroinflammation 11:39
Horikawa, Yousuke T; Tsutsumi, Yasuo M; Patel, Hemal H et al. (2014) Signaling epicenters: the role of caveolae and caveolins in volatile anesthetic induced cardiac protection. Curr Pharm Des 20:5681-9
Patel, Hemal H; McDonough, Alicia A (2014) Of mice and men: modeling cardiovascular complexity in diabetes. Focus on "Mitochondrial inefficiencies and anoxic ATP hydrolysis capacities in diabetic rat heart". Am J Physiol Cell Physiol 307:C497-8
Panneerselvam, Mathivadhani; Ali, Sameh S; Finley, J Cameron et al. (2013) Epicatechin regulation of mitochondrial structure and function is opioid receptor dependent. Mol Nutr Food Res 57:1007-14

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