Abstract

Moderate alcohol intake has been shown to reduce coronary heart disease in numerous epidemiological studies. We propose that moderate ethanol consumption causes cardioprotection by increasing epsilonPKC protein expression in cardiac myocytes. To test this hypothesis, we will use multiple approaches to examine resistance of ischemia-reperfusion injury in hearts receiving ethanol in drinking water for at least 12 weeks. In addition, we will investigate the requirement for epsilonPKC function in ethanol-mediated cardioprotection using techniques routinely available in our laboratory with the following specific aims:
Aim A: Examine epsilonPKC enzyme activity and subcellular localization in hearts from ethanol-fed mice and age-matched controls. We plan to identify ethanol-induced changes in epsilonPKC kinase function and distribution among subcellular compartments in adult cardiac myocytes and in left ventricular tissue from ethanol-fed mice and age-matched controls using immunofluorescence staining, confocal microscopy, immunoprecipitation, and western blotting techniques.
Aim B: Determine whether acute isozyme-selective inhibition of epsilonPKC function blocks sustained ethanol-mediated cardioprotection. We will examine the effects of peptide modulators of PKC isozyme translocation and function introduced acutely into cultured adult cardiac myocytes or intact hearts on chronic ethanol-induced resistance to ischemia-reperfusion injury and PKC interactions with other signaling proteins.
Aim C: Investigate the effects of moderate alcohol consumption on cardiac function and resistance to ischemia-reperfusion injury in epsilonPKC knockout mice. We will use adult cardiac myocytes and intact hearts to determine whether cardioprotection develops in epsilonPKC knockout mice in response to ethanol feeding and whether ethanol-mediated regulation of related signaling pathways is altered by the absence of epsilonPKC. One overall goal of this research is to understand the cellular mechanisms of cardioprotection mediated by chronic moderate alcohol consumption. A second goal is to identify therapeutic targets for sustained protection against coronary heart disease that do not require ethanol ingestion because of concerns regarding alcohol abuse and potential adverse effects on other organ systems in humans.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011135-08
Application #
6732025
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Brown, Ricardo A
Project Start
1996-09-30
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
8
Fiscal Year
2004
Total Cost
$330,000
Indirect Cost

  Institution

Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121

  Publications

Collins, Michael A; Neafsey, Edward J; Mukamal, Kenneth J et al. (2009) Alcohol in moderation, cardioprotection, and neuroprotection: epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res 33:206-19
Zhang, Jianqing; Honbo, Norman; Goetzl, Edward J et al. (2007) Signals from type 1 sphingosine 1-phosphate receptors enhance adult mouse cardiac myocyte survival during hypoxia. Am J Physiol Heart Circ Physiol 293:H3150-8
Zhou, Hui-Zhong; Swanson, Raymond A; Simonis, Ursula et al. (2006) Poly(ADP-ribose) polymerase-1 hyperactivation and impairment of mitochondrial respiratory chain complex I function in reperfused mouse hearts. Am J Physiol Heart Circ Physiol 291:H714-23
Gray, Mary O; Zhou, Hui-Zhong; Schafhalter-Zoppoth, Ingeborg et al. (2004) Preservation of base-line hemodynamic function and loss of inducible cardioprotection in adult mice lacking protein kinase C epsilon. J Biol Chem 279:3596-604
Zhou, Hui-Zhong; Karliner, Joel S; Gray, Mary O (2002) Moderate alcohol consumption induces sustained cardiac protection by activating PKC-epsilon and Akt. Am J Physiol Heart Circ Physiol 283:H165-74
Maklashina, Elena; Sher, Yelizaveta; Zhou, Hui-Zhong et al. (2002) Effect of anoxia/reperfusion on the reversible active/de-active transition of NADH-ubiquinone oxidoreductase (complex I) in rat heart. Biochim Biophys Acta 1556:6-12
Zhu, P; Zhou, H Z; Gray, M O (2000) Chronic ethanol-induced myocardial protection requires activation of mitochondrial K(ATP) channels. J Mol Cell Cardiol 32:2091-5
Figueredo, V M; Diamond, I; Zhou, H Z et al. (1999) Chronic dipyridamole therapy produces sustained protection against cardiac ischemia-reperfusion injury. Am J Physiol 277:H2091-7
Halow, J M; Figueredo, V M; Shames, D M et al. (1999) Role of slowed Ca(2+) transient decline in slowed relaxation during myocardial ischemia. J Mol Cell Cardiol 31:1739-48
Miyamae, M; Rodriguez, M M; Camacho, S A et al. (1998) Activation of epsilon protein kinase C correlates with a cardioprotective effect of regular ethanol consumption. Proc Natl Acad Sci U S A 95:8262-7

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