Abstract

Moderate ethanol use is associated with protection against fatal coronary events. However, in addition to a decreased incidence of coronary events, improved recovery following an event may be important in ethanol's prevention of fatal outcomes due to coronary artery disease. Attenuation of post-ischemic reperfusion injury is a mechanism by which myocardial recovery, and thereby survival, may be improved following a coronary event. Pilot studies suggest that moderate ethanol use attenuates reperfusion injury through activation of adenosine receptors in guinea pig hearts. Hypotheses I and II will be tested addressing questions #1-5: I. Moderate ethanol use protects against myocardial post-ischemic reperfusion injury. 1. Does moderate ethanol use improve functional and metabolic recovery during reperfusion? 2. Following post-ischemic reperfusion, does moderate ethanol use decrease the amount of myocyte necrosis in perfused hearts and infarct size in vivo? 3. Does moderate ethanol use protect against Ca2+ overload during post-ischemic reperfusion? II. The protective effect of moderate ethanol use against reperfusion injury is the result of adenosine receptor mediated protein kinase C translocation. 4. Is ethanol's protective effect abolished by adenosine A1, A2, and/or A3 receptor antagonists? 5. Are delta and epsilon PKC translocated in myocytes from ethanol exposed hearts versus controls? Isolated guinea pig hearts (fed 10% ethanol for 6 weeks) will undergo ischemia - reperfusion. Energy depletion and recovery will be assessed with 31P-MRS; myocyte necrosis by creatine kinase release; cytosolic CA2+ by indo-1 fluorescence; and PKC isozyme translocation by immunofluorescence localization and western blot analysis. In vivo, infarct size will be measured after occlusion-reperfusion of the left coronary artery. The ultimate goals of this research are 1) to establish the mechanisms underlying the positive association between moderate alcohol use and cardiac health and 2) aid in the development of therapeutic interventions which mimic this effect in patients at risk for fatal coronary events who require elective or emergent reperfusion.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011135-02
Application #
2516843
Study Section
Special Emphasis Panel (SRCA (59))
Project Start
1996-09-30
Project End
2001-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  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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