Reactive oxygen species, such as superoxide, hydrogen peroxide, and hydroxyl radical, are formed excessively during the initial phase of reoxygenation of the ischemic heart. Increasing evidence suggests that these oxygen byproducts initiate a cascade of damage in membrane integrity, calcium sequestration, and energy homeostasis. The inability of the myocardium to defend itself against the toxic effect of the reactive oxygen species leads to reperfusion injury. Therefore, modulation of antioxidant defense mechanism has clinical significance with respect to the preservation of the myocardium during reperfusion.There exists in cells a universal adaptive response to thermal stress, which is termed the stress response. It has been reported that whole-body hyperthermia protects the isolated heart during ischemia-reperfusion. The applicant has studied heat-induced protection in H9c2 rat heart myocytes, a simple and manipulable model of the myocardium in vitro. The investigator has found that transient or chronic induction of the stress response in heart cells improved the survival to subsequent lethal doses of hydrogen peroxide. Also, she observed a positive correlation between oxidative resistance and induction of heat shock proteins or antioxidant enzymes. The overall objectives of this study are to examine the beneficial effect of continuous activation of the stress response on oxidative resistance, and the mechanism of the acquired oxidative protection. The applicant proposes to study these objectives: (1) To develop the conditions which allow continuous activation of the stress response by long-term conditioning of myocytes with mild hyperthermia or ethanol treatment. (2) To examine if eliciting the chronic stress response enhances myocardial resistance to reactive oxygen species, by measuring the changes in cell survival, plasma membrane structures, intracellular ATP and calcium homeostasis. (3) To test if suppression of the endogenous antioxidant enzyme activities or heat shock proteins results in an increased susceptibility to reactive oxygen species. (4) To study the other factors involved in the stress-induced protection by two- dimensional gel electrophoresis followed with the isolation of their cDNAs by the expression cloning strategy. This study should improve one's understanding of the protective nature of the stress response. Furthermore, identification of potential regulatory mechanisms or other defense mechanisms involved in stress response may lead to a new avenue of clinical management for reperfusion injury.
| Su, C Y; Chong, K Y; Chen, J et al. (1999) A physiologically relevant hyperthermia selectively activates constitutive hsp70 in H9c2 cardiac myoblasts and confers oxidative protection. J Mol Cell Cardiol 31:845-55 |
| Su, C Y; Chong, K Y; Edelstein, K et al. (1999) Constitutive hsp70 attenuates hydrogen peroxide-induced membrane lipid peroxidation. Biochem Biophys Res Commun 265:279-84 |
| Chong, K Y; Lai, C C; Lille, S et al. (1998) Stable overexpression of the constitutive form of heat shock protein 70 confers oxidative protection. J Mol Cell Cardiol 30:599-608 |
| Su, C Y; Chong, K Y; Owen, O E et al. (1998) Constitutive and inducible hsp70s are involved in oxidative resistance evoked by heat shock or ethanol. J Mol Cell Cardiol 30:587-98 |
