Constitutive HSC70 in Ischemia/Reperfusion Protection

Reactive oxygen species (ROS) are excessively formed during the early stage of reoxygenation of the ischemic heart. These oxygen byproducts may initiate a cascade of damages in membrane integrity, calcium sequestration, and energy homeostasis. The inability of the myocardium to defend itself against the toxic effect of ROS leads to ischemia/reperfusion (I/R) injury. Therefore, modulation of cellular oxidative defenses has a clinical significance with respect to the preservation of ischemic tissues during reperfusion. There exists in cells a unique set of beneficial proteins, the heat shock proteins (hsps). The inducible 70-kD hsp (hsp70) has been demonstrated to have a cardioprotective effect during I/R episodes. Using a simple myocardial model in vitro, H9c2 rat heart-derived myoblasts, we recently found that its constitutive counterpart (hsc70) is also cytoprotective against ROS toxicity. Furthermore, hsc70 has a lower threshold for induction, and thus is suitable for pharmacological manipulation. Our preliminary data show that hsc70 overexpression in cells attenuates lipid peroxidation induced by hydrogen peroxide (H2O2), and that a simultaneous increase in hsc70 and hsp70 confers a greater thermal protection than individual protein alone. Based upon our data, we postulate a hypothesis that hsc70 alone can protect against oxidative and I/R injury, and by its interaction with hsp70, this protein delivers a marked oxidative or I/R resistance. To vigorously test this hypothesis, both H9c2 cell and animal models will be employed. We will examine (1) whether lipid protection is a contributing factor to the antioxidative effect of hsc70; (2) whether hsc70 overexpression alone confers upon the heart and skeletal muscle I/R protection; and (3) the potential interaction between hsc70/hsp70 to improve survival during oxidative or I/R challenge. This study should improve our understanding of the protective potency and mechanism(s) of hsc70, and moreover it will prove feasibility for using hsc70 protein in the treatment of I/R injury.

Project ID:PC9706-0161
External Project ID:NSC95-2320-B182-028-MY3