Abstract 3353: Novel Pharmacologic Induction of and Protection with the Endogenous Cytoprotective Myocardial Heat Shock Protein 70i by the Anti-Ulcer Agent, GGA, is Associated with Improved Ventricular Function after Global Ischemia and a Reduction in Troponin T Release.
Introduction: Endogenous heat shock proteins (HSP) especially HSP70i, have been shown to be cardioprotective against ischemia-reperfusion. We therefore tested the hypothesis that IV geranylgeranylacetone (GGA), a novel agent used to treat human peptic ulcer disease and HSP70i inducer, would increase myocardial HSP70i, resulting in improved myocardial function after surgical I-R.
Methods and Results: New Zealand adult rabbits (N=5 each) received IV 50 mg/kg GGA 24 hrs prior to intervention, which consisted of Langendorff perfusion, 30 min of global normothermic cardioplegic arrest, followed by reperfusion. Peak LV developed pressure (DevP) and myocardial release of troponin T (TnT) were measured, expressed as the summed area under the curve. HSP70 was quantified by western blot. Differences between GGA+ and GGA- groups pre- and post-ischemia were analyzed by unpaired t-tests. GGA pretreatment did not alter constitutive HSPBB70 but significantly induced HSP70i. GGA pretreatment resulted in marked improvement in peak LV DevP and the LV pressure-volume area at all time points. In the GGA- group, TnT increased immediately at one minute reperfusion and throughout the duration of reperfusion, whereas in GGA+ hearts, TnT also increased at one min of reperfusion but then continued to decrease throughout the remainder of reperfusion. Overall TnT release throughout reperfusion was 7 fold greater in GGA- vs GGA+ hearts (1.54 +/− 0.2 vs 0.24 +/−0.1 ng/ml; p=0.019).
Conclusion: GGA induced myocardial HSP70i and improved recovery of left ventricular function following global normothermic surgical ischemia. Importantly, GGA caused a marked decrease in TnT release during reperfusion, which is also consistent with reduced myocardial damage. This is the first demonstration that GGA can be administered intravenously to effectively and non-toxically induce myocardial HSP70i and reduce myocardial damage. Further study of the effects and mechanisms involved is indicated.