Abstract 1401: The Role of Chronic PPARα Activation During Ischemia and Reperfusion Injury in the Female Rat Heart
Introduction: The mechanism(s) which underlie estrogen-related benefits to ischemic tolerance are poorly understood.
Purpose: To determine the singular and combined effects of chronic peroxisome proliferator-activated receptor-α (PPARα) activation and estrogen deficiency on ischemia and reperfusion (I/R) injury in the female heart.
Methods: Adult ovary intact (4 months, n =18) and ovariectomized (OVX, n =17) female Sprague-Dawley rats were subjected to 4 days of the 0.1% PPARα agonist WY 14643 (WY), or fed control chow. Hearts were then subjected to 47 min of global I followed by 30 min R. Functional recovery and mRNA levels for PPARα, PPARβ and associated target genes through real-time PCR were assessed.
Results: Chronic PPARα activation via WY improved percent recovery of left ventricular developed pressure following I in hearts isolated from OVX rats as revealed by a significant OVX X drug interaction (p <0.0001). End diastolic pressure (EDP) was significantly greater throughout the reperfusion period in OVX control fed when compared to ovary-intact and fed groups (p <0.0001). In contrast, treatment of OVX animals with WY attenuated the EDP response during reperfusion. I/R decreased PPARα mRNA levels relative to baseline in all groups (p <0.001). Carnitine palmitoyltransferase I (CPT-1) and pyruvate dehydrogenase kinase 4 (PDK4) mRNA levels were increased in the WY fed animals, independent of estrogen status (p <0.0001). WY increased medium chain acyl CoA dehydrogenase (MCAD) levels in intact but not OVX WY-fed animals. PPARα nuclear protein levels were also greater in the OVX animals fed with WY vs control (p <0.05).
Conclusion: Taken together, our data suggest that chronic activation of PPARα may be beneficial to the female heart in the estrogen-deficient but not estrogen-sufficient state. The mechanism of this cardioprotection is likely due, in part, to altered myocardial substrate utilization during I/R.