Abstract 129: Transient Activation of AMPK Prior to Cardiac Pressure Overload Alleviates Fibrotic Accumulation and Functional Decline

Abstract

The multiple adaptive pathways activated during cardiac stress must communicate with each other for an efficient response; however, little is known about the molecular mechanisms underlying this coordination. During left ventricular pressure overload induced by transverse aortic constriction (TAC), an increase in metabolic flux to meet the ATP demand is the first molecular change observed in the heart. Following initial metabolic changes, there is genetic remodeling of the metabolic machinery and activation of other acute and long-term adaptive pathways to control hypertrophy, fibrosis, and contraction. In order to better understand how the early metabolic changes affect the activation and magnitude of the downstream pathways, we treated mice with the AMPK activator AICAR for 6 days prior to TAC and then monitored effects on the cardiac stress response for 4 weeks. This treatment was performed in both WT mice and in mice lacking cardiomyocyte expression of steroid receptor coactivator-2 (SRC-2 CKO), a model we have previously shown to be genetically similar to a stressed mouse and whose function declines rapidly in response to TAC. Interestingly, we found that this small transient treatment with AICAR is sufficient to blunt hypertrophy (20% reduction) and fibrotic accumulation (56% reduction) and prevent left ventricular dilation and pleural edema. Furthermore, AICAR treatment in the SRC-2 CKO animals was able to rescue the functional decline observed post-TAC. We are currently investigating the molecular pathways underlying these changes. Our results strongly suggest that there are very early events during cardiac stress that are key determinants in the ability of the heart to adapt and maintain function under stress, even in late stages post-stress. Disruption of these determinants can lead to rapid failure, whereas their promotion could hold a key for therapeutic intervention.