Abstract 86: Compromised Sarcolemmal Membrane Repair Contributes to the Progression of Heart Failure

Abstract

A conserved sarcolemmal membrane repair response exist to counteract membrane damage and restore membrane barrier function in order to maintain normal cellular homeostasis. This response can involve various mechanisms including activation of signaling pathways that trigger vesicular trafficking to the site of injury followed by vesicular fusion with the damaged portion of the membrane to patch the membrane disruption. Previous studies indicate that compromised repair capacity can exacerbate cardiac injury while increasing membrane repair capacity can reduce cardiac pathology. In our studies, membrane repair assays on cardiac and non-cardiac cell lines demonstrated that this process is dependent on activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling axis through the downstream target Akt1. One mechanism found to increase membrane repair following PI3K/Akt1 activation is elevated exocytotic and endocytotic activity. Further studies indicate that the PI3K/Akt1 pathway is relevant to membrane repair in native hearts. Thick slices of myocardium from explanted human and mouse hearts were probed using multi-photon microscopy to determine the membrane repair capacity. These studies indicate decreased repair capacity in failing human myocardium as well as in mouse hearts following transaortic constriction (TAC). This membrane repair response requires PI3K/Akt1 signaling as genetically modified mice null for Akt1 show compromised sarcolemmal membrane repair. Additionally, PI3K or Akt1 inhibition prevents membrane resealing in non-failing human or mouse myocardium. The compromised membrane repair observed in failing human myocardium can be ameliorated by PI3K or Akt1 agonists. Treatment of TAC mice with multiple therapeutic compounds known to increase membrane repair capacity can minimize the development of structural and functional hallmarks of heart failure. Our results indicate that failing cardiomyocytes exhibit compromised membrane repair and that increased PI3K/Akt1 signaling can increase repair capacity thereby demonstrating potential as a heart failure treatment.