Abstract P2021: Targeting Of Cdc42-interacting Protein 4 -calcineurin Signaling Complexes Is Cardioprotective During Ischemia/Reperfusion Injury

Abstract

Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. Heart failure due to MI results from both acute ischemic/reperfusion (I/R) injury and subsequent post-MI pathological cardiac remodeling. The Ca 2+ /calmodulin-dependent protein phosphatase calcineurin (CaN), which promotes pathological cardiac remodeling, has been problematic as a therapeutic target due to its role in cardioprotection, including during I/R injury. We have shown that a select pool of CaNAβ holoenzyme is localized within the cardiomyocyte by scaffold protein Cdc42-Interacting Protein 4 (CIP4/TRIP10), such that the CaNAβ N-terminal polyproline (PP) domain binds directly to the CIP4 C-terminal SH3 domain. Pathological cardiac remodeling induced by pressure overload was inhibited by CIP4 gene knock-out and by inhibition of CaNAβ binding to CIP4 using an adeno-associated virus (AAV) vector that expresses the CaNAβ PP peptide. We now consider whether targeting CIP4-CaNAβ signalosomes is beneficial in ischemic cardiomyopathy. To test the relevance of CIP4 in vivo to ischemic reperfusion (IR) injury, tamoxifen-inducible, cardiac-specific CIP4 knock-out (CIP4 CKO), control Tg(Myh6-cre/Esr1*), and control CIP4 f/f mice were subjected to 30 minutes of ischemia by transient left anterior descending coronary artery (LAD) ligation. Cardiac function and structure were evaluated 24 hours after reperfusion by echocardiography and histology. Left ventricular ejection fraction was significantly preserved, while infarct size was significantly decreased by CIP4 CKO when compared to the two control cohorts. Separate mice subjected to permanent LAD ligation showed that CIP4 CKO resulted in long-term preservation of cardiac function. To disrupt CaNAβ-CIP4 complexes in vivo, AAV has been used to express the CaNAβ PP domain peptide. In contrast to the expression of the VIVIT pan-CaN inhibitory peptide, CaNAβ PP peptide expression did not worsen I/R injury. Together, these results suggest that PP-anchored CaNAβ does not contribute to cardioprotection. Targeting CIP4 signalosomes may constitute a novel strategy for inhibiting I/R injury and preventing the development of heart failure in response to diverse forms of cardiovascular disease.