Inhibition of Cdc42-Interacting Protein 4-calcineurin complexes attenuate pathological cardiac remodeling after myocardial infarction

Abstract

Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. Heart failure due to MI results from both acute ischemia/reperfusion (I/R) injury and subsequent post-MI pathological cardiac remodeling. The Ca2+/calmodulin-dependent protein phosphatase calcineurin (CaN) is a critical mediator of pathological cardiac remodeling. Along with its role in the immune system, the pro-survival function of CaN complicates the targeting of the phosphatase in heart disease. CaNAβ is a CaN isoform uniquely associated with pathological cardiac hypertrophy. We have discovered that pools of cardiomyocyte CaNAβ are anchored via the unique CaNAβ N-terminal polyproline domain (PP) to scaffold proteins such as CIP4 (Cdc42 interacting protein 4, TRIP10), creating discrete Ca2+-CaN signaling compartments. 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. It remains unknown whether PP-anchored CaNAβ also participates in CaN-dependent cardioprotective signaling in I/R injury. We now consider whether CIP4-CaNAβ signalosomes are required for myocyte survival in ischemic cardiomyopathy. To test the relevance of CIP4 to ischemic reperfusion (IR) injury, tamoxifen-inducible, cardiac-specific CIP4 knock-out (CIP4 CKO), control Tg(Myh6-cre/Esr1*), and control CIP4f/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 I/R 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, the CaNAβ PP domain peptide was expressed again using AAV. In contrast to the expression of the VIVIT pan-CaN inhibitory peptide, CaNAβ PP peptide expression did not exacerbate I/R injury and in fact preserved cardiac function immediately after infarction. Moreover, VIVIT peptide expression worsened, while CaNAβ PP peptide expression improved cardiac function long term after induction of MI by permanent LAD ligation. Together, these results suggest that CIP4-CaNAβ signalosomes do not contribute to cardioprotection, while inducing pathological cardiac remodeling. These results suggest that targeting of CIP4-CaNAβ signalosomes constitute a novel strategy for inhibiting I/R injury and preventing the development of heart failure in response to diverse forms of cardiovascular disease. This work was supported by National Institutes of Health R01 grants HL126950 and HL158052. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.