ArticleJournal of the American Heart Association2026
Targeting of Cdc42-Interacting Protein 4-Calcineurin Signalosomes Improves Cardiac Structure and Function After Myocardial Infarction.
Article in Journal of the American Heart Association, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Tacrolimus inhibits CVB3-targeted regulation of TFEB by PPP3/calcineurin.Frontiers in cellular and infection microbiology · 2026Article
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Abstract
backgroundCaN (calcineurin) promotes pathological cardiac remodeling but also cardioprotection in ischemia-reperfusion injury. CaN inhibitors are also immunosuppressants. This pleiotropy complicates targeting calcineurin in cardiovascular disease. CIP4/TRIP10 (Cdc42-interacting protein 4) is a scaffold protein that binds the CaNAβ (calcineurin Aβ) N-terminal polyproline domain and organizes a calcium and CaNAβ2 signaling compartment independent of contractile calcium. We showed that CIP4-CaNAβ2 signalosomes promote pathological cardiac hypertrophy induced by pressure overload. It is unknown whether CIP4-CaNAβ2 signalosomes contribute to cardioprotection and remodeling in ischemic disease.
methodsCIP4 conditional knockout mice were studied following ischemia-reperfusion and permanent left coronary artery ligation that induce myocardial infarction. C57BL/6NJ mice were transduced with cardiotropic adeno-associated virus expressing a CaNAβ2 small hairpin RNA to inhibit CaNAβ2 expression, a VIVIT peptide to inhibit CaN-NFAT (nuclear factor of activated T cells) signaling, or a CaNAβ polyproline peptide to block CIP4-CaNAβ2 binding and similarly studied by ischemia-reperfusion injury and left coronary artery ligation. CaNAβ polyproline-dependent signaling was also studied in T cells.
resultsCIP4 conditional knockout and cardiomyocyte-specific CaNAβ polyproline peptide expression improved cardiac function after ischemia-reperfusion injury and decreased infarct size and improved cardiac function after permanent left coronary artery ligation. In contrast, cardiomyocyte-specific CaNAβ2 depletion and VIVIT expression worsened outcome after myocardial infarction. The polyproline peptide had no effect on T-cell activation and cytokine expression in vitro.
conclusionsCIP4-CaNAβ2 signalosomes promote adverse cardiac remodeling and are not cardioprotective. Proof of concept is provided for the treatment of ischemic cardiomyopathy by a polyproline peptide gene therapy. Targeting these complexes may be beneficial in cardiovascular diseases, including ischemic cardiomyopathy and acute myocardial infarction.
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