{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:19:22Z","timestamp":1783556362842,"version":"3.55.0"},"reference-count":62,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">CaN (calcineurin) promotes pathological cardiac remodeling but also cardioprotection in ischemia\u2013reperfusion injury. CaN inhibitors are also immunosuppressants. This pleiotropy complicates targeting calcineurin in cardiovascular disease. CIP4\/TRIP10 (Cdc42\u2010interacting protein 4) is a scaffold protein that binds the CaNA\u03b2 (calcineurin A\u03b2) N\u2010terminal polyproline domain and organizes a calcium and CaNA\u03b22 signaling compartment independent of contractile calcium. We showed that CIP4\u2010CaNA\u03b22 signalosomes promote pathological cardiac hypertrophy induced by pressure overload. It is unknown whether CIP4\u2010CaNA\u03b22 signalosomes contribute to cardioprotection and remodeling in ischemic disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">CIP4 conditional knockout mice were studied following ischemia\u2013reperfusion and permanent left coronary artery ligation that induce myocardial infarction. C57BL\/6NJ mice were transduced with cardiotropic adeno\u2010associated virus expressing a CaNA\u03b22 small hairpin RNA to inhibit CaNA\u03b22 expression, a VIVIT peptide to inhibit CaN\u2010NFAT (nuclear factor of activated T cells) signaling, or a CaNA\u03b2 polyproline peptide to block CIP4\u2010CaNA\u03b22 binding and similarly studied by ischemia\u2013reperfusion injury and left coronary artery ligation. CaNA\u03b2 polyproline\u2010dependent signaling was also studied in T cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">CIP4 conditional knockout and cardiomyocyte\u2010specific CaNA\u03b2 polyproline peptide expression improved cardiac function after ischemia\u2013reperfusion injury and decreased infarct size and improved cardiac function after permanent left coronary artery ligation. In contrast, cardiomyocyte\u2010specific CaNA\u03b22 depletion and VIVIT expression worsened outcome after myocardial infarction. The polyproline peptide had no effect on T\u2010cell activation and cytokine expression in\u00a0vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">CIP4\u2010CaNA\u03b22 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.044692","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T10:46:56Z","timestamp":1765968416000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting of Cdc42\u2010Interacting Protein 4\u2010Calcineurin Signalosomes Improves Cardiac Structure and Function After Myocardial Infarction"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6317-2016","authenticated-orcid":false,"given":"Anne\u2010Maj","family":"Samuelsson","sequence":"first","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University","place":["Palo Alto, 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