{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:58:47Z","timestamp":1784329127706,"version":"3.55.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,1,14]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Excitation-contraction (E-C) coupling processes become disrupted in heart failure (HF), resulting in abnormal Ca\n              <jats:sup>2+<\/jats:sup>\n              homeostasis, maladaptive structural and transcriptional remodeling, and cardiac dysfunction. Junctophilin-2 (JP2) is an essential component of the E-C coupling apparatus but becomes site-specifically cleaved by calpain, leading to disruption of E-C coupling, plasmalemmal transverse tubule degeneration, abnormal Ca\n              <jats:sup>2+<\/jats:sup>\n              homeostasis, and HF. However, it is not clear whether preventing site-specific calpain cleavage of JP2 is sufficient to protect the heart against stress-induced pathological cardiac remodeling in vivo.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Calpain-resistant JP2 knock-in mice (JP2\n              <jats:sup>CR<\/jats:sup>\n              ) were generated by deleting the primary JP2 calpain cleavage site. Stress-dependent JP2 cleavage was assessed through in vitro cleavage assays and in isolated cardiomyocytes treated with 1 \u03bcmol\/L isoproterenol by immunofluorescence. Cardiac outcomes were assessed in wild-type and JP2\n              <jats:sup>CR<\/jats:sup>\n              mice 5 weeks after transverse aortic constriction compared with sham surgery using echocardiography, histology, and RNA-sequencing methods. E-C coupling efficiency was measured by in situ confocal microscopy. E-C coupling proteins were evaluated by calpain assays and Western blotting. The effectiveness of adeno-associated virus gene therapy with JP2\n              <jats:sup>CR<\/jats:sup>\n              , JP2, or green fluorescent protein to slow HF progression was evaluated in mice with established cardiac dysfunction.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              JP2 proteolysis by calpain and in response to transverse aortic constriction and isoproterenol was blocked in JP2\n              <jats:sup>CR<\/jats:sup>\n              cardiomyocytes. JP2\n              <jats:sup>CR<\/jats:sup>\n              hearts are more resistant to pressure-overload stress, having significantly improved Ca\n              <jats:sup>2+<\/jats:sup>\n              homeostasis and transverse tubule organization with significantly attenuated cardiac dysfunction, hypertrophy, lung edema, fibrosis, and gene expression changes relative to wild-type mice. JP2\n              <jats:sup>CR<\/jats:sup>\n              preserves the integrity of calpain-sensitive E-C coupling\u2013related proteins, including ryanodine receptor 2, Ca\n              <jats:sub>V<\/jats:sub>\n              1.2, and sarcoplasmic reticulum calcium ATPase 2a, by attenuating transverse aortic constriction\u2013induced increases in calpain activity. Furthermore, JP2\n              <jats:sup>CR<\/jats:sup>\n              gene therapy after the onset of cardiac dysfunction was found to be effective at slowing the progression of HF and superior to wild-type JP2.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>The data presented here demonstrate that preserving JP2-dependent E-C coupling by prohibiting the site-specific calpain cleavage of JP2 offers multifaceted beneficial effects, conferring cardiac protection against stress-induced proteolysis, hypertrophy, and HF. Our data also indicate that specifically targeting the primary calpain cleavage site of JP2 by gene therapy approaches holds great therapeutic potential as a novel precision medicine for treating HF.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.124.069329","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T09:03:43Z","timestamp":1726650223000},"page":"171-187","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["Preventing Site-Specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-Induced Excitation-Contraction Uncoupling and Heart Failure Development"],"prefix":"10.1161","volume":"151","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7349-6153","authenticated-orcid":true,"given":"Jinxi","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center (J.W., B.C., Q.S., W.Z., G.Z. R.M.W., D.D.H., L.-S.S.), Carver College of Medicine, University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0402-7537","authenticated-orcid":true,"given":"Biyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center (J.W., B.C., Q.S., W.Z., G.Z. R.M.W., D.D.H., L.-S.S.), Carver College of Medicine, University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2634-9553","authenticated-orcid":true,"given":"Qian","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center (J.W., B.C., Q.S., W.Z., G.Z. R.M.W., D.D.H., L.-S.S.), Carver College of Medicine, University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5418-996X","authenticated-orcid":true,"given":"Grace","family":"Ciampa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology (G.C., L.-S.S.), Carver College of Medicine, University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5707-376X","authenticated-orcid":true,"given":"Weiyang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center (J.W., B.C., Q.S., W.Z., G.Z. R.M.W., D.D.H., L.-S.S.), Carver College of Medicine, University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangqin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center (J.W., B.C., Q.S., W.Z., G.Z. R.M.W., D.D.H., L.-S.S.), Carver College of Medicine, University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1307-2647","authenticated-orcid":true,"given":"Robert M.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center (J.W., B.C., Q.S., W.Z., G.Z. 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