{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T06:02:09Z","timestamp":1791180129990,"version":"4.1.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2009,7,17]]},"abstract":"<jats:p>\n            Protein kinase (PK)C\u03b1, PKC\u03b2, and PKC\u03b3 comprise the conventional PKC isoform subfamily, which is thought to regulate cardiac disease responsiveness. Indeed, mice lacking the gene for\n            <jats:italic>PKC<\/jats:italic>\n            \u03b1 show enhanced cardiac contractility and reduced susceptibility to heart failure. Recent data also suggest that inhibition of conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 enhances heart function and antagonizes failure, although the isoform responsible for these effects is unknown. Here, we investigated mice lacking\n            <jats:italic>PKC<\/jats:italic>\n            \u03b1,\n            <jats:italic>PKC<\/jats:italic>\n            \u03b2, and\n            <jats:italic>PKC<\/jats:italic>\n            \u03b3 for effects on cardiac contractility and heart failure susceptibility.\n            <jats:italic>PKC<\/jats:italic>\n            \u03b1\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice, but not\n            <jats:italic>PKC<\/jats:italic>\n            \u03b2\u03b3\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice, showed increased cardiac contractility, myocyte cellular contractility, Ca\n            <jats:sup>2+<\/jats:sup>\n            transients, and sarcoplasmic reticulum Ca\n            <jats:sup>2+<\/jats:sup>\n            load.\n            <jats:italic>PKC\u03b1<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice were less susceptible to heart failure following long-term pressure-overload stimulation or 4 weeks after myocardial infarction injury, whereas\n            <jats:italic>PKC<\/jats:italic>\n            \u03b2\u03b3\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice showed more severe failure. Infusion of ruboxistaurin (LY333531), an orally available PKC\u03b1\/\u03b2\/\u03b3 inhibitor, increased cardiac contractility in wild-type and\n            <jats:italic>PKC<\/jats:italic>\n            \u03b2\u03b3\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice, but not in\n            <jats:italic>PKC<\/jats:italic>\n            \u03b1\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice. More importantly, ruboxistaurin prevented death in wild-type mice throughout 10 weeks of pressure-overload stimulation, reduced ventricular dilation, enhanced ventricular performance, reduced fibrosis, and reduced pulmonary edema comparable to or better than metoprolol treatment. Ruboxistaurin was also administered to\n            <jats:italic>PKC<\/jats:italic>\n            \u03b2\u03b3\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice subjected to pressure overload, resulting in less death and heart failure, implicating PKC\u03b1 as the primary target of this drug in mitigating heart disease. As an aside,\n            <jats:italic>PKC<\/jats:italic>\n            \u03b1\u03b2\u03b3 triple-null mice showed no defect in cardiac hypertrophy following pressure-overload stimulation. In conclusion, PKC\u03b1 functions distinctly from PKC\u03b2 and PKC\u03b3 in regulating cardiac contractility and heart failure, and broad-acting PKC inhibitors such as ruboxistaurin could represent a novel therapeutic approach in treating human heart failure.\n          <\/jats:p>","DOI":"10.1161\/circresaha.109.195313","type":"journal-article","created":{"date-parts":[[2009,6,26]],"date-time":"2009-06-26T01:55:16Z","timestamp":1245981316000},"page":"194-200","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":137,"title":["Protein Kinase C\u03b1, but Not PKC\u03b2 or PKC\u03b3, Regulates Contractility and Heart Failure Susceptibility"],"prefix":"10.1161","volume":"105","author":[{"given":"Qinghang","family":"Liu","sequence":"first","affiliation":[{"name":"From the Departments of Pediatrics (Q.L., J.D.M.), Pharmacology (E.G.K.), and Systems Biology (J.N.L.), Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.); and The Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Ohio; Biotechnology Centre of Oslo (M.L.), University of Oslo, Norway; and Department of Physiology (S.M.M., X.C., S.R.H.), Temple University School of Medicine, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongwen","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics (Q.L., J.D.M.), Pharmacology (E.G.K.), and Systems Biology (J.N.L.), Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.); and The Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Ohio; Biotechnology Centre of Oslo (M.L.), University of Oslo, Norway; and Department of Physiology (S.M.M., X.C., S.R.H.), Temple University School of Medicine, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M.","family":"MacDonnell","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics (Q.L., J.D.M.), Pharmacology (E.G.K.), and Systems Biology (J.N.L.), Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.); and The Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Ohio; Biotechnology Centre of Oslo (M.L.), University of Oslo, Norway; and Department of Physiology (S.M.M., X.C., S.R.H.), Temple University School of Medicine, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia G.","family":"Kranias","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics (Q.L., J.D.M.), Pharmacology (E.G.K.), and Systems Biology (J.N.L.), Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.); and The Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Ohio; Biotechnology Centre of Oslo (M.L.), University of Oslo, Norway; and Department of Physiology (S.M.M., X.C., S.R.H.), Temple University School of Medicine, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John N.","family":"Lorenz","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics (Q.L., J.D.M.), Pharmacology (E.G.K.), and Systems Biology (J.N.L.), Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.); and The Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Ohio; Biotechnology Centre of Oslo (M.L.), University of Oslo, Norway; and Department of Physiology (S.M.M., X.C., S.R.H.), Temple University School of Medicine, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Leitges","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics (Q.L., J.D.M.), Pharmacology (E.G.K.), and Systems Biology (J.N.L.), Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.); and The Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Ohio; Biotechnology Centre of Oslo (M.L.), University of Oslo, Norway; and Department of Physiology (S.M.M., X.C., S.R.H.), Temple University School of Medicine, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven R.","family":"Houser","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics (Q.L., J.D.M.), Pharmacology (E.G.K.), and Systems Biology (J.N.L.), Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.); and The Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Ohio; Biotechnology Centre of Oslo (M.L.), University of Oslo, Norway; and Department of Physiology (S.M.M., X.C., S.R.H.), Temple University School of Medicine, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics (Q.L., J.D.M.), Pharmacology (E.G.K.), and Systems Biology (J.N.L.), Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.); and The Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Ohio; Biotechnology Centre of Oslo (M.L.), University of Oslo, Norway; and Department of Physiology (S.M.M., X.C., S.R.H.), Temple University School of Medicine, Philadelphia, 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Approach"],"short-title":[],"issued":{"date-parts":[[2009,7,17]]},"references-count":37,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2009,7,17]]}},"alternative-id":["10.1161\/CIRCRESAHA.109.195313"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.109.195313","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,7,17]]},"assertion":[{"value":"2009-06-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}