{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:34:57Z","timestamp":1791686097754,"version":"4.3.4"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,9,17]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Plakophilin-2 (PKP2) is classically defined as a desmosomal protein. Mutations in PKP2 associate with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy. A better understanding of PKP2 cardiac biology can help elucidate the mechanisms underlying arrhythmic and cardiomyopathic events consequent to PKP2 deficiency. Here, we sought to capture early molecular\/cellular events that can act as nascent arrhythmic\/cardiomyopathic substrates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>We used multiple imaging, biochemical and high-resolution mass spectrometry methods to study functional\/structural properties of cells\/tissues derived from cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mice (PKP2cKO) 14 days post-tamoxifen injection, a time point preceding overt electrical or structural phenotypes. Myocytes from right or left ventricular free wall were studied separately.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Most properties of PKP2cKO left ventricular myocytes were not different from control; in contrast, PKP2cKO right ventricular (RV) myocytes showed increased amplitude and duration of Ca\n                      <jats:sup>2+<\/jats:sup>\n                      transients, increased Ca\n                      <jats:sup>2+<\/jats:sup>\n                      in the cytoplasm and sarcoplasmic reticulum, increased frequency of spontaneous Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release events (sparks) even at comparable sarcoplasmic reticulum load, and dynamic Ca\n                      <jats:sup>2+<\/jats:sup>\n                      accumulation in mitochondria. We also observed early- and delayed-after transients in RV myocytes and heightened susceptibility to arrhythmias in Langendorff-perfused hearts. In addition, ryanodine receptor 2 in PKP2cKO-RV cells presented enhanced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      sensitivity and preferential phosphorylation in a domain known to modulate Ca\n                      <jats:sup>2+<\/jats:sup>\n                      gating. RNAseq at 14 days post-tamoxifen showed no relevant difference in transcript abundance between RV and left ventricle, neither in control nor in PKP2cKO cells. Instead, we found an RV-predominant increase in membrane permeability that can permit Ca\n                      <jats:sup>2+<\/jats:sup>\n                      entry into the cell. Connexin 43 ablation mitigated the membrane permeability increase, accumulation of cytoplasmic Ca\n                      <jats:sup>2+<\/jats:sup>\n                      , increased frequency of sparks and early stages of RV dysfunction. Connexin 43 hemichannel block with GAP19 normalized [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      homeostasis. Similarly, protein kinase C inhibition normalized spark frequency at comparable sarcoplasmic reticulum load levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Loss of PKP2 creates an RV-predominant arrhythmogenic substrate (Ca\n                      <jats:sup>2+<\/jats:sup>\n                      dysregulation) that precedes the cardiomyopathy; this is, at least in part, mediated by a Connexin 43-dependent membrane conduit and repressed by protein kinase C inhibitors. Given that asymmetric Ca\n                      <jats:sup>2+<\/jats:sup>\n                      dysregulation precedes the cardiomyopathic stage, we speculate that abnormal Ca\n                      <jats:sup>2+<\/jats:sup>\n                      handling in RV myocytes can be a trigger for gross structural changes observed at a later stage.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.119.039710","type":"journal-article","created":{"date-parts":[[2019,7,18]],"date-time":"2019-07-18T05:00:19Z","timestamp":1563426019000},"page":"1015-1030","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":124,"title":["Disruption of Ca\n                    <sup>2+<\/sup>\n                    <sub>i<\/sub>\n                    Homeostasis and Connexin 43 Hemichannel Function in the Right Ventricle Precedes Overt Arrhythmogenic Cardiomyopathy in Plakophilin-2\u2013Deficient Mice"],"prefix":"10.1161","volume":"140","author":[{"given":"Joon-Chul","family":"Kim","sequence":"first","affiliation":[{"name":"The Leon H. Charney Division of Cardiology (J.C.K., M.P.H., M.Z., X.L., C.V., M.C., M.D.), New York University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"P\u00e9rez-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"The Leon H. Charney Division of Cardiology (J.C.K., M.P.H., M.Z., X.L., C.V., M.C., M.D.), New York University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Alvarado","sequence":"additional","affiliation":[{"name":"Department of Medicine and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health (F.J.A., H.H.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana R.","family":"Maurya","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences (S.R.M., A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Montnach","sequence":"additional","affiliation":[{"name":"Institut du Thorax, Nouvelle Universite a Nantes, INSERM, Nantes Cedex 1, France (J.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yandong","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Biochemistry (Y.Y., E.R.), New York University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Leon H. Charney Division of Cardiology (J.C.K., M.P.H., M.Z., X.L., C.V., M.C., M.D.), New York University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianming","family":"Lin","sequence":"additional","affiliation":[{"name":"The Leon H. Charney Division of Cardiology (J.C.K., M.P.H., M.Z., X.L., C.V., M.C., M.D.), New York University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Vasquez","sequence":"additional","affiliation":[{"name":"The Leon H. Charney Division of Cardiology (J.C.K., M.P.H., M.Z., X.L., C.V., M.C., M.D.), New York University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Heguy","sequence":"additional","affiliation":[{"name":"Department of Pathology and Genome Technology Center (A.H., G.E.M.), New York University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-Xia","family":"Liang","sequence":"additional","affiliation":[{"name":"Microscopy Laboratory, Division of Advanced Research Technologies (F.X.L.), New York University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun-Hee","family":"Woo","sequence":"additional","affiliation":[{"name":"Laboratory of Physiology, College of Pharmacy, Chungam National University, Daejeon, South Korea (S.H.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory E.","family":"Morley","sequence":"additional","affiliation":[{"name":"Department of Pathology and Genome Technology Center (A.H., G.E.M.), New York University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Rothenberg","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Biochemistry (Y.Y., E.R.), New York University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Lundby","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences (S.R.M., A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark."},{"name":"NNF Center for Protein Research (A.L.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector H.","family":"Valdivia","sequence":"additional","affiliation":[{"name":"Department of Medicine and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health (F.J.A., H.H.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Cerrone","sequence":"additional","affiliation":[{"name":"The Leon H. 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