{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:42:09Z","timestamp":1791981729150,"version":"4.4.0"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2015,1,2]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Rnd3, a small Rho GTPase, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration, and proliferation. The biological function of Rnd3 in the heart remains unexplored.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              To define the functional role of the\n              <jats:italic>Rnd3<\/jats:italic>\n              gene in the animal heart and investigate the associated molecular mechanism.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              By loss-of-function approaches, we discovered that Rnd3 is involved in calcium regulation in cardiomyocytes. Rnd3-null mice died at the embryonic stage with fetal arrhythmias. The deletion of\n              <jats:italic>Rnd3<\/jats:italic>\n              resulted in severe Ca\n              <jats:sup>2+<\/jats:sup>\n              leakage through destabilized ryanodine receptor type 2 Ca\n              <jats:sup>2+<\/jats:sup>\n              release channels. We further found that downregulation of Rnd3 attenuated \u03b2\n              <jats:sub>2<\/jats:sub>\n              -adrenergic receptor lysosomal targeting and ubiquitination, which in turn resulted in the elevation of \u03b2\n              <jats:sub>2<\/jats:sub>\n              -adrenergic receptor protein levels leading to the hyperactivation of protein kinase A (PKA) signaling. The PKA activation destabilized ryanodine receptor type 2 channels. This irregular spontaneous Ca\n              <jats:sup>2+<\/jats:sup>\n              release can be curtailed by PKA inhibitor treatment. Increases in the PKA activity along with elevated cAMP levels were detected in Rnd3-null embryos, in neonatal rat cardiomyocytes, and noncardiac cell lines with Rnd3 knockdown, suggesting a general mechanism for Rnd3-mediated PKA signaling activation. \u03b2\n              <jats:sub>2<\/jats:sub>\n              -Adrenergic receptor blocker treatment reduced arrhythmia and improved cardiac function.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              Rnd3 is a novel factor involved in intracellular Ca\n              <jats:sup>2+<\/jats:sup>\n              homeostasis regulation in the heart. Deficiency of the protein induces ryanodine receptor type 2 dysfunction by a mechanism that attenuates Rnd3-mediated \u03b2\n              <jats:sub>2<\/jats:sub>\n              -adrenergic receptor ubiquitination, which leads to the activation of PKA signaling. Increased PKA signaling in turn promotes ryanodine receptor type 2 hyperphosphorylation, which contributes to arrhythmogenesis and heart failure.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.116.304940","type":"journal-article","created":{"date-parts":[[2014,10,28]],"date-time":"2014-10-28T06:01:14Z","timestamp":1414476074000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":34,"title":["Genetic Deletion of Rnd3\/RhoE Results in Mouse Heart Calcium Leakage Through Upregulation of Protein Kinase A Signaling"],"prefix":"10.1161","volume":"116","author":[{"given":"Xiangsheng","family":"Yang","sequence":"first","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiannan","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Lin","sequence":"additional","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Yue","sequence":"additional","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiongling","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoliang","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Fu","sequence":"additional","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Ai","sequence":"additional","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Y.","family":"Chiang","sequence":"additional","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina Y.","family":"Miyake","sequence":"additional","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xander H.T.","family":"Wehrens","sequence":"additional","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Chang","sequence":"additional","affiliation":[{"name":"From the Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&amp;M University Health Science Center, Houston (X. Yang, X.L., X. Yue, J.C.); Department of Molecular Physiology and Biophysics and Medicine (Cardiology) (T.W., Q.W., G.W., D.Y.C., X.H.T.W.) and Department of Pediatrics, Texas Children\u2019s Hospital (C.Y.M.), Baylor College of Medicine, Houston, TX; Department of Pharmacology, University of California at Davis (Q.F.); and Department of Cell 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