title: Type III Transforming Growth Factor-β Receptor Drives Cardiac Hypertrophy Through β-Arrestin2-Dependent Activation of Calmodulin-Dependent Protein Kinase II.
abstract: The role of type III transforming growth factor-β receptor (TβRIII) in the pathogenesis of heart diseases remains largely unclear. Here, we investigated the functional role and molecular mechanisms of TβRIII in the development of myocardial hypertrophy. Western blot and quantitative real time-polymerase chain reaction analyses revealed that the expression of TβRIII was significantly elevated in human cardiac hypertrophic samples. Consistently, TβRIII expression was substantially increased in transverse aortic constriction (TAC)- and isoproterenol-induced mouse cardiac hypertrophy in vivo and in isoproterenol-induced cardiomyocyte hypertrophy in vitro. Overexpression of TβRIII resulted in cardiomyocyte hypertrophy, whereas isoproterenol-induced cardiomyocyte hypertrophy was greatly attenuated by knockdown of TβRIII in vitro. Cardiac-specific transgenic expression of TβRIII independently led to cardiac hypertrophy in mice, which was further aggravated by isoproterenol and TAC treatment. Cardiac contractile function of the mice was not altered in TβRIII transgenic mice; however, TAC led to significantly decreased cardiac contractile function in TβRIII transgenic mice compared with control mice. Conversely, isoproterenol- and TAC-induced cardiac hypertrophy and TAC-induced cardiac contractile function impairment were partially reversed by suppression of TβRIII in vivo. Our data suggest that TβRIII mediates stress-induced cardiac hypertrophy through activation of Ca(2+)/calmodulin-dependent protein kinase II, which requires a physical interaction of β-arrestin2 with both TβRIII and calmodulin-dependent protein kinase II. Our findings indicate that stress-induced increase in TβRIII expression results in cardiac hypertrophy through β-arrestin2-dependent activation of calmodulin-dependent protein kinase II and that transforming growth factor-β and β-adrenergic receptor signaling are not involved in spontaneous cardiac hypertrophy in cardiac-specific transgenic expression of TβRIII mice. Our findings may provide a novel target for control of myocardial hypertrophy.
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Jie
authors.initials: J
authors.lastname: Lou
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.). zhaodan7719@163.com chuwenfeng@aliyun.com zhirenz@yahoo.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Shu-Ying
authors.initials: SY
authors.lastname: Song
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Yan-Chao
authors.initials: YC
authors.lastname: Li
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Ding
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Li
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Mei-Tong
authors.initials: MT
authors.lastname: Liu
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Dong
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Yong
authors.initials: Y
authors.lastname: Ji
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.).
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.). zhaodan7719@163.com chuwenfeng@aliyun.com zhirenz@yahoo.com.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Chu
authors.affiliation: From the Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, China (J.L., S.-Y.S., Y.-C.L., X.-Q.D., C.-J.Y., Z.-R.Z.); Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, China (D.Z., Z.-R.Z.); Department of Pharmacology, Harbin Medical University, China (L.-L.Z., F.S., Y.-Y.L., M.-T.L., C.-J.D., W.C.); Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, China (Y.J.); and Department of Cardiology, Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University, China (H.L.). zhaodan7719@163.com chuwenfeng@aliyun.com zhirenz@yahoo.com.
authors.forename: Zhi-Ren
authors.initials: ZR
authors.lastname: Zhang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011897:Random Allocation; D012680:Sensitivity and Specificity; D020825:T-Box Domain Proteins / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000071560:beta-Arrestin 2 / Q000378:metabolism*
chemical_list: C491198:Eomes protein, mouse; D020825:T-Box Domain Proteins; D016212:Transforming Growth Factor beta; D000071560:beta-Arrestin 2; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007545:Isoproterenol
keywords: cardiac myocyte; hypertrophy; transforming growth factor; transgenic mice