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: Jie Lou, Dan Zhao, Ling-Ling Zhang, Shu-Ying Song, Yan-Chao Li, Fei Sun, Xiao-Qing Ding, Chang-Jiang Yu, Yuan-Yuan Li, Mei-Tong Liu, Chang-Jiang Dong, Yong Ji, Hongliang Li, Wenfeng Chu, Zhi-Ren Zhang
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 68 Issue 3 Pg. 654-66 (09 2016) ISSN: 1524-4563 [Electronic] United States
• PMID: 27432858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 American Heart Association, Inc.

Chemical References

• Eomes protein, mouse
• T-Box Domain Proteins
• Transforming Growth Factor beta
• beta-Arrestin 2
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Isoproterenol

Topics

• Analysis of Variance
• Animals
• Biopsy, Needle
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Cardiomegaly (genetics, pathology)
• Cells, Cultured
• Disease Models, Animal
• Humans
• Immunohistochemistry
• Isoproterenol (pharmacology)
• Mice
• Mice, Transgenic
• Myocytes, Cardiac (drug effects, metabolism)
• Random Allocation
• Sensitivity and Specificity
• T-Box Domain Proteins (genetics)
• Transforming Growth Factor beta (metabolism)
• beta-Arrestin 2 (metabolism)