title: Cardiac-Specific EPI64C Blunts Pressure Overload-Induced Cardiac Hypertrophy.
abstract: The calcium-responsive molecule, calcineurin, has been well characterized to play a causal role in pathological cardiac hypertrophy over the past decade. However, the intrinsic negative regulation of calcineurin signaling during the progression of cardiomyocyte hypertrophy remains enigmatic. Herein, we explored the role of EPI64C, a dual inhibitor of both Ras and calcineurin signaling during T-cell activation, in pressure overload-induced cardiac hypertrophy. We generated a cardiac-specific Epi64c conditional knockout mouse strain and showed that loss of Epi64c remarkably exacerbates pressure overload-induced cardiac hypertrophy. In contrast, EPI64C gain-of-function in cardiomyocyte-specific Epi64c transgenic mice exerts potent protective effects against cardiac hypertrophy. Mechanistically, the cardioprotective effects of EPI64C are largely attributed to the disrupted calcineurin signaling but are independent of its Ras suppressive capability. Molecular studies have indicated that the 406 to 446 C-terminal amino acids in EPI64C directly bind to the 287 to 337 amino acids in the catalytic domain of calcineurin, which is responsible for the EPI64C-mediated suppressive effects. We further extrapolated our studies to cynomolgus monkeys and showed that gene therapy based on lentivirus-mediated EPI64C overexpression in the monkey hearts blunted pressure overload-induced cardiac hypertrophy. Our study thus identified EPI64C as a novel negative regulator in cardiac hypertrophy by targeting calcineurin signaling and demonstrated the potential of gene therapy and drug development for treating cardiac hypertrophy.
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery (X.Z, J.F., X.W.), Heart-Lung Transplantation Center (X.Z., J.F., X.W.), Sino-Swiss Heart-Lung Transplantation Institute (X.Z., J.F., X.W.), Department of Medical Ultrasound (H.-Y.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.); and Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.).
authors.forename: Xuehai
authors.initials: X
authors.lastname: Zhu
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery (X.Z, J.F., X.W.), Heart-Lung Transplantation Center (X.Z., J.F., X.W.), Sino-Swiss Heart-Lung Transplantation Institute (X.Z., J.F., X.W.), Department of Medical Ultrasound (H.-Y.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.); and Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.).
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery (X.Z, J.F., X.W.), Heart-Lung Transplantation Center (X.Z., J.F., X.W.), Sino-Swiss Heart-Lung Transplantation Institute (X.Z., J.F., X.W.), Department of Medical Ultrasound (H.-Y.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.); and Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.).
authors.forename: Jun
authors.initials: J
authors.lastname: Gong
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery (X.Z, J.F., X.W.), Heart-Lung Transplantation Center (X.Z., J.F., X.W.), Sino-Swiss Heart-Lung Transplantation Institute (X.Z., J.F., X.W.), Department of Medical Ultrasound (H.-Y.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.); and Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.).
authors.forename: Jun-Hong
authors.initials: JH
authors.lastname: Guo
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery (X.Z, J.F., X.W.), Heart-Lung Transplantation Center (X.Z., J.F., X.W.), Sino-Swiss Heart-Lung Transplantation Institute (X.Z., J.F., X.W.), Department of Medical Ultrasound (H.-Y.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.); and Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.).
authors.forename: Guang-Nian
authors.initials: GN
authors.lastname: Zhao
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery (X.Z, J.F., X.W.), Heart-Lung Transplantation Center (X.Z., J.F., X.W.), Sino-Swiss Heart-Lung Transplantation Institute (X.Z., J.F., X.W.), Department of Medical Ultrasound (H.-Y.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.); and Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.).
authors.forename: Yan-Xiao
authors.initials: YX
authors.lastname: Ji
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery (X.Z, J.F., X.W.), Heart-Lung Transplantation Center (X.Z., J.F., X.W.), Sino-Swiss Heart-Lung Transplantation Institute (X.Z., J.F., X.W.), Department of Medical Ultrasound (H.-Y.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.); and Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.).
authors.forename: Hong-Yun
authors.initials: HY
authors.lastname: Liu
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery (X.Z, J.F., X.W.), Heart-Lung Transplantation Center (X.Z., J.F., X.W.), Sino-Swiss Heart-Lung Transplantation Institute (X.Z., J.F., X.W.), Department of Medical Ultrasound (H.-Y.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.); and Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.). lihl@whu.edu.cn xiangwei@tjh.tjmu.edu.cn.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wei
authors.affiliation: From the Division of Cardiothoracic and Vascular Surgery (X.Z, J.F., X.W.), Heart-Lung Transplantation Center (X.Z., J.F., X.W.), Sino-Swiss Heart-Lung Transplantation Institute (X.Z., J.F., X.W.), Department of Medical Ultrasound (H.-Y.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.); and Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.). lihl@whu.edu.cn xiangwei@tjh.tjmu.edu.cn.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism*; D016534:Cardiac Output, High; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D011312:Pressure; D011897:Random Allocation; D020127:Recovery of Function; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000502:physiology
chemical_list: C515119:EPI64 protein, mouse; D020690:GTPase-Activating Proteins; D000804:Angiotensin II; D019703:Calcineurin
keywords: TBC1D10C protein, mouse; calcineurin; cardiomegaly; heart failure; mice, knockout