Caspase recruitment domain 6 protects against cardiac hypertrophy in response to pressure overload.
Caspase recruitment domain 6 (CARD6), a crucial member of the CARD family, was initially shown to be involved in the immune system and oncogenesis. However, the role of CARD6 in chronic pressure overload-induced cardiac hypertrophy remains unexplored. To evaluate the impact of CARD6 on pathological cardiac hypertrophy, cardiac-specific CARD6 knockout mice and transgenic mice with cardiac-specific CARD6 overexpression were generated and subjected to aortic banding for 4 weeks. Our results demonstrated that CARD6-deficient mice aggravated aortic banding-triggered cardiac hypertrophy, ventricular dilation, fibrosis, and dysfunction, as measured by echocardiography, immunostaining, and molecular/biochemical analyses. Conversely, CARD6-overexpressing mice exhibited an attenuated hypertrophic response to chronic pressure overload. Similarly, using cultured neonatal rat cardiomyocytes, we found that adenovirus vector-driven overexpression of CARD6 dramatically limited angiotensin II-induced myocyte hypertrophy, whereas knockdown of CARD6 by AdshCARD6 (adenoviral short hairpin CARD6) exhibited the opposite phenotypes. Furthermore, analysis of the signaling events in vitro and in vivo revealed that CARD6-mediated protection against cardiac hypertrophy was attributed to the interruption of mitogen-activated protein kinase kinase (MEK) kinase-1-dependent MEK-extracellular signal-regulated protein kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase 1/2 (JNK1/2) activation. Altogether, these data indicated that CARD6 serves as a novel cardioprotective factor via negative regulation of MEK kinase-1-dependent MEK-ERK1/2 and JNK1/2 signaling. Thus, our study suggests that CARD6 may be a novel target for the treatment of pathological cardiac hypertrophy and failure.
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Liangpeng
L
Li
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Wen
W
Chen
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Yifan
Y
Zhu
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Xiaodi
X
Wang
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Ding-Sheng
DS
Jiang
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Fuhua
F
Huang
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Liming
L
Wang
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Fei
F
Xiang
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Wei
W
Qin
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Qiang
Q
Wang
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Rui
R
Zhang
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Xueyong
X
Zhu
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.).
Hongliang
H
Li
From the Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., W.C., Y.Z., X.W., F.H., L.W., F.X., W.Q., X.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.); and Cardiovascular Research Institute, Wuhan University, Wuhan, China (D.-S.J., Q.W., R.Z., X.Z., H.L.). stevecx@njmu.edu.cn.
Xin
X
Chen
D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology
D053468:CARD Signaling Adaptor Proteins; C527301:Card6 protein, mouse
CARD6 protein, human; MEKK1 protein kinase; cardiomegaly; signal transduction