Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling.
On pathological stress, Wnt signaling is reactivated and induces genes associated with cardiac remodeling and fibrosis. We have previously shown that a cell surface receptor Cdon (cell-adhesion associated, oncogene regulated) suppresses Wnt signaling to promote neuronal differentiation however its role in heart is unknown. Here, we demonstrate a critical role of Cdon in cardiac function and remodeling. Cdon is expressed and predominantly localized at intercalated disk in both mouse and human hearts. Cdon-deficient mice develop cardiac dysfunction including reduced ejection fraction and ECG abnormalities.Cdon-/-hearts exhibit increased fibrosis and up-regulation of genes associated with cardiac remodeling and fibrosis. Electrical remodeling was demonstrated by up-regulation and mislocalization of the gap junction protein, Connexin 43 (Cx43) inCdon-/-hearts. In agreement with altered Cx43 expression, functional analysis both usingCdon-/-cardiomyocytes and shRNA-mediated knockdown in rat cardiomyocytes shows aberrant gap junction activities. Analysis of the underlying mechanism reveals thatCdon-/-hearts exhibit hyperactive Wnt signaling as evident by β-catenin accumulation and Axin2 up-regulation. On the other hand, the treatment of rat cardiomyocytes with a Wnt activator TWS119 reduces Cdon levels and aberrant Cx43 activities, similarly to Cdon-deficient cardiomyocytes, suggesting a negative feedback between Cdon and Wnt signaling. Finally, inhibition of Wnt/β-catenin signaling by XAV939, IWP2 or dickkopf (DKK)1 prevented Cdon depletion-induced up-regulation of collagen 1a and Cx43. Taken together, these results demonstrate that Cdon deficiency causes hyperactive Wnt signaling leading to aberrant intercellular coupling and cardiac fibrosis. Cdon exhibits great potential as a target for the treatment of cardiac fibrosis and cardiomyopathy.
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea 16419.|Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 06351.
Myong-Ho
MH
Jeong
Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 06351.|Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, Korea 16419.
Hyun-Ji
HJ
Kim
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea 16419.|Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 06351.
Jung-Hoon
JH
Pyun
Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 06351.
Kyu-Sil
KS
Choi
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Dong I
DI
Lee
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Soroosh
S
Solhjoo
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Brian
B
O'Rourke
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Gordon F
GF
Tomaselli
Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 06351.
Dong Seop
DS
Jeong
Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 06351; kangj01@skku.edu hanacho@skku.edu.|Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, Korea 16419.
Hana
H
Cho
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea 16419; kangj01@skku.edu hanacho@skku.edu.|Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 06351.
Jong-Sun
JS
Kang
D000818:Animals; D015815:Cell Adhesion Molecules / Q000172:deficiency* / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
C510744:Cdon protein, mouse; D015815:Cell Adhesion Molecules; D018031:Connexin 43; D017630:Connexins; D011743:Pyrimidines; D011758:Pyrroles; C547688:TWS 119; D051176:beta Catenin
Cdon; Wnt; cardiac fibrosis; connexin 43; gap junction