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Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/?-catenin signaling.

ABSTRACT: 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) in Cdon^-/- hearts. In agreement with altered Cx43 expression, functional analysis both using Cdon^-/- cardiomyocytes and shRNA-mediated knockdown in rat cardiomyocytes shows aberrant gap junction activities. Analysis of the underlying mechanism reveals that Cdon^-/- hearts exhibit hyperactive Wnt signaling as evident by ?-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/?-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.

SUBMITTER: Jeong MH

PROVIDER: S-EPMC5338397 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling.

Jeong Myong-Ho MH Kim Hyun-Ji HJ Pyun Jung-Hoon JH Choi Kyu-Sil KS Lee Dong I DI Solhjoo Soroosh S O'Rourke Brian B Tomaselli Gordon F GF Jeong Dong Seop DS Cho Hana H Kang Jong-Sun JS

Proceedings of the National Academy of Sciences of the United States of America 20170202 8

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 hea ...[more]

PMID: 28154134

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Project description:BackgroundThe serum levels of sclerostin (SOST) are significant elevated in patients with pathological cardiac remodeling after myocardial infarction (MI). However, the mechanisms of SOST in cardiac remodeling remain largely uncharacterized.MethodsCollecting patients with MI who presented with or without left ventricular (LV) remodeling, we investigated differences in SOST expression. The influence of overexpression and silenced of SOST on the angiogenesis of cardiac microvascular endothelial cells (CMECs) was explored through in vitro experiments, and the impact of SOST on Wnt signaling marker proteins was examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Finally, we observed the effects of SOST on cardiac function and morphology in mice MI model, and verified the role of the Wnt signaling marker proteins in vivo.ResultsSerum SOST was significantly increased in patients with cardiac remodeling. Increased SOST expression was also observed in the infarcted hearts of C57BL/6 mice that underwent ligation of the left anterior descending branch of the coronary artery to induce MI. Furthermore, loss and gain of function experiments were conducted to investigate the role of SOST in post-infarct cardiac remodeling in vivo and in vitro. Overexpression of SOST promoted the proliferation and migration of cardiac fibroblasts (CFs), and inhibited angiogenesis of CMECs. In addition, overexpressing SOST in mice significantly deteriorated the post-infarct cardiac remodeling, as shown by the increased LV end systolic and end diastolic dimensions, decreased ejection fraction, and increased myocyte cross-section area and myocardial fibrosis. However, suppressing SOST expression showed the opposite results. The expression of Wnt signaling marker proteins was inhibited after overexpression of SOST, and enhanced after suppression of SOST in vivo and in vitro, suggesting involvement of the Wnt signaling pathway.ConclusionsThe present study demonstrated that SOST aggravates post-infarct pathological myocardial remodeling by inhibiting angiogenesis of CMECs while promoting the proliferation of CFs, and this may be mediated by the Wnt signaling pathway. These results suggested that SOST might act as a biomarker to predict detrimental postinfarct cardiac remodeling, and may be a potential therapeutic target for the treatment of MI.

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Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/?-catenin signaling.

Publications

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling.

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