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

CK1 inhibitor affects in vitro maturation and developmental competence of bovine oocytes

“…The expression of CX43 in CCs around matured oocytes was significantly higher than that of immature oocytes (Li et al, ). Furthermore, expression level of Cx43 regulated by Wnt/β‐catenin signalling pathway (Heyden et al, ; Jeong et al, ; Le et al, ; Wang, Song, Liu, & Zhao, ) was one of marked for oocytes maturation, and its function required the phosphorylation modified of CK1 (Cooper & Lampe, ).…”

Repression ofPdzrn3is required for heart maturation and protects against heart failure

“…Both canonical and non-canonical Wnt signalling have been implicated in the multistep process of cardiogenesis (Gessert & Kühl, 2010;Jeong et al, 2017;Mazzotta et al, 2016), however, understanding of the outcome of activating and inhibiting the Wnt pathways at specific times during the development of the heart is still not fully understood. Our data seems to favour the hypothesis that in the heart, PDZRN3 is acting in the PCP pathway.…”

Multiple Roles of sFRP2 in Cardiac Development and Cardiovascular Disease

“…Wnt activity is normally low in the adult organism, and it is generally believed that it is reactivated under pathological conditions. It was reported that Wnt signaling is activated shortly after myocardial infarction and is significantly associated with cardiac remodeling and fibrosis [36][37][38]. Duan et al found that the canonical Wnt/β-catenin pathway was activated after acute ischemic myocardial injury in mice.…”