Ccdc80 Functions as a PKGIa Substrate and is Secreted From Cardiac Myocytes

Abstract

Background: Protein kinase G I alpha (PKGIa) inhibits cardiac hypertrophy, remodeling, and dysfunction. Downstream PKGI substrates remain incompletely understood and represent potential novel therapeutic targets for myocardial disease. We previously identified through a molecular screen that PKGIa binds and phosphorylates the protein coiled-coiled domain containing 80 (Ccdc80; also termed SSG1 and URB) in vascular smooth muscle cells. Previous work also identified that Ccdc80 is secreted from adipocytes. However, the expression and secretion of Ccdc80 from the cardiac myocyte has not been investigated. The current study tested the hypothesis that Ccdc80 is expressed in and secreted from the cardiac myocyte. Results: In cultured rat cardiac myocytes (CM), we detected Ccdc80 by western blot. Western blot for Ccdc80 also detected a band of the predicted Ccdc80 molecular weight present in media from these cells, but not in uncultured media. Ccdc80 could be detected in the human left ventricle (LV), though expression did not differ between hearts of normal controls and patients with hypertrophic cardiomyopathy. In the setting of LV pressure overload induced by transaortic constriction (TAC), we observed an increase in Ccdc80 expression in 1 week TAC LVs, compared with sham LVs (5.0 + /− 0.3 arbitrary densitometric units in sham versus 9.6 + /− 0.9 in TAC; n = 4 per group). Conclusion: Taken together, our findings identify that the PKGIa substrate Ccdc80 expresses in cardiac myocytes, becomes secreted from CMs, resides in the human heart, and increases in expression in the mouse LV in response to pressure overload. Given the anti-remodeling role of PKGIa, these findings support future studies to understand the in vivo role of Ccdc80 in the cardiovascular system. Future studies will also explore the significance of Ccdc80 secretion from the CM and its potential regulation by PKG.