Cardiomyocyte nucleoporin 35 regulates pathological cardiac remodelling through Wif1

AIMS: Nucleoporin 35, a member of nucleoporins in the nuclear pore complex, is involved in in vitro cultured cardiomyocyte pHi homeostasis. The in vivo roles of cardiomyocyte Nup35 in pathological cardiac remodelling have not been determined. METHODS AND RESULTS: Cardiac Nup35 expression is significantly down-regulated during angiotensin II- and transverse aortic constriction-induced pathological cardiac remodelling. Cardiac-specific Nup35 knockout mice display severe cardiac fibrosis, hypertrophy, and cardiac dysfunction. Conversely, Nup35 overexpression in cardiomyocytes exhibits the opposite protective phenotypes. Mechanistically, Nup35 directly bound to WNT inhibitory factor 1 (Wif1) mRNA assessed by RNA immunoprecipitation sequencing, resulting in the increased localization of pre-mRNA of Wif1 in the nucleus and decreased Wif1 protein level in Nup35-deficient cardiomyocytes. Finally, the deteriorated pathological hypertrophy, cardiac fibrosis, and dysfunction in Nup35-deficient cardiomyocytes were suppressed by cardiac-specific adeno-associated virus subtype 9 target delivery of Wif1 mRNA. CONCLUSION: Cardiomyocyte Nup35, via its regulation of Wif1 mRNA transport in cardiomyocytes, alleviates pathological cardiac remodelling. Our study highlights potential therapeutic target in cardiac pathological remodelling.