Cardiomyocyte Nup35 alleviates pathological cardiac remodelling by regulating Wif1 mRNA transport, with Nup35 deficiency causing severe cardiac fibrosis, hypertrophy, and dysfunction in mice.
Does Nup35 regulate pathological cardiac remodelling through Wif1 in cardiomyocytes?
Cardiomyocyte Nup35 alleviates pathological cardiac remodelling by regulating Wif1 mRNA transport, identifying a potential therapeutic target.
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.
Pan et al. (Mon,) conducted a other in Pathological cardiac remodelling. Nup35 knockout or overexpression; AAV9-Wif1 mRNA vs. Control/wild-type was evaluated on Cardiac fibrosis, hypertrophy, and cardiac dysfunction. Cardiomyocyte Nup35 alleviates pathological cardiac remodelling by regulating Wif1 mRNA transport, with Nup35 deficiency causing severe cardiac fibrosis, hypertrophy, and dysfunction in mice.