Cardiomyocyte nucleoporin 35 regulates pathological cardiac remodelling through Wif1

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Nuclear Pore Complex Biology

Background:

• Nucleoporin 35 (Nup35) is crucial for pHi homeostasis in cultured cardiomyocytes.
• The in vivo role of Nup35 in pathological cardiac remodeling remains largely unknown.

Purpose of the Study:

• To investigate the role of cardiomyocyte Nup35 in pathological cardiac remodeling.
• To elucidate the underlying molecular mechanisms of Nup35 in cardiac disease.

Main Methods:

• Utilized angiotensin II infusion and transverse aortic constriction models in mice.
• Generated cardiac-specific Nup35 knockout and overexpression models.
• Performed RNA immunoprecipitation sequencing to identify Nup35 targets.
• Employed adeno-associated virus subtype 9 for gene delivery.

Main Results:

• Cardiac Nup35 expression decreased during pathological cardiac remodeling.
• Nup35 deficiency led to severe cardiac fibrosis, hypertrophy, and dysfunction.
• Nup35 directly binds Wif1 mRNA, regulating its nuclear transport and protein levels.
• Wif1 mRNA delivery ameliorated cardiac pathologies in Nup35-deficient models.

Conclusions:

• Cardiomyocyte Nup35 alleviates pathological cardiac remodeling by controlling Wif1 mRNA transport.
• Nup35 represents a potential therapeutic target for cardiac remodeling diseases.