Farnesyltransferase Deficiency in Cardiomyocytes Initiates Senescence and Contributes to Cardiac Fibrosis

Area of Science:

• Cardiovascular Biology
• Molecular Mechanisms of Disease
• Cellular Senescence

Background:

• Cardiomyocyte senescence is linked to cardiac fibrosis, but underlying mechanisms are poorly understood.
• Farnesylation, mediated by FNTB, is crucial for cholesterol metabolism but its role in cardiac senescence and fibrosis is unclear.

Purpose of the Study:

• To investigate the role of FNTB in cardiomyocyte senescence and cardiac fibrosis.
• To elucidate the molecular mechanisms linking lipid overload, FNTB, and cardiac remodeling.

Main Methods:

• Generated cardiomyocyte-specific Fntb knockout mice.
• Utilized RNA sequencing, DNA damage assays, and senescence markers.
• Performed nuclear envelope ultrastructure analysis and assessed lamin A.
• Analyzed human heart samples from hyperlipidemic patients.

Main Results:

• FNTB deletion in cardiomyocytes induced progressive cardiac fibrosis and exacerbated pressure overload-induced dysfunction.
• Loss of FNTB impaired lamin A maturation, destabilized nuclear envelope, activated DNA damage response, and induced cardiomyocyte senescence.
• Senescent cardiomyocytes secreted Tgf-β2 and Gdf15, activating cardiac fibroblasts.
• Lipid overload suppressed Fntb transcription via Srebf2 downregulation, observed in human hyperlipidemic hearts.
• Fntb overexpression attenuated high-fat diet-induced cardiac fibrosis.

Conclusions:

• Lipid overload suppresses cardiomyocyte FNTB, compromising nuclear integrity and triggering senescence and fibrosis.
• This study reveals a novel mechanism in lipotoxic cardiomyopathy.
• Farnesylation represents a potential therapeutic target for fibrotic remodeling in metabolic heart diseases.