Metformin Inhibits Cardiac Fibroblast Differentiation by Promoting Fatty Acid β-Oxidation: Implications for...

Area of Science:

• Cardiovascular Biology
• Metabolic Regulation
• Cellular Senescence

Background:

• Cardiac fibrosis, a key feature of pathological cardiac remodeling, involves fibroblast activation and extracellular matrix deposition, leading to cardiac dysfunction.
• Aging worsens cardiac fibrosis through metabolic stress and impaired mitochondrial function.

Purpose of the Study:

• To investigate the anti-fibrotic effects of metformin.
• To elucidate the role of fatty acid β-oxidation (FAO) in metformin's regulation of cardiac fibroblast differentiation.

Main Methods:

• Assessed metformin's impact on transforming growth factor-β (TGF-β)-induced cardiac fibroblast activation and senescence.
• Measured FAO, mitochondrial oxygen consumption rate (OCR), and key metabolic intermediates (acetyl-CoA, malonyl-CoA).
• Utilized etomoxir to inhibit carnitine palmitoyltransferase-1 (CPT1) and examined metformin's effects in aged Apoe-/- mice.

Main Results:

• Metformin attenuated TGF-β-induced fibroblast activation and senescence, correlating with enhanced FAO and OCR.
• CPT1 inhibition with etomoxir reversed metformin's beneficial effects on mitochondrial function and fibroblast phenotype.
• Metformin increased CPT1 activity and acetyl-CoA while decreasing malonyl-CoA, promoting fatty acid utilization.
• In aged mice, metformin reduced cardiac fibroblast markers and increased FAO markers.

Conclusions:

• Metformin suppresses cardiac fibroblast differentiation and senescence via FAO-dependent mechanisms that preserve mitochondrial bioenergetics.
• These findings reveal a metabolic basis for metformin's anti-fibrotic actions.
• Metformin demonstrates therapeutic potential for age-related cardiovascular diseases characterized by fibrosis.