NF-κB p65 Attenuates Cardiomyocyte PGC-1α Expression in Hypoxia

Area of Science:

• Cardiology
• Molecular Biology
• Cellular Physiology

Background:

• Hypoxia significantly impacts cardiomyocyte function, metabolism, and survival.
• Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is crucial for cardiomyocyte metabolism and mitochondrial health.
• PGC-1α is downregulated during hypoxia, but the mechanism remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which hypoxia down-regulates PGC-1α expression in cardiomyocytes.
• To investigate the role of Nuclear Factor-kappa B (NF-κB) signaling in this process.

Main Methods:

• Primary rat and mouse cardiomyocytes were used.
• Electrophoretic mobility shift assays (EMSA) and luciferase assays were performed.
• RNA sequencing (RNA-seq) was conducted on p65 knockout mouse cardiomyocytes.
• NF-κB and histone deacetylase inhibitors (parthenolide, trichostatin A) were utilized.

Main Results:

• Hypoxia impaired mitochondrial energetics and increased nuclear localization of NF-κB p65.
• NF-κB p65 associated with the PGC-1α promoter, inhibiting its expression.
• Tumor necrosis factor α (TNFα) mimicked hypoxia effects, reducing PGC-1α expression and p65 binding.
• NF-κB inhibition reversed TNFα-induced PGC-1α downregulation.
• p65 knockout altered chromatin remodeling genes; histone deacetylase inhibition partially restored PGC-1α transactivation.

Conclusions:

• NF-κB signaling, particularly the p65 subunit, acts as a key inhibitor of PGC-1α expression in cardiomyocytes under hypoxic conditions.
• This study reveals a novel regulatory pathway linking hypoxia, NF-κB, and cardiomyocyte metabolic adaptation via PGC-1α.