Nuclear Receptor Subfamily 4 Group A Member 1 Exacerbates Cardiac Remodeling by Inhibiting Mitochondrial Function Through the Peroxisome Proliferator‐Activated Receptor γ Coactivator‐1α/Nuclear Respiratory Factor 1/Transcription Factor A Mitochondrial Axis

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BACKGROUND: Heart failure is characterized by cardiac dysfunction, cardiac remodeling, and mitochondrial dysfunction. NR4a1 (nuclear receptor subfamily 4 group A member 1) plays a crucial role in regulating mitochondrial function and biological performance in various diseases. The main objective of this study was to investigate the influence of NR4a1 on cardiac hypertrophy and uncover its underlying mechanism. METHODS: A mouse model was established by transverse aortic constriction surgery, and an in vitro model was established by phenylephrine-treated neonatal rat ventricular myocytes. Mice were transfected with adeno-associated virus 9 to assess the role of NR4a1 in cardiac hypertrophy. We used PGC1α (peroxisome proliferator-activated receptor γ coactivator-1α) cardiac-specific knockout mice for subsequent experiments to investigate the impact of NR4a1 on mitochondrial bioenergetics. RESULTS: NR4a1 overexpression significantly exacerbates transverse aortic constriction-induced cardiac remodeling and cardiac dysfunction, and NR4a1 knockdown attenuates cardiac remodeling and cardiac dysfunction. Mechanistically, NR4a1 modulated cardiac remodeling and heart failure by impairing mitochondrial bioenergetics through PGC1α/NRF1 (nuclear respiratory factor 1)/TFAM (transcription factor A mitochondrial) axis. Inhibition of PGC1α activation is critical for NR4a1 to impair mitochondrial bioenergetics in cardiac hypertrophy. Furthermore, cardiac-specific PGC1α knockdown counteracts heart failure and mitochondrial dysfunction ameliorated by NR4a1 knockdown. CONCLUSIONS: Collectively, our findings demonstrate that NR4a1 drives pathological cardiac remodeling and heart failure progression by suppressing the PGC1α/NRF1/TFAM axis, leading to impaired mitochondrial function. Targeting NR4a1 and its interactions with PGC1α may hold promise for the development of novel therapeutic strategies for treating cardiac hypertrophy.

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