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Omaveloxolone ameliorates isoproterenol-induced pathological cardiac hypertrophy in mice
Xianchao Li1, Yang Wu2, Yunzhao Yang2
1Health Science Center, Yangtze University, Huanggang Central Hospital of Yangtze University, Huanggang, China.
Abstract:
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcriptional regulator that plays a protective role against various cardiovascular diseases. Omaveloxolone is a newly discovered potent activator of Nrf2 that has a variety of cytoprotective functions. However, the potential role of omaveloxolone in the process of pathological cardiac hypertrophy and heart failure are still unknown. In this study, an isoproterenol (ISO)-induced pathological cardiac hypertrophy model was established to investigate the protective effect of omaveloxolone in vivo and in vitro. Our study first confirmed that omaveloxolone administration improved ISO-induced pathological cardiac hypertrophy in mice and neonatal cardiomyocytes. Omaveloxolone administration also diminished ISO-induced cardiac oxidative stress, inflammation and cardiomyocyte apoptosis. In addition, omaveloxolone administration activated the Nrf2 signaling pathway, and Nrf2 knockdown almost completely abolished the cardioprotective effect of omaveloxolone, indicated that the cardioprotective effect of omaveloxolone was directly related to the activation of the Nrf2 signaling. In summary, our study identified that omaveloxolone may be a promising therapeutic agent to mitigate pathological cardiac hypertrophy.
Insights
Omaveloxolone, a Nuclear factor erythroid 2-related factor 2 (Nrf2) activator, protects against pathological cardiac hypertrophy and heart failure by reducing oxidative stress and inflammation. Its therapeutic potential is linked to Nrf2 pathway activation.
Area of Science:
- Cardiovascular Biology
- Pharmacology
- Molecular Medicine
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator in cardiovascular protection.
- Omaveloxolone is a potent Nrf2 activator with known cytoprotective functions.
- The role of omaveloxolone in pathological cardiac hypertrophy and heart failure remains unexplored.
Purpose of the Study:
- To investigate the protective effects of omaveloxolone against isoproterenol (ISO)-induced pathological cardiac hypertrophy.
- To elucidate the underlying mechanism of omaveloxolone's action, particularly its relation to the Nrf2 signaling pathway.
Main Methods:
- Establishment of an ISO-induced pathological cardiac hypertrophy model in mice.
- In vivo and in vitro assessments of omaveloxolone's effects on cardiac function and cellular processes.
- Evaluation of omaveloxolone's impact on oxidative stress, inflammation, and cardiomyocyte apoptosis.
- Analysis of Nrf2 signaling pathway activation and the effect of Nrf2 knockdown.
Main Results:
- Omaveloxolone administration significantly improved ISO-induced pathological cardiac hypertrophy in both mice and neonatal cardiomyocytes.
- Omaveloxolone treatment reduced cardiac oxidative stress, inflammation, and cardiomyocyte apoptosis.
- Omaveloxolone activated the Nrf2 signaling pathway.
- Nrf2 knockdown largely abrogated the cardioprotective effects of omaveloxolone, confirming its mechanism of action.
Conclusions:
- Omaveloxolone demonstrates significant cardioprotective effects against pathological cardiac hypertrophy.
- The therapeutic benefits of omaveloxolone are mediated through the activation of the Nrf2 signaling pathway.
- Omaveloxolone shows promise as a potential therapeutic agent for mitigating pathological cardiac hypertrophy and related heart conditions.
