Ning-Ning Wang1, Huan-Hua Xu1, Wei Zhou2, Hong-Xing Yang2, Jia Wang2, Zeng-Chun Ma3, Yue Gao4. 1. Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Beijing Institute of Radiation Medicine, Beijing, 100850, China. 2. Beijing Institute of Radiation Medicine, Beijing, 100850, China. 3. Beijing Institute of Radiation Medicine, Beijing, 100850, China. Electronic address: mazchun@139.com. 4. Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Beijing Institute of Radiation Medicine, Beijing, 100850, China. Electronic address: gaoyue@bmi.ac.cn.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Aconite is a processed product of seminal root of perennial herbaceous plant Aconitum Carmichaclii Debx. of Ranunculaceae. It has the effects of warming and tonifying heart yang and restoring yang to save from collapse. Aconitine is the main effective constituent of aconite and used to prevent and treat heart disease. However, how aconitine exerts myocardial protection is still poorly understood. AIM OF THE STUDY: The present study aimed to investigate the effects of aconitine on mitochondrial dysfunction and explore its mechanism of action. MATERIALS AND METHODS: The model of myocardial injury was induced by Angiotensin II (Ang II) (1 × 10-6 mol L-1), and H9c2 cells were incubated with different concentrations of aconitine. The effect of aconitine on mitochondrial was determined by flow cytometry, transmission electron microscopy, luciferase, Seahorse technique and Western blot. The effects of aconitine on sirtuin-3 (Sirt3) activity and Cyclophilin D (CypD) acetylation were detected by immunofluorescence, RT-PCR and co-immunoprecipitation. RESULTS: We demonstrate that aconitine alleviates the energy metabolic dysfunction of H9c2 cells by activating Sirt3 to deacetylate CypD and inhibiting mitochondrial permeability transition pore (mPTP) opening. In cardiomyocytes, aconitine significantly reduced mitochondrial fragmentation, inhibited acetylation of CypD, suppressed the mPTP opening, mitigated mitochondrial OXPHOS disorders, and improved the synthesis ability of ATP. In contrast, Sirt3 deficiency abolished the effects of aconitine on mPTP and OXPHOS, indicating that aconitine improves mitochondrial function by activating Sirt3. CONCLUSIONS: These results showed that aconitine attenuated the energy metabolism disorder by promoting Sirt3 expression and reducing CypD-mediated mPTP excess openness, rescuing mitochondrial function. Improve mitochondrial function may be a therapeutic approach for treating heart disease, which will generate fresh insight into the cardioprotective of aconitine.
ETHNOPHARMACOLOGICAL RELEVANCE: Aconite is a processed product of seminal root of perennial herbaceous plant Aconitum Carmichaclii Debx. of Ranunculaceae. It has the effects of warming and tonifying heart yang and restoring yang to save from collapse. Aconitine is the main effective constituent of aconite and used to prevent and treat heart disease. However, how aconitine exerts myocardial protection is still poorly understood. AIM OF THE STUDY: The present study aimed to investigate the effects of aconitine on mitochondrial dysfunction and explore its mechanism of action. MATERIALS AND METHODS: The model of myocardial injury was induced by Angiotensin II (Ang II) (1 × 10-6 mol L-1), and H9c2 cells were incubated with different concentrations of aconitine. The effect of aconitine on mitochondrial was determined by flow cytometry, transmission electron microscopy, luciferase, Seahorse technique and Western blot. The effects of aconitine on sirtuin-3 (Sirt3) activity and Cyclophilin D (CypD) acetylation were detected by immunofluorescence, RT-PCR and co-immunoprecipitation. RESULTS: We demonstrate that aconitine alleviates the energy metabolic dysfunction of H9c2 cells by activating Sirt3 to deacetylate CypD and inhibiting mitochondrial permeability transition pore (mPTP) opening. In cardiomyocytes, aconitine significantly reduced mitochondrial fragmentation, inhibited acetylation of CypD, suppressed the mPTP opening, mitigated mitochondrial OXPHOS disorders, and improved the synthesis ability of ATP. In contrast, Sirt3 deficiency abolished the effects of aconitine on mPTP and OXPHOS, indicating that aconitine improves mitochondrial function by activating Sirt3. CONCLUSIONS: These results showed that aconitine attenuated the energy metabolism disorder by promoting Sirt3 expression and reducing CypD-mediated mPTP excess openness, rescuing mitochondrial function. Improve mitochondrial function may be a therapeutic approach for treating heart disease, which will generate fresh insight into the cardioprotective of aconitine.