1. Research Projects
(1) National Natural Science Foundation of China: The characterization of mild mitochondrial uncoupling of vascular smooth muscle cells and the vascular intimal hyperplasia inhibition by chemical mitochondrial uncouplers. (2018.01-2020.12)
(2) National Natural Science Foundation of China: The impairment of myocardial mitochondrial oxidative phosphorylation inhibits STAT3 signaling-the novel mechanism of the transition from heart hypertrophy to heart failure. (2018.01-2021.12)
(3) National Natural Science Foundation of China: A novel autophagy inhibitor and its mechanism of inhibiting pathological cardiac hypertrophy. (2014.01-2017.12)
(4) National Natural Science Foundation of China: Role of BMP4 in pathological heart hypertrophy. (2012.01-2015.12)
2. Academic Awards
Top Paper Award in Hypertension (2014) (American Heart Association)
3. Representative Research Achievements
(1) Piezo1 channels are mechanosensitive cationic channels that are activated by mechanical stretch or shear stress. Endothelial Piezo1 activation by shear stress caused by blood flow induces ATP release from endothelial cells; however, the link between shear stress and endothelial ATP production is unclear. We found that Piezo1 channel activation stimulated ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells. Piezo1 activation-induced cytosolic Ca2+ increase was involved in glycolysis process but not mitochondrial respiration. Piezo1 channels were present in mitochondria of endothelial cells. The work suggests a novel role of Piezo1 channel in endothelial ATP production.
(2) Lipid metabolism disorders contribute to hyperlipidemia and hepatic steatosis. It is ideal to develop drugs simultaneous improving both hyperlipidemia and hepatic steatosis. Nitazoxanide is an FDA-approved oral antiprotozoal drug with excellent pharmacokinetic and safety profile. We found that nitazoxanide and its metabolite tizoxanide induced mild mitochondrial uncoupling and subsequently activated AMPK in HepG2 cells. Gavage administration of nitazoxanide inhibited high-fat diet (HFD)-induced increases of liver weight, blood and liver lipids, and ameliorated HFD-induced renal lipid accumulation in hamsters. Nitazoxanide significantly improved HFD-induced histopathologic changes of hamster livers. In the hamsters with pre-existing hyperlipidemia and hepatic steatosis, nitazoxanide also showed therapeutic effect. Gavage administration of nitazoxanide improved HFD-induced hepatic steatosis in C57BL/6J mice and western diet (WD)-induced hepatic steatosis in Apoe -/- mice. The present study suggests that repurposing nitazoxanide as a drug for hyperlipidemia and hepatic steatosis treatment is promising.
(3) Cardiomyocyte loss and cardiac fibrosis are the main characteristics of cardiac ischemia and heart failure, and mitochondrial function of cardiomyocytes is impaired in cardiac ischemia and heart failure, we aim to identify fate variability of cardiomyocytes and cardiac fibroblasts with mitochondria inhibition and explore the underlying mechanism. Cardiomyocytes and cardiac fibroblasts displayed different morphology. The mitochondrial respiratory function and the expressions of mitochondrial complex I, II, III, IV, and V of cardiac fibroblasts were lower than that of cardiomyocytes. Mitochondrial respiratory complex I inhibitor rotenone and H2O2 treatment induced cell death of cardiomyocyte but not cardiac fibroblasts. The function of complex I/II was impaired in cardiomycytes but not cardiac fibroblasts stimulated with H2O2 and in ischemic heart of mice. Rotenone and H2O2 treatment reduced STAT3 expression and activity in cardiomyocytes but not cardiac fibroblasts. Inhibition of STAT3 impaired mitochondrial respiratory capacity and exacerbated H2O2-induced cell injury in cardiomycytes but not significantly in cardiac fibroblasts. In conclusion, the different susceptibility of cardiomyocytes and cardiac fibroblasts to mitochondria inhibition determines the cell fate under the same pathological stimuli and in which STAT3 plays a critical role.
Mitochondrial metabolism; Cardiovascular pharmacology.
1. Research Projects
(1) National Natural Science Foundation of China: The characterization of mild mitochondrial uncoupling of vascular smooth muscle cells and the vascular intimal hyperplasia inhibition by chemical mitochondrial uncouplers. (2018.01-2020.12)
(2) National Natural Science Foundation of China: The impairment of myocardial mitochondrial oxidative phosphorylation inhibits STAT3 signaling-the novel mechanism of the transition from heart hypertrophy to heart failure. (2018.01-2021.12)
(3) National Natural Science Foundation of China: A novel autophagy inhibitor and its mechanism of inhibiting pathological cardiac hypertrophy. (2014.01-2017.12)
(4) National Natural Science Foundation of China: Role of BMP4 in pathological heart hypertrophy. (2012.01-2015.12)
2. Academic Awards
Top Paper Award in Hypertension (2014) (American Heart Association)
3. Representative Research Achievements
(1) Piezo1 channels are mechanosensitive cationic channels that are activated by mechanical stretch or shear stress. Endothelial Piezo1 activation by shear stress caused by blood flow induces ATP release from endothelial cells; however, the link between shear stress and endothelial ATP production is unclear. We found that Piezo1 channel activation stimulated ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells. Piezo1 activation-induced cytosolic Ca2+ increase was involved in glycolysis process but not mitochondrial respiration. Piezo1 channels were present in mitochondria of endothelial cells. The work suggests a novel role of Piezo1 channel in endothelial ATP production.
(2) Lipid metabolism disorders contribute to hyperlipidemia and hepatic steatosis. It is ideal to develop drugs simultaneous improving both hyperlipidemia and hepatic steatosis. Nitazoxanide is an FDA-approved oral antiprotozoal drug with excellent pharmacokinetic and safety profile. We found that nitazoxanide and its metabolite tizoxanide induced mild mitochondrial uncoupling and subsequently activated AMPK in HepG2 cells. Gavage administration of nitazoxanide inhibited high-fat diet (HFD)-induced increases of liver weight, blood and liver lipids, and ameliorated HFD-induced renal lipid accumulation in hamsters. Nitazoxanide significantly improved HFD-induced histopathologic changes of hamster livers. In the hamsters with pre-existing hyperlipidemia and hepatic steatosis, nitazoxanide also showed therapeutic effect. Gavage administration of nitazoxanide improved HFD-induced hepatic steatosis in C57BL/6J mice and western diet (WD)-induced hepatic steatosis in Apoe -/- mice. The present study suggests that repurposing nitazoxanide as a drug for hyperlipidemia and hepatic steatosis treatment is promising.
(3) Cardiomyocyte loss and cardiac fibrosis are the main characteristics of cardiac ischemia and heart failure, and mitochondrial function of cardiomyocytes is impaired in cardiac ischemia and heart failure, we aim to identify fate variability of cardiomyocytes and cardiac fibroblasts with mitochondria inhibition and explore the underlying mechanism. Cardiomyocytes and cardiac fibroblasts displayed different morphology. The mitochondrial respiratory function and the expressions of mitochondrial complex I, II, III, IV, and V of cardiac fibroblasts were lower than that of cardiomyocytes. Mitochondrial respiratory complex I inhibitor rotenone and H2O2 treatment induced cell death of cardiomyocyte but not cardiac fibroblasts. The function of complex I/II was impaired in cardiomycytes but not cardiac fibroblasts stimulated with H2O2 and in ischemic heart of mice. Rotenone and H2O2 treatment reduced STAT3 expression and activity in cardiomyocytes but not cardiac fibroblasts. Inhibition of STAT3 impaired mitochondrial respiratory capacity and exacerbated H2O2-induced cell injury in cardiomycytes but not significantly in cardiac fibroblasts. In conclusion, the different susceptibility of cardiomyocytes and cardiac fibroblasts to mitochondria inhibition determines the cell fate under the same pathological stimuli and in which STAT3 plays a critical role.
1. Jiang M, Zhang YX, Bu WJ, Li P, Chen JH, Cao M, Dong YC, Sun ZJ, Dong DL. Piezo1 channel activation stimulates ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells. Br J Pharmacol. 2023 Feb 5. doi: 10.1111/bph.16050. Epub ahead of print. PMID: 36740831.
2. Ma MH, Li FF, Li WF, Zhao H, Jiang M, Yu YY, Dong YC, Zhang YX, Li P, Bu WJ, Sun ZJ, Dong DL. Repurposing nitazoxanide as a novel anti-atherosclerotic drug based on mitochondrial uncoupling mechanisms. Br J Pharmacol. 2023 ;180(1):62-79.
3. Li F, Jiang M, Ma M, Chen X, Zhang Y, Zhang Y, Yu Y, Cui Y, Chen J, Zhao H, Sun Z, Dong D. Anthelmintics nitazoxanide protects against experimental hyperlipidemia and hepatic steatosis in hamsters and mice. Acta Pharm Sin B. 2022;12(3):1322-1338.
4. Zhao J, Gao JL, Zhu JX, Zhu HB, Peng X, Jiang M, Fu Y, Xu J, Mao XH, Hu N, Ma MH, Dong DL. The different response of cardiomyocytes and cardiac fibroblasts to mitochondria inhibition and the underlying role of STAT3. Basic Res Cardiol. 2019;114(2):12.
5. Xiao XL, Hu N, Zhang XZ, Jiang M, Chen C, Ma R, Ma ZG, Gao JL, Xuan XC, Sun ZJ, Dong DL. Niclosamide inhibits vascular smooth muscle cell proliferation, migration, and attenuates neointimal hyperplasia in injured rat carotid arteries. Br J Pharmacol. 2018;175(10):1707-1718.
6. Zhang YQ, Shen X, Xiao XL, Liu MY, Li SL, Yan J, Jin J, Gao JL, Zhen CL, Hu N, Zhang XZ, Tai Y, Zhang LS, Bai YL, Dong DL. Mitochondrial uncoupler CCCP induces vasorelaxation without involving KATP channel activation in smooth muscle cells of arteries. Br J Pharmacol. 2016;173(21):3145-3158.
7. Liu MY, Jin J, Li SL, Yan J, Zhen CL, Gao JL, Zhang YH, Zhang YQ, Shen X, Zhang LS, Wei YY, Zhao Y, Wang CG, Bai YL, Dong DL. Mitochondrial Fission of Smooth Muscle Cells Is Involved in Artery Constriction. Hypertension.2016; 68:1245-1254.
8. Wang YC, Xiao XL, Li N, Yang D, Xing Y, Huo R, Liu MY, Zhang YQ, Dong DL. Estrogen inhibits BMP4-induced BMP4 expression in cardiomyocytes: a potential mechanism of estrogen-mediated protection against cardiac hypertrophy. Br J Pharmacol. 2015, 172(23):5586–5595.
9. Xie X, Zhao Y, Ma CY, Xu XM, Zhang YQ, Wang CG, Jin J, Shen X, Gao JL, Li N, Sun ZJ, Dong DL. Dimethyl fumarate induces necroptosis in colon cancer cells through glutathione depletion/ROS increase/MAPKs activation pathway. Br J Pharmacol. 2015;172(15):3929-43.
10.Sheng Y, Sun B, Guo WT, Liu X, Wang YC, Xie X, Xiao XL, Li N, Dong DL. DMH1 (4-[6-(4-Isopropoxyphenyl)pyrazolo [1,5-a]pyrimidin-3-yl] quinoline) is a novel autophagy inhibitor. Br J Pharmacol. 2014;171(21):4970-80.
