Juan Peng1, Yun-Cheng Lv2, Ping-Ping He3, Yan-Yan Tang2, Wei Xie2, Xiang-Yu Liu4, Yuan Li2, Gan Lan2, Min Zhang2, Chi Zhang2, Jin-Feng Shi2, Xi-Long Zheng5, Wei-Dong Yin6, Chao-Ke Tang7. 1. Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China; Yongzhou Vocational and Technical College, Yongzhou, Hunan 425000, China. 2. Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China. 3. Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China; School of Nursing, University of South China, Hengyang, Hunan 421001, China. 4. Department of Biochemistry and Molecular Biology, School of Life Sciences and Technology, University of South, Hengyang, Hunan 421001, China. 5. Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada. 6. Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China. Electronic address: wdy20042004@126.com. 7. Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China. Electronic address: tangchaoke@qq.com.
Abstract
BACKGROUND: Atherosclerosis is a major cause of coronary artery disease, which is characterized by cellular lipid accumulation. Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism. Studies have shown that macrophage-derived LPL exhibits proatherogenic properties, and plays a major role in lipid accumulation in macrophages. Evidence suggests that oxidative stress can effectively enhance macrophage LPL production. Betulinic acid (BA) is a pentacyclic lupane triterpene with a potent antioxidant activity. In this study, we investigated whether BA affects the expression of macrophage LPL and how it regulates cellular lipid accumulation. METHODS AND RESULTS: We revealed that BA downregulated H2O2-simulated macrophage LPL protein, mRNA levels and its activity in both concentration- and time-dependent manners. Furthermore, BA decreased LPL-involved total cholesterol and triglyceride levels in macrophages. In addition, cellular lipid staining by Oil Red O showed that BA decreased cellular lipid droplet deposition. Next, we confirmed that pretreatment with BA decreased H2O2-induced production of intracellular reactive oxygen species in a concentration-dependent manner. Further studies demonstrated that BA inhibited H2O2-induced membrane translocation of PKC, phosphorylation of ERK1/2 and c-Fos. Finally, the induction of LPL production and activity by H2O2 was abolished by BA, inhibition of PKC or ERK or depletion c-Fos, respectively. CONCLUSIONS: BA, through its role of antioxidant activity, attenuated macrophage-derived LPL expression and activity induced by oxidative stress, and effectively reduced cellular lipid accumulation, likely through inhibition of the pathways involving PKC, ERK and c-Fos. These effects of BA may contribute to its mitigation of atherosclerosis and help develop BA as a therapeutic compound in treatment of atherosclerosis.
BACKGROUND:Atherosclerosis is a major cause of coronary artery disease, which is characterized by cellular lipid accumulation. Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism. Studies have shown that macrophage-derived LPL exhibits proatherogenic properties, and plays a major role in lipid accumulation in macrophages. Evidence suggests that oxidative stress can effectively enhance macrophage LPL production. Betulinic acid (BA) is a pentacyclic lupanetriterpene with a potent antioxidant activity. In this study, we investigated whether BA affects the expression of macrophage LPL and how it regulates cellular lipid accumulation. METHODS AND RESULTS: We revealed that BA downregulated H2O2-simulated macrophage LPL protein, mRNA levels and its activity in both concentration- and time-dependent manners. Furthermore, BA decreased LPL-involved total cholesterol and triglyceride levels in macrophages. In addition, cellular lipid staining by Oil Red O showed that BA decreased cellular lipid droplet deposition. Next, we confirmed that pretreatment with BA decreased H2O2-induced production of intracellular reactive oxygen species in a concentration-dependent manner. Further studies demonstrated that BA inhibited H2O2-induced membrane translocation of PKC, phosphorylation of ERK1/2 and c-Fos. Finally, the induction of LPL production and activity by H2O2 was abolished by BA, inhibition of PKC or ERK or depletion c-Fos, respectively. CONCLUSIONS:BA, through its role of antioxidant activity, attenuated macrophage-derived LPL expression and activity induced by oxidative stress, and effectively reduced cellular lipid accumulation, likely through inhibition of the pathways involving PKC, ERK and c-Fos. These effects of BA may contribute to its mitigation of atherosclerosis and help develop BA as a therapeutic compound in treatment of atherosclerosis.
Authors: Can Cheng; Songming Zhuo; Bo Zhang; Xu Zhao; Ying Liu; Chaoliang Liao; Jing Quan; Zhenzhen Li; Ann M Bode; Ya Cao; Xiangjian Luo Journal: Int J Biol Sci Date: 2019-06-04 Impact factor: 6.580
Authors: Israel Pérez-Torres; Vicente Castrejón-Téllez; María Elena Soto; María Esther Rubio-Ruiz; Linaloe Manzano-Pech; Verónica Guarner-Lans Journal: Int J Mol Sci Date: 2021-02-11 Impact factor: 5.923
Authors: Gang Deng; Chao Ma; Haitian Zhao; Shenqi Zhang; Jun Liu; Fuyao Liu; Zeming Chen; Ann T Chen; Xin Yang; Jonathan Avery; Pan Zou; Fengyi Du; Keun-Poong Lim; Daniel Holden; Songye Li; Richard E Carson; Yiyun Huang; Qianxue Chen; W Taylor Kimberly; J Marc Simard; Kevin N Sheth; Jiangbing Zhou Journal: Theranostics Date: 2019-09-21 Impact factor: 11.556