Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling

Li，Tangzhiming1; Li，Tangzhiming2; Li，Suqi3; Feng，Yilu2; Feng，Yilu4; Zeng，Xiaofang2; Dong，Shaohong1; Li，Jianghua1; Zha，Lihuang2; Zha，Lihuang4; Luo，Hui2; Zhao，Lin5; Liu，Bin2; Liu，Bin4; Ou，Ziwei; Ou，Ziwei2,4; Lin，Wenchao2; Lin，Wenchao4; Zhang，Mengqiu2; Zhang，Mengqiu4; Li，Sheng2; Jiang，Qiuqiong1; Qi，Qiangqiang2; Xu，Qingyao2; Yu，Zaixin2; Yu，Zaixin4

2020

10.1155/2020/6973636

Oxidative Medicine and Cellular Longevity   影响因子和分区

1942-0900

1942-0994

Pulmonary arterial hypertension (PAH) is a lethal disease generally characterized by pulmonary artery remodeling. Mitochondrial metabolic disorders have been implicated as a critical regulator of excessively proliferative- and apoptosis-resistant phenotypes in pulmonary artery smooth muscle cells (PASMCs). Dichloroacetate (DCA) is an emerging drug that targets aerobic glycolysis in tumor cells. Atorvastatin (ATO) is widely used for hyperlipemia in various cardiovascular diseases. Considering that DCA and ATO regulate glucose and lipid metabolism, respectively, we hypothesized that the combination of DCA and ATO could be a potential treatment for PAH. A notable decrease in the right ventricular systolic pressure accompanied by reduced right heart hypertrophy was observed in the DCA/ATO combination treatment group compared with the monocrotaline treatment group. The DCA/ATO combination treatment alleviated vascular remodeling, thereby suppressing excessive PASMC proliferation and macrophage infiltration. In vitro, both DCA and ATO alone reduced PASMC viability by upregulating oxidative stress and lowering mitochondrial membrane potential. Surprisingly, when combined, DCA/ATO was able to decrease the levels of reactive oxygen species and cell apoptosis without compromising PASMC proliferation. Furthermore, suppression of the p38 pathway through the specific inhibitor SB203580 attenuated cell death and oxidative stress at a level consistent with that of DCA/ATO combination treatment. These observations suggested a complementary effect of DCA and ATO on rescuing PASMCs from a PAH phenotype through p38 activation via the regulation of mitochondrial-related cell death and oxidative stress. DCA in combination with ATO may represent a novel therapeutic strategy for PAH treatment.

SCI ; EI

英语

第一

National Natural Science Foundation of China[81873416][81770496][81570050] ; National Science and Technology Plan of China[2017ZX0930401405]

Cell Biology

Cell Biology

WOS:000544595600001

HINDAWI LTD

2-s2.0-85087146261

Scopus

1.Department of Cardiology,Shenzhen People's Hospital,First Affiliated Hospital of Southern University of Science and Technology,Second Clinical Medical College of Jinan University,Guangdong,China
2.Department of Cardiology,Xiangya Hospital,Central South University,Changsha,China
3.State Key Laboratory of Cardiovascular Disease,Fu Wai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China
4.National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha, Hunan,87 Xiangya Road,China
5.Centre for Pharmacology and Therapeutics,Division of Experimental Medicine,Imperial College London,Hammersmith Hospital,London,W12 0NN,United Kingdom

Li，Tangzhiming,Li，Tangzhiming,Li，Suqi,et al. Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling[J]. Oxidative Medicine and Cellular Longevity,2020,2020.

Li，Tangzhiming.,Li，Tangzhiming.,Li，Suqi.,Feng，Yilu.,Feng，Yilu.,...&Yu，Zaixin.(2020).Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling.Oxidative Medicine and Cellular Longevity,2020.

Li，Tangzhiming,et al."Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling".Oxidative Medicine and Cellular Longevity 2020(2020).