Compound Danshen Dripping Pill inhibits hypercholesterolemia/atherosclerosis-induced heart failure in ApoE and LDLR dual deficient mice via multiple mechanisms

Yanfang Yang; Ke Feng; Liying Yuan; Yuxin Liu; Mengying Zhang; Kaimin Guo; Zequn Yin; Wenjia Wang; Shuiping Zhou; He Sun; Kaijing Yan; Xijun Yan; Xuerui Wang; Yajun Duan; Yunhui Hu; Jihong Han

doi:10.1016/j.apsb.2022.11.012

Compound Danshen Dripping Pill inhibits hypercholesterolemia/atherosclerosis-induced heart failure in ApoE and LDLR dual deficient mice via multiple mechanisms

Acta Pharm Sin B. 2023 Mar;13(3):1036-1052. doi: 10.1016/j.apsb.2022.11.012. Epub 2022 Nov 15.

Authors

Yanfang Yang¹, Ke Feng², Liying Yuan¹, Yuxin Liu¹, Mengying Zhang³, Kaimin Guo³, Zequn Yin⁴, Wenjia Wang³, Shuiping Zhou^{5

6}, He Sun^{3

5

6}, Kaijing Yan^{3

5

6}, Xijun Yan^{5

6}, Xuerui Wang⁴, Yajun Duan^{4

7}, Yunhui Hu³, Jihong Han^{1

4}

Affiliations

¹ College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin 300071, China.
² Department of Physiology, Binzhou Medical University, Yantai 264003, China.
³ Cloudphar Pharmaceuticals Co., Ltd., Shenzhen 518000, China.
⁴ Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei 230009, China.
⁵ The State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Academy, Tasly Holding Group Co., Ltd., Tianjin 300410, China.
⁶ Tasly Pharmaceutical Group Co., Ltd., Tianjin 300410, China.
⁷ Department of Cardiology, the First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, China.

Abstract

Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE^-/-LDLR^-/-) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.

Keywords: ApoE–/–LDLR–/– mice; Atherosclerosis; Compound danshen dripping pill; Heart failure; Hypercholesterolemia; Inflammation; Oxidative stress; Simvastatin.