DanHong injection targets endothelin receptor type B and angiotensin II receptor type 1 in protection against cardiac hypertrophy
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Min-Yu Zhang1,2,*, Fei-Fei Guo1,*, Hong-Wei Wu1, Yang-Yang Yu3, Jun-Ying Wei1, Shi-Feng Wang4, Yu-Xin Zhang4, Ming-Hua Xian1, Qing-Hua Wu3, Bu-Chang Zhao5, Shi-You Li3 and Hong-Jun Yang1
1Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
2Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
3Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
4School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
5Buchang Pharmacy Group, Xi’an, China
*These authors contributed equally to this work
Hong-Jun Yang, email: [email protected]
Shi-You Li, email: [email protected]
Keywords: cardiac hypertrophy, human induced pluripotent stem cell-derived cardiomyocytes, endothlin B receptor, angiotensin II receptor 1, DanHong injection
Received: August 05, 2017 Accepted: September 23, 2017 Published: October 13, 2017
Cardiac hypertrophy (CH) is an independent risk factor for cardiovascular diseases (CVDs). Mitigating or preventing CH is the most effective strategy for the treatment of CVDs. DanHong injection (DH) is a Chinese herbal medicine preparation (CHMP) widely used in clinical treatment of several CVDs in China. However, the direct targets and cellular mechanisms for these protective effects remain unclear. This study was designed to illustrate the direct targets of DH in protecting against CH and investigate CH molecular pathogenesis. A hypertrophic cell model was induced by endothelin-1 (ET-1) on human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Real time cellular analysis (RTCA) cardio system and high content analysis (HCA) were used to detect the changes in contractile function, morphology and protein level of hypertrophic hiPS-CMs. Agonist and antagonist assay on receptors were performed using calcium mobilization high-throughput screening (HTS). DH significantly attenuated CH by modulating myocardial contractility, suppressing cell area enlargement and down-regulating ET-1-induced brain natriuretic peptide (BNP), actinin alpha 2 (ACTN2) and cardiac muscle troponin T (TNNT2) protein expression (P < 0.05). Endothelin receptor type B (ETBR) and angiotensin II receptor type 1 (AT1R) were DH direct targets, with IC50 value of 25.67 μL/mL and 1.10 μL/mL, respectively. Proteomics analysis showed that proteins involved in cell cycle inhibition, RNA processing, mitochondrial translation and cytoskeleton are significant regulated by DH treatment. These data revealed that ETBR and AT1R are DH direct targets on protecting against CH, providing a strategy to explore direct targets of CHMPs.
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