2. Academic Validation
  3. Huanglian Jiedu decoction inhibits vascular smooth muscle cell-derived foam cell formation by activating autophagy via suppressing P2RY12

Huanglian Jiedu decoction inhibits vascular smooth muscle cell-derived foam cell formation by activating autophagy via suppressing P2RY12

  • J Ethnopharmacol. 2024 Jun 28:328:118125. doi: 10.1016/j.jep.2024.118125.
Jinhai Lin 1,  Mingyang Gu 2,  Xiaolong Wang 3,  Yuanyuan Chen 4,  Nhi Van Chau 5,  Junlong Li 6,  Qingmin Chu 7,  Lijin Qing 8,  Wei Wu 9
Affiliations

Affiliations

  • 1 The First Clinical Medical College, Guangzhou University of Chinese Medicine, 12 Jichang Road, Guangzhou, 510405, Guangdong, China; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, 12 Jichang Road, Guangzhou, 510405, Guangdong, China. Electronic address: 2458780647@qq.com.
  • 2 The First Clinical Medical College, Guangzhou University of Chinese Medicine, 12 Jichang Road, Guangzhou, 510405, Guangdong, China. Electronic address: gmy19990514@163.com.
  • 3 The First Clinical Medical College, Guangzhou University of Chinese Medicine, 12 Jichang Road, Guangzhou, 510405, Guangdong, China. Electronic address: 3067375329@qq.com.
  • 4 Qinchengda Community Health Service Center, Shenzhen Bao'an Traditional Chinese Medicine Hospital Group, No. 225, Block 10A, Qinchengda Yueyuan Commercial and Residential Building, Shenzhen, 518100, Guangdong, China. Electronic address: 916958133@qq.com.
  • 5 The First Clinical Medical College, Guangzhou University of Chinese Medicine, 12 Jichang Road, Guangzhou, 510405, Guangdong, China; Traditional Medicine Department, Can Tho University of Medicine and Pharmacy, 179 Nguyen Van Cu Street, An Khanh, Ninh Kieu, Can Tho, 94000, Viet Nam. Electronic address: cnvan@ctump.edu.vn.
  • 6 The Department of Cardiology, First Affiliated Hospital, Guangzhou University of Chinese Medicine, 16 Jichang Road, Guangzhou, 510405, Guangdong, China. Electronic address: 18561883898@163.com.
  • 7 The Department of Cardiology, First Affiliated Hospital, Guangzhou University of Chinese Medicine, 16 Jichang Road, Guangzhou, 510405, Guangdong, China. Electronic address: 13929504676@163.com.
  • 8 The Department of Cardiology, First Affiliated Hospital, Guangzhou University of Chinese Medicine, 16 Jichang Road, Guangzhou, 510405, Guangdong, China. Electronic address: qljin@126.com.
  • 9 The Department of Cardiology, First Affiliated Hospital, Guangzhou University of Chinese Medicine, 16 Jichang Road, Guangzhou, 510405, Guangdong, China. Electronic address: wuweigzucm@163.com.
PMID: 38561055 DOI: 10.1016/j.jep.2024.118125
Abstract

Ethnopharmacological relevance: Huanglian Jiedu Decoction (HLJDD) is a Chinese medicine with a long history of therapeutic application. It is widely used in treating atherosclerosis (AS) in Chinese medicine theory and clinical practice. However, the mechanism of HLJDD in treating AS remains unclear.

Aim of the study: To investigate the efficacy and mechanism of HLJDD in treating AS.

Materials and methods: AS was induced on high-fat diet-fed apoE-/- mice, with the aorta pathological changes evaluated with lipid content and plaque progression. In vitro, foam cells were induced by subjecting primary mouse aortic vascular smooth muscle cells (VSMCs) to oxLDL incubation. After HLJDD intervention, VSMCs were assessed with lipid stack, Apoptosis, oxidative stress, and the expression of foam cell markers. The effects of P2RY12 were tested by adopting clopidogrel hydrogen sulfate (CDL) in vivo and transfecting P2RY12 over-expressive plasmid in vitro. Autophagy was inhibited by Chloroquine or transfecting siRNA targeting Atg7 (siATG7). The mechanism of HLJDD treating atherosclerosis was explored using network pharmacology and validated with molecular docking and co-immunoprecipitation.

Results: HLJDD exhibited a dose-dependent reduction in lipid deposition, collagen loss, and necrosis within plaques. It also reversed lipid accumulation and down-regulated the expression of foam cell markers. P2RY12 inhibition alleviated AS, while P2RY12 overexpression enhanced foam cell formation and blocked the therapeutic effects of HLJDD. Network pharmacological analysis suggested that HLJDD might mediate PI3K/Akt signaling pathway-induced Autophagy. P2RY12 overexpression also impaired Autophagy. Similarly, inhibiting Autophagy counteracted the effect of CDL, exacerbated AS in vivo, and promoted foam cell formation in vitro. However, HLJDD treatment mitigated these detrimental effects by suppressing the PI3K/Akt signaling pathway. Immunofluorescence and molecular docking revealed a high affinity between P2RY12 and PIK3CB, while co-immunoprecipitation assays illustrated their interaction.

Conclusions: HLJDD inhibited AS in vivo and foam cell formation in vitro by restoring P2RY12/PI3K/Akt signaling pathway-suppressed Autophagy. This study is the first to reveal an interaction between P2RY12 and PI3K3CB.

Keywords

Atherosclerosis; Autophagy; Foam cell formation; Huanglian jiedu decoction; Vascular smooth muscle cell.

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