2. Academic Validation
  3. Sinapine targeting PLCβ3 EF hands disrupts Gαq-PLCβ3 interaction and ameliorates cardiovascular diseases

Sinapine targeting PLCβ3 EF hands disrupts Gαq-PLCβ3 interaction and ameliorates cardiovascular diseases

  • Phytomedicine. 2024 Apr:126:155200. doi: 10.1016/j.phymed.2023.155200.
Simeng Chu 1,  Fukui Shen 1,  Wenjuan Liu 1,  Jin Zhang 1,  Xiaoying Wang 2,  Min Jiang 3,  Gang Bai 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China.
  • 2 Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China. Electronic address: [email protected].
  • 3 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China. Electronic address: [email protected].
  • 4 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China. Electronic address: [email protected].
PMID: 38387273 DOI: 10.1016/j.phymed.2023.155200
Abstract

Background: The renin-angiotensin-aldosterone system (RAAS) over-activation is highly involved in cardiovascular diseases (CVDs), with the Gαq-PLCβ3 axis acting as a core node of RAAS. PLCβ3 is a potential target of CVDs, and the lack of inhibitors has limited its drug development.

Purpose: Sinapine (SP) is a potential leading compound for treating CVDs. Thus, we aimed to elucidate the regulation of SP towards the Gαq-PLCβ3 axis and its molecular mechanism.

Study design: Aldosteronism and hypertension animal models were employed to investigate SP's inhibitory effect on the abnormal activation of the RAAS through the Gαq-PLCβ3 axis. We used chemical biology methods to identify potential targets and elucidate the underlying molecular mechanisms.

Methods: The effects of SP on aldosteronism and hypertension were evaluated using an established animal model in our laboratory. Target identification and underlying molecular mechanism research were performed using activity-based protein profiling with a bio-orthogonal click chemistry reaction and Other biochemical methods.

Results: SP alleviated aldosteronism and hypertension in animal models by targeting PLCβ3. The underlying mechanism for blocking the Gαq-PLCβ3 interaction involves targeting the EF hands through the Asn-260 amino acid residue. SP regulated the Gαq-PLCβ3 axis more precisely than the Gαq-GEFT or Gαq-PKCζ axis in the cardiovascular system.

Conclusion: SP alleviated RAAS over-activation via Gαq-PLCβ3 interaction blockade by targeting the PLCβ3 EF hands domain, which provided a novel PLC inhibitor for treating CVDs. Unlike selective Gαq inhibitors, SP reduced the risk of side effects compared to Gαq inhibitors in treating CVDs.

Keywords

Cardiovascular disease; EF hands; Gαq; PLCs inhibitor; Protein-protein interaction; Sinapine.

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