%0 Journal Article
%T Sinapine targeting PLCβ3 EF hands disrupts Gαq-PLCβ3 interaction and ameliorates cardiovascular diseases.
%A Chu S
%A Shen F
%A Liu W
%A Zhang J
%A Wang X
%A Jiang M
%A Bai G
%J Phytomedicine
%V 126
%N 0
%D 2024 Apr 15
%M 38387273
%F 6.656
%R 10.1016/j.phymed.2023.155200
%X 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.
OBJECTIVE: 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.
METHODS: 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.
CONCLUSIONS: 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.