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.
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.
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.
摘要：
背景：肾素-血管紧张素-醛固酮系统（RAAS）过度激活与心血管疾病（CVD）高度相关，Gαq-PLCβ3轴作为RAAS的核心节点。PLCβ3是心血管疾病的潜在靶点,缺乏抑制剂限制了其药物开发。
目的：芥子碱（SP）是治疗心血管疾病的潜在先导化合物。因此，我们旨在阐明SP对Gαq-PLCβ3轴的调节及其分子机制。
方法：采用醛固酮增多症和高血压动物模型，研究SP通过Gαq-PLCβ3轴对RAAS异常激活的抑制作用。我们使用化学生物学方法来识别潜在的靶标并阐明潜在的分子机制。
方法：使用我们实验室建立的动物模型评估SP对醛固酮增多症和高血压的影响。使用基于活性的蛋白质谱分析与生物正交点击化学反应和其他生化方法进行靶标鉴定和潜在的分子机制研究。
结果：SP通过靶向PLCβ3减轻动物模型的醛固酮增多症和高血压。阻断Gαq-PLCβ3相互作用的潜在机制涉及通过Asn-260氨基酸残基靶向EF手。在心血管系统中，SP比Gαq-GEFT或Gαq-PKCζ轴更精确地调节Gαq-PLCβ3轴。
结论：SP通过靶向PLCβ3EF手域，通过Gαq-PLCβ3相互作用阻断缓解RAAS过度激活，提供了一种用于治疗CVD的新型PLC抑制剂。与选择性Gαq抑制剂不同,与Gαq抑制剂相比，SP降低了治疗CVD的副作用风险。
目的：芥子碱（SP）是治疗心血管疾病的潜在先导化合物。因此，我们旨在阐明SP对Gαq-PLCβ3轴的调节及其分子机制。
方法：采用醛固酮增多症和高血压动物模型，研究SP通过Gαq-PLCβ3轴对RAAS异常激活的抑制作用。我们使用化学生物学方法来识别潜在的靶标并阐明潜在的分子机制。
方法：使用我们实验室建立的动物模型评估SP对醛固酮增多症和高血压的影响。使用基于活性的蛋白质谱分析与生物正交点击化学反应和其他生化方法进行靶标鉴定和潜在的分子机制研究。
结果：SP通过靶向PLCβ3减轻动物模型的醛固酮增多症和高血压。阻断Gαq-PLCβ3相互作用的潜在机制涉及通过Asn-260氨基酸残基靶向EF手。在心血管系统中，SP比Gαq-GEFT或Gαq-PKCζ轴更精确地调节Gαq-PLCβ3轴。
结论：SP通过靶向PLCβ3EF手域，通过Gαq-PLCβ3相互作用阻断缓解RAAS过度激活，提供了一种用于治疗CVD的新型PLC抑制剂。与选择性Gαq抑制剂不同,与Gαq抑制剂相比，SP降低了治疗CVD的副作用风险。
