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Myocardial Ischemia by Activating Vascular Smooth Muscle Cell Soluble Guanylate Cyclase to Inhibit Abnormal Vasomotion

Shuang Yang,Yixiu Zhao,Xiaoling Cheng,Tingting Zhan,Jiaying Tian,Xue Liu,Chunyue Ma,Zhiqi Wang,Luying Jin,Qian Liu,Yanli Wang,Jian Huang,Jinhui Wang,Yan Zhang,Baofeng Yang,

Engineering doi: 10.1016/j.eng.2023.06.009

Abstract: Myocardial ischemia is a serious threat to human health, and vascular dysfunction is its main cause. Buxu Tongyu Granule (BXTY) is an effective traditional Chinese medicine (TCM) for treating myocardial ischemia. However, the underlying mechanism of BXTY is still unclear. In this study, we demonstrate that BXTY ameliorates myocardial ischemia by activating the soluble guanylate cyclase (sGC)–3′,5′-cyclic guanosine monophosphate (cGMP)–protein kinase G (PKG) signaling pathway in vascular smooth muscle cells (VSMCs) to dilate the arteries. BXTY was given by gavage for ten consecutive days before establishing an animal model of acute myocardial ischemia in mice via the intraperitoneal injection of pituitrin. The results showed that BXTY alleviated the symptoms of myocardial ischemia induced by pituitrin in mice, including electrocardiogram abnormalities and changes in plasma enzymes. In addition, BXTY dilated pre-constricted blood vessels and inhibited the vasoconstriction of the superior mesenteric artery in a dose-dependent but endothelial-independent manner. These effects were eliminated by pre-incubating vascular rings with the sGC inhibitors NS 2028 or ODQ, or with the PKG inhibitor KT 5823. Moreover, BXTY increased the protein expression of sGC-β1 and the intracellular second messenger cGMP level in mouse aortic vascular smooth muscle cells (MOVAs). NS 2028 or ODQ reversed these effects of BXTY. The expression level of the cGMP downstream effector protein PKG-1 increased after treating MOVAs with BXTY. NS 2028, ODQ, or KT 5823 also reversed this effect of BXTY. In conclusion, BXTY can improve the symptoms of acute myocardial ischemia in mice, and activating the sGC–cGMP–PKG pathway in VSMCs to induce vasodilation is its key pharmacodynamic mechanism.

Keywords： Myocardial ischemia     Vasomotion     Soluble guanylate cyclase     Buxu Tongyu Granule    

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Myocardial Ischemia by Activating Vascular Smooth Muscle Cell Soluble Guanylate Cyclase to Inhibit Abnormal Vasomotion

Shuang Yang,Yixiu Zhao,Xiaoling Cheng,Tingting Zhan,Jiaying Tian,Xue Liu,Chunyue Ma,Zhiqi Wang,Luying Jin,Qian Liu,Yanli Wang,Jian Huang,Jinhui Wang,Yan Zhang,Baofeng Yang,

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