Calhex231 Attenuates Rat Myocardial Infarction Size and Fibrosis by Suppressing Pyroptosis
Objective Calcium-sensing receptor(CaSR)plays an important role in the development of myocardial infarction(MI).Thus,we investigated whether Calhex231,a negative allosteric modulator of CaSR,could protect the myocardium in a rat MI model.Methods Wistar rats were randomly divided into three groups:sham,MI and MI+Calhex231.Myocardial infarct size and necrosis were assessed by TTC staining.Myocardial fibrosis,collagen Ⅲ and collagen synthesis of fibroblasts were examined by Masson staining,immunohistochemistry and electron microscopy.CaSR expression was detected by both immunofluorescence and Western blot analysis.Protein expression levels of the NOD-like receptor thermal protein domain associated protein 3(NLRP3),caspase-1(Casp-1),gasdermin D(GSDMD),N-terminal domain of GSDMD(NT-GSDMD)and interleukin-1β(IL-1β)were detected by Western blot analysis.NT-GSDMD and IL-1β were also assessed by immunohistochemistry.Results Compared with those of the sham group,myocardial infarct size and fibrosis were obviously increased in the rats of the MI group.Collagen Ⅲ deposition and collagen synthesis of fibroblasts were evidently increased in myocardial tissues of the MI group compared with the sham group.The expression levels of CaSR,NLRP3,Casp-1,GSDMD,NT-GSDMD and IL-1β were significantly increased in the MI group compared with the sham group.The increased expression of NT-GSDMD and IL-1β was further confirmed by immunohistochemical staining.Moreover,Calhex231 administration inhibited all these alterations in the MI+Calhex231 group compared to the MI group.Conclusion Calhex231 reduced myocardial infarct size and fibrosis in rats,probably by inhibiting pyroptosis and collagen Ⅲ deposition via CaSR,which contributes to the potential clinical application of Calhex231 in myocardial fibrotic disease.
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维普
