Calhex231 ameliorates myocardial fibrosis post myocardial infarction in rats through the autophagy‐NLRP3 inflammasome pathway in macrophages

Abstract

The calcium‐sensing receptor (CaSR) is involved in the pathophysiology of many cardiovascular diseases, including myocardial infarction (MI) and hypertension. The role of Calhex231, a specific inhibitor of CaSR, in myocardial fibrosis following MI is still unclear. Using Wistar rats, we investigated whether Calhex231 ameliorates myocardial fibrosis through the autophagy‐NLRP3 inflammasome pathway in macrophages post myocardial infarction (MI). The rats were randomly divided into sham, MI and MI + Calhex231 groups. Compared with the sham rats, the MI rats consistently developed severe cardiac function, myocardial fibrosis and infiltration of inflammatory cells including macrophages. Moreover, inflammatory pathway including activation of NLRP3 inflammasome, IL‐1β and autophagy was significantly up‐regulated in myocardial tissue, infiltrated cardiac macrophages and peritoneal macrophages of the MI rats. These impacts were reversed by Calhex231. In vitro, studies revealed that calindol and rapamycin exacerbated MI‐induced autophagy and NLRP3 inflammasome activation in peritoneal macrophages. Calhex231 and 3‐Methyladenine (a specific inhibitor of autophagy) attenuated both autophagy and NLRP3 inflammasome activation; however, the caspase‐1 inhibitor Z‐YVAD‐FMK did not. Our study indicated that Calhex231 improved cardiac function and ameliorated myocardial fibrosis post MI, likely via the inhibition of autophagy‐mediated NLRP3 inflammasome activation; this provides a new therapeutic target for ventricular remodelling‐related cardiovascular diseases.

Blockade of the Notch Signaling Pathway Promotes M2 Macrophage Polarization to Suppress Cardiac Fibrosis Remodeling in Mice With Myocardial Infarction

“…Additionally, further experimentation revealed that treatment with sh-RBP-J also brought about a decrease in collagen content and degree of fibrosis, which is particularly important as macrophages are heralded as highly significant in the process of fibrosis ( 23 ). Interestingly, there is a plethora of evidence to suggest the involvement of macrophages in MI, such that macrophage polarization is regarded as critical to cardiac remodeling after MI in humans ( 4 , 6 ). Moreover, an insufficiency of macrophages was previously associated with impaired wound healing and promoted left ventricular remodeling after the occurrence of MI ( 24 ).…”

“…There is also evidence to suggest that M2 macrophages can suppress extracellular matrix synthesis and inflammatory responses in the process of tissue repair ( 26 ). Meanwhile, Liu et al recently demonstrated that Calhex231 can improve myocardial fibrosis after MI by regulating the autophagy-NLRP3 pathway in macrophages ( 4 ). Altogether, the aforementioned evidence supported our results such that blockade of Notch signaling exerts a reductive effect on cardiac inflammation and that Notch signaling-mediated macrophage polarization can regulate fibrosis by affecting the inflammatory response.…”

“…Unsurprisingly, macrophages are often implicated in the inflammation that ensues after MI ( 4 ). More precisely, the M1 form of macrophages is known to promote the progression of inflammatory responses, whereas M2 macrophages exert a certain anti-inflammatory effect and a promoting effect on the proliferation of endothelial cells and fibroblasts, thus collectively regulating the immune microenvironment at the site of infarction by influencing their functional characteristics ( 5 ).…”

Identification and Validation of Autophagy-Related Genes as Potential Biomarkers and Therapeutic Targets in Atrial Fibrillation

“…23 Calhex231 may ameliorate myocardial fibrosis by inhibiting autophagymediated activation of NLRP3 inflammasome. 26 However, extensive validation is needed to improve our understanding of autophagy in the pathogenesis of AF.…”

LINC00961 Attenuates TGF-β-induced Endothelial-mesenchymal Transition and Myocardial Fibrosis Following Myocardial Infarction

“…Myocardial infarction (MI) is one of the most prevailing lethal diseases around the world, characterized by inadequate cardiac blood supply, typically developing into myocardial brosis [1][2][3] . MI triggers mass death of cardiomyocyte through necrosis or apoptosis, leading to the reduction of cardiomyocyte number 4,5 .…”