Bone marrow‐derived mesenchymal stem cells microvesicles stabilize atherosclerotic plaques by inhibiting NLRP3‐mediated macrophage pyroptosis

Abstract

Rupture of atherosclerotic plaques constitutes the major cause of thrombosis and acute ischemic coronary syndrome. Bone marrow‐derived mesenchymal stem cells microvesicles (BMSCs‐MVs) are reported to promote angiogenesis. This study investigated the role of BMSCs‐MVs in stabilizing atherosclerotic plaques. BMSCs‐MVs in mice were isolated and identified. The mouse model of atherosclerosis was established, and mice were injected with BMSCs‐MVs via the tail vein. The macrophage model with high glucose and oxidative damage was established and then incubated with BMSCs‐MVs. Nod‐like receptor protein 3 (NLRP3) expression, pyroptosis‐related proteins, and inflammatory factors were detected. Actinomycin D was used to inhibit the secretion of BMSCs‐MVs to verify the source of microRNA‐223 (miR‐223). The binding relationship between miR‐223 and NLRP3 was predicted and verified. BMSCs‐MVs with knockdown of miR‐223 were cocultured with bone marrow‐derived macrophages with knockdown of NLRP3, and then levels of miR‐223, NLRP3, pyroptosis‐related proteins, and inflammatory factors were detected. BMSCs‐MVs could reduce the vulnerability index of atherosclerotic plaques and intima‐media thickness in mice, and inhibit pyroptosis and inflammation. BMSCs‐MVs inhibited pyroptosis and inflammatory factors in macrophages. BMSCs‐MVs carried miR‐223 to inhibit NLRP3 expression and reduce macrophage pyroptosis, thereby stabilizing the atherosclerotic plaques.

Pyroptosis in the Initiation and Progression of Atherosclerosis

“…When p65 is silenced with siRNA, the nicotine-induced protein expression of cleaved Caspase1, IL-1β, IL-18 are decreased remarkably in RAW264.7 cells (Xu et al, 2021). Moreover, experimental data confirms that ox-LDL activates the NLRP3-mediated pyroptosis pathway in macrophages (Lin et al, 2020;Mu et al, 2020). Peng et al reported that mitochondrial outer membrane protein NIX inhibits ox-LDL-induced macrophages pyroptosis by activating mitophagy.…”

“…The latest research confirms that PIC up-regulates miR-200a and Nrf2 to inhibit macrophage pyroptosis and ultimately alleviate atherosclerosis ( Mu et al, 2020 ). The study of bone marrow-derived mesenchymal stem cells microvesicles (BMSCs-MVs) on the treatment of atherosclerosis in mice showed that miR-223 inhibited macrophages pyroptosis by reducing the expression of NLRP3 ( Lin et al, 2020 ). Non-coding RNA-dependent way will become the new treatment ideas of atherosclerosis.…”

Autophagy, Pyroptosis, and Ferroptosis: New Regulatory Mechanisms for Atherosclerosis

“…Subsequently, Varghese et al also demonstrated the close relationship between the upregulation of NLRP3 inflammasome-related components and plaque vulnerability, suggesting the possibility of NLRP3 inflammasome activation in promoting plaque instability ( Paramel Varghese et al, 2016 ). Inhibiting NLRP3 expression and reducing macrophage pyroptosis could stabilize atherosclerotic plaques, which undoubtedly hinted at the potential value of blocking pyroptosis ( Lin et al, 2021 ).…”

Role of pyroptosis in atherosclerosis and its therapeutic implications

“…As another natural antiatherosclerotic drug, piceatannol suppressed pyroptosis and oxLDL‐induced lipid storage in macrophages via regulating miR‐200a/Nrf2/GSDMD signaling (Mu et al, 2020). Another study reported that miR‐223 carried by bone marrow‐derived mesenchymal stem cells microvesicles stabilized the atherosclerotic plaques by reducing macrophage pyroptosis (Y. Lin et al, 2020). Circular RNAs (circRNAs) are a group of ncRNAs characterized by a covalently closed loop.…”