VX-765 attenuates atherosclerosis in ApoE deficient mice by modulating VSMCs pyroptosis

Recent clinical evidences show that patients with atherosclerotic cardiovascular disease can benefit from a targeting IL-1β treatment. Caspase-1 is an important factor for pyroptosis and is responsible for mature and release of interleukin (IL)-1β. Here we investigated the effect of caspase-1 inhibitor VX-765 on atherosclerosis and vascular smooth muscle cells (VSMCs) pyroptosis. Human carotid artery plaques and aortas from ApoE−/− mice which were gavaged with VX-765 or vehicle while fed with western diet were examined for plaque burden using Oil Red O staining and Immunohistochemistry staining. Dedifferentiated primary cultured mice VSMCs treated with oxidized low-density lipoprotein (OxLDL) were applied to examine cell pyroptosis. The distribution of a-SMA and active pyroptotic indicators had a lot of overlaps near the necrotic core, at the lesion surface and in the intra-plaque hemorrhage area in human or mice plaque. In vitro studies further demonstrated that OxLDL induced VSMCs pyroptosis through activating NLRP3 inflammasome. What's more, VX-765 significantly inhibited the progression of established atheroma and the development of atherosclerosis, without substantially influence lipoprotein level in plasma. VX-765 also significantly reduced VSMCs pyroptosis and IL-1β processing induced by OxLDL. VX-765 inhibits VSMCs pyroptosis during atherogenesis and targeting caspase-1 activity may be a potential treatment strategy for atherosclerotic diseases. [Display omitted] •VX-765 inhibits the development and progression of mice atheroma without affecting total cholesterol and LDL-C in plasma.•VSMCs pyroptosis exists in human carotid plaques and participated in mice atherogenesis.•VX-765 inhibits OxLDL-induced VSMCs pyroptosis.