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

Background and aims: Recent clinical evidences show that patients with atherosclerotic cardiovascular disease can benefit from a targeting IL-1 beta treatment. Caspase-1 is an important factor for pyroptosis and is responsible for mature and release of interleukin (IL)-1 beta. Here we investigated the effect of caspase-1 inhibitor VX-765 on atherosclerosis and vascular smooth muscle cells (VSMCs) pyroptosis. Methods: 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. Results: 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-1 beta processing induced by OxLDL. Conclusions: VX-765 inhibits VSMCs pyroptosis during atherogenesis and targeting caspase-1 activity may be a potential treatment strategy for atherosclerotic diseases.