Yiyi Li1, Xuan Niu1, Haitao Xu2, Qingwen Li3, Lanxia Meng1, Mingyang He1, Jie Zhang1, Zhentao Zhang1, Zhaohui Zhang4. 1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. 2. Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China. 3. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. 4. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. Electronic address: zhzhqing1990@163.com.
Abstract
BACKGROUND AND AIMS: 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. 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-1β 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.
BACKGROUND AND AIMS: 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. 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-1β 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.
Authors: Tiantian Du; Jie Gao; Peilong Li; Yunshan Wang; Qiuchen Qi; Xiaoyan Liu; Juan Li; Chuanxin Wang; Lutao Du Journal: Clin Transl Med Date: 2021-08