{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:07:21Z","timestamp":1790723241623,"version":"4.1.0"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2016,5,13]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Endothelial injury is an initial mechanism mediating cardiovascular disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Here, we investigated the effect of hyperhomocysteinemia on programed cell death in endothelial cells (EC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      We established a novel flow-cytometric gating method to define pyrotosis (Annexin V\n                      <jats:sup>\u2212<\/jats:sup>\n                      \/Propidium iodide\n                      <jats:sup>+<\/jats:sup>\n                      ). In cultured human EC, we found that: (1) homocysteine and lipopolysaccharide individually and synergistically induced inflammatory pyroptotic and noninflammatory apoptotic cell death; (2) homocysteine\/lipopolysaccharide induced caspase-1 activation before caspase-8, caspase-9, and caspase-3 activations; (3) caspase-1\/caspase-3 inhibitors rescued homocysteine\/lipopolysaccharide-induced pyroptosis\/apoptosis, but caspase-8\/caspase-9 inhibitors had differential rescue effect; (4) homocysteine\/lipopolysaccharide-induced nucleotide-binding oligomerization domain, and leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) protein caused NLRP3-containing inflammasome assembly, caspase-1 activation, and interleukin (IL)-1\u03b2 cleavage\/activation; (5) homocysteine\/lipopolysaccharide elevated intracellular reactive oxygen species, (6) intracellular oxidative gradient determined cell death destiny as intermediate intracellular reactive oxygen species levels are associated with pyroptosis, whereas high reactive oxygen species corresponded to apoptosis; (7) homocysteine\/lipopolysaccharide induced mitochondrial membrane potential collapse and cytochrome-\n                      <jats:italic>c<\/jats:italic>\n                      release, and increased B-cell lymphoma 2\u2013associated X protein\/B-cell lymphoma 2 ratio which were attenuated by antioxidants and caspase-1 inhibitor; and (8) antioxidants extracellular superoxide dismutase and catalase prevented homocysteine\/lipopolysaccharide -induced caspase-1 activation, mitochondrial dysfunction, and pyroptosis\/apoptosis. In cystathionine \u03b2-synthase\u2013deficient (\n                      <jats:italic>Cbs<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ) mice, severe hyperhomocysteinemia-induced caspase-1 activation in isolated lung EC and caspase-1 expression in aortic endothelium, and elevated aortic caspase-1, caspase-9 protein\/activity and B-cell lymphoma 2\u2013associated X protein\/B-cell lymphoma 2 ratio in\n                      <jats:italic>Cbs<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      aorta and human umbilical vein endothelial cells. Finally, homocysteine-induced DNA fragmentation was reversed in caspase-1\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      EC. Hyperhomocysteinemia-induced aortic endothelial dysfunction was rescued in\n                      <jats:italic>caspase-1<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      and\n                      <jats:italic>NLRP3<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Hyperhomocysteinemia preferentially induces EC pyroptosis via caspase-1\u2013dependent inflammasome activation leading to endothelial dysfunction. We termed caspase-1 responsive pyroptosis and apoptosis as pyrop-apoptosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.116.308501","type":"journal-article","created":{"date-parts":[[2016,3,22]],"date-time":"2016-03-22T23:50:06Z","timestamp":1458690606000},"page":"1525-1539","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":225,"title":["Caspase-1 Inflammasome Activation Mediates Homocysteine-Induced Pyrop-Apoptosis in Endothelial Cells"],"prefix":"10.1161","volume":"118","author":[{"given":"Hang","family":"Xi","sequence":"first","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjie","family":"Xu","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Y.","family":"Yang","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Jiang","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojin","family":"Sha","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshu","family":"Cheng","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuebin","family":"Qin","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yu","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Ji","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Yang","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China (Y.Z., J.W.); Department of Cardiology, Second Hospital of Nanchang University, Institute of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Centers for Metabolic Disease Research (H.X., Y.Z., Y.X., W.Y.Y., X.J., J.Y., X.Y., H.W.), Cardiovascular Research (X.S., X.Y., H.W.), Thrombosis Research (X.Y., H.W.), Departments of Pharmacology (X.Y., H.W.), Neuroscience (X.Q.), Temple University School of Medicine, Philadelphia, PA; 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