{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T06:37:57Z","timestamp":1793083077184,"version":"4.5.0"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2012,5,25]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction caused, in part, by pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Mitochondrial fragmentation and normoxic activation of hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) have been observed in PAH PASMCs; however, their relationship and relevance to the development of PAH are unknown. Dynamin-related protein-1 (DRP1) is a GTPase that, when activated by kinases that phosphorylate serine 616, causes mitochondrial fission. It is, however, unknown whether mitochondrial fission is a prerequisite for proliferation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>We hypothesize that DRP1 activation is responsible for increased mitochondrial fission in PAH PASMCs and that DRP1 inhibition may slow proliferation and have therapeutic potential.<\/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                      Experiments were conducted using human control and PAH lungs (n=5) and PASMCs in culture. Parallel experiments were performed in rat lung sections and PASMCs and in rodent PAH models induced by the HIF-1\u03b1 activator, cobalt, chronic hypoxia, and monocrotaline. HIF-1\u03b1 activation in human PAH leads to mitochondrial fission by cyclin B1\/CDK1\u2013dependent phosphorylation of DRP1 at serine 616. In normal PASMCs, HIF-1\u03b1 activation by CoCl\n                      <jats:sub>2<\/jats:sub>\n                      or desferrioxamine causes DRP1-mediated fission. HIF-1\u03b1 inhibition reduces DRP1 activation, prevents fission, and reduces PASMC proliferation. Both the DRP1 inhibitor Mdivi-1 and siDRP1 prevent mitotic fission and arrest PAH PASMCs at the G2\/M interphase. Mdivi-1 is antiproliferative in human PAH PASMCs and in rodent models. Mdivi-1 improves exercise capacity, right ventricular function, and hemodynamics in experimental PAH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>DRP-1\u2013mediated mitotic fission is a cell-cycle checkpoint that can be therapeutically targeted in hyperproliferative disorders such as PAH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.111.263848","type":"journal-article","created":{"date-parts":[[2012,4,18]],"date-time":"2012-04-18T01:42:26Z","timestamp":1334713346000},"page":"1484-1497","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":444,"title":["Dynamin-Related Protein 1\u2013Mediated Mitochondrial Mitotic Fission Permits Hyperproliferation of Vascular Smooth Muscle Cells and Offers a Novel Therapeutic Target in Pulmonary Hypertension"],"prefix":"10.1161","volume":"110","author":[{"given":"Glenn","family":"Marsboom","sequence":"first","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T.","family":"Toth","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Ryan","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Hong","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xichen","family":"Wu","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Hu","family":"Fang","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thenappan","family":"Thenappan","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Piao","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah J.","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Pogoriler","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimei","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Morrow","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Kenneth","family":"Weir","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology Group (X.W.), University of Alberta, Edmonton, Alberta, Canada; Section of Cardiology (E.K.W.), VA Medical Center and University of Minnesota, Minneapolis, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalees","family":"Rehman","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Section of Cardiology (G.M., P.T.T., J.J.R., Z.H., Y.H.F., T.T., L.P., H.J.Z., E.M., S.L.A.), Department of Pathology (J.P.), Electron Microscopy Facility (Y.C.), and Departments of Medicine and Pharmacology (J.R.), University of Illinois at Chicago, Chicago, IL; Vascular Biology 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