title: Essential role of Pin1 via STAT3 signalling and mitochondria-dependent pathways in restenosis in type 2 diabetes.
abstract: Type 2 diabetes (T2D) is associated with accelerated restenosis rates after angioplasty. We have previously proved that Pin1 played an important role in vascular smooth muscle cell (VSMC) cycle and apoptosis. But neither the role of Pin1 in restenosis by T2D, nor the molecular mechanism of Pin1 in these processes has been elucidated. A mouse model of T2D was generated by the combination of high-fat diet (HFD) and streptozotocin (STZ) injections. Both Immunohistochemistry and Western blot revealed that Pin1 expression was up-regulated in the arterial wall in T2D mice and in VSMCs in culture conditions mimicking T2D. Next, increased activity of Pin1 was observed in neointimal hyperplasia after arterial injury in T2D mice. Further analysis confirmed that 10% serum of T2D mice and Pin1-forced expression stimulated proliferation, inhibited apoptosis, enhanced cell cycle progression and migration of VSMCs, whereas Pin1 knockdown resulted in the converse effects. We demonstrated that STAT3 signalling and mitochondria-dependent pathways played critical roles in the involvement of Pin1 in cell cycle regulation and apoptosis of VSMCs in T2D. In addition, VEGF expression was stimulated by Pin1, which unveiled part of the mechanism of Pin1 in regulating VSMC migration in T2D. Finally, the administration of juglone via pluronic gel onto injured common femoral artery resulted in a significant inhibition of the neointima/media ratio. Our findings demonstrated the vital effect of Pin1 on the VSMC proliferation, cell cycle progression, apoptosis and migration that underlie neointima formation in T2D and implicated Pin1 as a potential therapeutic target to prevent restenosis in T2D.
authors.affiliation: Department of Vascular Surgery, Renji Hospital, Shanghai Jiaotong University, College of Medicine, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lv
authors.forename: Jiwei
authors.initials: J
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.forename: Guanhua
authors.initials: G
authors.lastname: Xue
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Qiurong
authors.initials: Q
authors.lastname: Meng
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D023903:Coronary Restenosis / Q000097:blood / Q000150:complications / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000378:metabolism*; D004789:Enzyme Activation; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000473:pathology; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D058426:Neointima / Q000378:metabolism / Q000473:pathology; D019696:Peptidylprolyl Isomerase / Q000172:deficiency / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse
keywords: Pin1; STAT3; mitochondria; restenosis; type 2 diabetes; vascular smooth muscle cells