title: The inhibition of calpains ameliorates vascular restenosis through MMP2/TGF-β1 pathway.
abstract: Restenosis limits the efficacy of vascular percutaneous intervention, in which vascular smooth muscle cell (VSMC) proliferation and activation of inflammation are two primary causal factors. Calpains influence VSMC proliferation and collagen synthesis. However, the roles of calpastatin and calpains in vascular restenosis remain unclear. Here, restenosis was induced by ligating the left carotid artery, and VSMCs were pretreated with platelet-derived growth factor (PDGF)-BB. Adenovirus vector carrying MMP2 sequence and specific small interfering RNA against calpain-1/2 were introduced. Finally, restenosis enhanced the expression of calpain-1/2, but reduced calpastatin content. In calpastatin transgenic mice, lumen narrowing was attenuated gradually and peaked on days 14-21. Cell proliferation and migration as well as collagen synthesis were inhibited in transgenic mice, and expression of calpain-1/2 and MMP2/transforming growth factor-β1 (TGF-β1). Consistently, in VSMCs pretreated with PDGF-BB, calpastatin induction and calpains inhibition suppressed the proliferation and migration of VSMCs and collagen synthesis, and reduced expression of calpain-1/2 and MMP2/TGF-β1. Moreover, simvastatin improved restenosis indicators by suppressing the HIF-1α/calpains/MMP2/TGF-β1 pathway. However, MMP2 supplementation eliminated the vascular protection of calpastatin induction and simvastatin. Collectively, calpains inhibition plays crucial roles in vascular restenosis by preventing neointimal hyperplasia at the early stage via suppression of the MMP2/TGF-β1 pathway.
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.|Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou 64600, China.
authors.forename: Lianghu
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Pei
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Center of Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: De
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Dachun
authors.initials: D
authors.lastname: Yang
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D023903:Coronary Restenosis / Q000378:metabolism* / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; C033668:calpastatin; D003094:Collagen; D019821:Simvastatin; D002154:Calpain; D020778:Matrix Metalloproteinase 2