title: Mechanical stretch enhances the expression and activity of osteopontin and MMP-2 via the Akt1/AP-1 pathways in VSMC.
abstract: Hemodynamic forces causing mechanical stretch (MS) of vascular smooth muscle cells (VSMC) play an important role in vascular remodeling, but the underlying mechanism involved is not fully understood. Thus, this study investigated whether osteopontin (OPN) expression in VSMC was induced by MS, and identified the intracellular signaling pathways involved in OPN production. The plasma level of OPN and its expression in aortic tissue were increased in various animal models of hypertension including spontaneous hypertensive rats and hypertensive mice induced by angiotensin II or L-NAME. When aortic VSMC was stimulated with MS, OPN production was increased, which was markedly attenuated in VSMC treated with PI3K/Akt inhibitor as well as in Akt1-depleted cells, but not in Akt2-depleted cells, suggesting a pivotal role of Akt1 isoform in OPN expression in VSMC. In the promoter assay, MS increased OPN promoter activity, which was attenuated when the region harboring AP-1 binding sites was mutated. The MS-enhanced promoter activity and OPN expression were also decreased in cells treated with AP-1 siRNA or inhibitor. Moreover, MS-induced MMP-2 production was attenuated in cells treated with OPN siRNA or anti-OPN antibody as well as in OPN-deficient VSMC cultured from aorta of OPN deficient mice. In in vivo experiments, the expressions of OPN and MMP-2 were increased in the aortic tissues from hypertensive mice, but these increases were markedly attenuated in OPN-deficient mice with hypertension. In conclusion, these results suggested that OPN expression in the hypertensive vasculature was increased via signaling pathways that involve Akt1/AP-1, leading to vascular remodeling by increasing the production of MMP-2.
authors.affiliation: Department of Pharmacology, School of Medicine, and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Kyo Won
authors.initials: KW
authors.lastname: Seo
authors.affiliation: Department of Pharmacology, School of Medicine, and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Byeong Hyeok
authors.initials: BH
authors.lastname: Ye
authors.affiliation: Department of Pharmacology, School of Medicine, and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Young Whan
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.affiliation: Department of Pharmacology, School of Medicine, and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: chidkim@pusan.ac.kr.
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
mesh_terms: D000818:Animals; D001665:Binding Sites; D001696:Biomechanical Phenomena; D002478:Cells, Cultured; D016384:Consensus Sequence; D018960:Hyaluronan Receptors / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D053495:Osteopontin / Q000097:blood*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C506896:Spp1 protein, mouse; D018808:Transcription Factor AP-1; D053495:Osteopontin; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: Hypertension; MMP; Mechanical stretch; OPN; VSMC