Mechanical stretch enhances the expression and activity of osteopontin and MMP-2 via the Akt1/AP-1 pathways in VSMC
| Autor: | Sun Sik Bae, Young Whan Kim, Chi Dae Kim, Kyo Won Seo, Byeong Hyeok Ye, Seung Jin Lee |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Vascular smooth muscle Myocytes Smooth Muscle AKT1 Vascular Remodeling Matrix metalloproteinase Mechanotransduction Cellular Rats Inbred WKY Muscle Smooth Vascular stomatognathic system In vivo Rats Inbred SHR Internal medicine Consensus Sequence medicine Animals Osteopontin Molecular Biology Cells Cultured PI3K/AKT/mTOR pathway Binding Sites biology Chemistry Angiotensin II Biomechanical Phenomena Cell biology Mice Inbred C57BL Transcription Factor AP-1 Hyaluronan Receptors Endocrinology Hypertension biology.protein Matrix Metalloproteinase 2 Signal transduction Cardiology and Cardiovascular Medicine Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 85:13-24 |
| ISSN: | 0022-2828 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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