Abstract
Phenotypic transformation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling in hypertension. High mobility group box-1 (HMGB1) has been reported to be involved in several pathogenic processes including VSMC proliferation and migration. The present study was designed to determine the role of HMGB1 in VSMC phenotypic transformation in hypertension. First, we demonstrated that HMGB1 was elevated in a model of Ang II-induced VSMC phenotypic transformation, which showed down-regulation of contractile proteins and up-regulation of synthetic proteins. Knockdown of HMGB1 and losartan could block the phenotypic transformation. Next, we identified three potential miRNAs for upstream regulation of HMGB1 by bioinformatic analysis; only miR-181b-5p was significantly down-regulated in Ang II-treated cells. Co-treating the cells with miR-181b-5p mimics suppressed HMGB1 expression as well as the phenotypic transformation, migration, and proliferation. Furthermore, the luciferase reporter gene assay confirmed the direct interaction between miR-181b-5p and HMGB1. Finally, to extend these cell-based studies to clinical patients, we demonstrated that plasma miR-181b-5p levels were decreased, while Ang II and HMGB1 levels, as well as the intima-media thickness (IMT) were increased in hypertensive patients; these effects were reversed following the administration of angiotensin receptor blockers. Based on these observations, we conclude that the down-regulation of miR-181b-5p leads to the elevation of HMGB1 levels in hypertensive patients, which accounts, at least partially, for VSMCs phenotypic transformation and vascular remodeling. Our findings also highlight that the plasma levels of miR-181b-5p and HMGB1 may serve as novel biomarkers for vascular remodeling in the hypertensive patients.
Highlights
Phenotypic transformation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling in hypertension
Following incubation with Angiotensin II (Ang II) (1 M) for 48h, Human aortic vascular smooth muscle cells (HAVSMCs) exhibited phenotypic transformation from a contractile to a synthetic type, as evidenced by down-regulation of contractile proteins α-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α) (Fig. 1 A, B, E, F, G) and up-regulation of the synthetic protein osteopontin (OPN) (Fig. 1C, E, H); these phenomena were abolished in the presence of losartan, suggesting that Ang II successfully induced the phenotypic transformation of HAVSMCs
Compared to the control group, High mobility group box-1 (HMGB1) mRNA and protein expression was up-regulated in Ang II-treated HAVSMCs, which was suppressed in the presence of losartan (Fig. 1D, E, I, J)
Summary
Phenotypic transformation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling in hypertension. To extend these cell-based studies to clinical patients, we demonstrated that plasma miR-181b-5p levels were decreased, while Ang II and HMGB1 levels, as well as the intima-media thickness (IMT) were increased in hypertensive patients; these effects were reversed following the administration of angiotensin receptor blockers Based on these observations, we conclude that the downregulation of miR-181b-5p leads to the elevation of HMGB1 levels in hypertensive patients, which accounts, at least partially, for VSMCs phenotypic transformation and vascular remodeling. HMGB1 levels are elevated in atherosclerotic plaques, promoting VSMCs migration and proliferation [5, 21, 22] Based on these reports, it is reasonable to speculate that HMGB1 plays a role in the mediation of Ang II- induced VSMCs phenotypic transformation in hypertension
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