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TNF-? elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155-5p-dependent down-regulation of cGMP-dependent kinase 1.

ABSTRACT: cGMP-dependent protein kinase 1 (PKG1) plays an important role in nitric oxide (NO)/cGMP-mediated maintenance of vascular smooth muscle cell (VSMC) phenotype and vasorelaxation. Inflammatory cytokines, including tumor necrosis factor-? (TNF?), have long been understood to mediate several inflammatory vascular diseases. However, the underlying mechanism of TNF?-dependent inflammatory vascular disease is unclear. Here, we found that TNF? treatment decreased PKG1 expression in cultured VSMCs, which correlated with NF-?B-dependent biogenesis of miR-155-5p that targeted the 3'-UTR of PKG1 mRNA. TNF? induced VSMC phenotypic switching from a contractile to a synthetic state through the down-regulation of VSMC marker genes, suppression of actin polymerization, alteration of cell morphology, and elevation of cell proliferation and migration. All of these events were blocked by treatment with an inhibitor of miR-155-5p or PKG1, whereas transfection with miR-155-5p mimic or PKG1 siRNA promoted phenotypic modulation, similar to the response to TNF?. In addition, TNF?-induced miR-155-5p inhibited the vasorelaxant response of de-endothelialized mouse aortic vessels to 8-Br-cGMP by suppressing phosphorylation of myosin phosphatase and myosin light chain, both of which are downstream signal modulators of PKG1. Moreover, TNF?-induced VSMC phenotypic alteration and vasodilatory dysfunction were blocked by NF-?B inhibition. These results suggest that TNF? impairs NO/cGMP-mediated maintenance of the VSMC contractile phenotype and vascular relaxation by down-regulating PKG1 through NF-?B-dependent biogenesis of miR-155-5p. Thus, the NF-?B/miR-155-5p/PKG1 axis may be crucial in the pathogenesis of inflammatory vascular diseases, such as atherosclerotic intimal hyperplasia and preeclamptic hypertension.

SUBMITTER: Choi S

PROVIDER: S-EPMC6153283 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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TNF-α elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155-5p-dependent down-regulation of cGMP-dependent kinase 1.

Choi Seunghwan S Park Minsik M Kim Joohwan J Park Wonjin W Kim Suji S Lee Dong-Keon DK Hwang Jong Yun JY Choe Jongseon J Won Moo-Ho MH Ryoo Sungwoo S Ha Kwon-Soo KS Kwon Young-Guen YG Kim Young-Myeong YM

The Journal of biological chemistry 20180813 38

cGMP-dependent protein kinase 1 (PKG1) plays an important role in nitric oxide (NO)/cGMP-mediated maintenance of vascular smooth muscle cell (VSMC) phenotype and vasorelaxation. Inflammatory cytokines, including tumor necrosis factor-α (TNFα), have long been understood to mediate several inflammatory vascular diseases. However, the underlying mechanism of TNFα-dependent inflammatory vascular disease is unclear. Here, we found that TNFα treatment decreased PKG1 expression in cultured VSMCs, which ...[more]

PMID: 30104414

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Project description:Introduction: Acute graft vs. host disease (aGvHD) is a frequent complication following allogeneic haematopoeitic transplantation (HSCT). Despite recent advances, there are no universally accepted biomarkers to determine development of aGvHD. MicroRNAs miR-146a and miR-155 have been previously associated with aGvHD and show promise as clinically translatable biomarkers. In this study, we performed comprehensive expression profiling of miR-146a, miR-155, and miR-155* expression in aGvHD target tissue and biofluids and relate expression to post-HSCT outcomes. Materials and Methods: MicroRNA expression was assessed by qRT-PCR in gastrointestinal (n = 31) and skin (n = 31) biopsies as well as serum (exploratory cohort n = 34, verification cohort n = 81, diagnostic cohort n = 65) and urine (exploratory cohort n = 30, verification cohort n = 56, diagnostic cohort n = 20) biofluids, including extracellular vesicle (EV) cohorts (serum EV n = 15, urine EV n = 30). Expression was related to aGvHD incidence, severity and overall survival. Results: In GI samples, expression of miR-155 (p = 0.03) and miR-146a (p = 0.03) was higher at aGvHD onset compared to patients with no GvHD. In skin biopsies, expression of miR-155 (p = 0.004) was upregulated in aGvHD patients compared to normal control skin. Expression of miR-146a was higher in aGvHD compared to no aGvHD biopsies (p = 0.002). In serum, miR-155 (p = 0.03) and miR-146a (p = 0.02) expression was higher at day 14 (D14), while in urine expression was elevated at D7 post-HSCT in patients who developed aGvHD compared to those disease-free. This was verified in an independent serum (miR-155 p = 0.005, miR-146a p = 0.003) and urine (miR-155 p = 0.02, miR-146a p = 0.04) cohort, where both microRNAs were also associated with aGvHD by ROC analysis. In serum and urine samples taken at the time of aGvHD symptoms, expression of miR-155 and miR-146a was also elevated (serum miR-155 p = 0.03, miR-146a p < 0.001; urine miR-155 p = 0.02, miR-146a p = 0.02). In contrast, miR-146a and miR-155 were downregulated at D14 in serum EVs and at D7 in urine EVs in patients who developed aGvHD compared to those that remained disease-free, in both an exploratory (serum miR-155 p = 0.02, miR-146a p = 0.06; urine miR-155 p = 0.02, miR-146a p = 0.07) and an independent cohort (serum miR-155 p = 0.01, miR-146a p = 0.02). Conclusions: These results further support a role for miR-155 and miR-146a as non-invasive, clinically relevant biomarkers for aGvHD. However, the link between their involvement in generalized inflammation and in specific pathophysiology requires further investigation at a systemic level.

Dataset Information

TNF-? elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155-5p-dependent down-regulation of cGMP-dependent kinase 1.

Publications

TNF-α elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155-5p-dependent down-regulation of cGMP-dependent kinase 1.

Similar Datasets

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