Role of the JAK2/STAT3 signaling pathway in the pathogenesis of type 2 diabetes mellitus with macrovascular complications

Yang, Ming; Tian, Mei; Zhang, Xuan; Xu, Jie; Yang, Bo; Li, Fengping; Li, Ya; Li, Sicheng; Li, Xianwen

doi:10.18632/oncotarget.18555

Cited by 23 publications

(14 citation statements)

References 24 publications

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“…In contrast to markers of inflammation, miR-181b levels did not correlate with blood glucose or HbA1c in our cohort. Although we and Sun et al [28] found that miR-181b expression in HMEC-1 and human umbilical vein endothelial cells (HUVEC) is reduced by high glucose concentrations, Yang et al [37] reported activation of the miR-181a/b-specific transcription factor signal transducer and activator of transcription (STAT) 3 in HUVEC treated with sera from diabetics pointing to a more complex regulation of miR-181b expression in humans. This may explain why the miR-181b expression in our healthy controls did not differ from those in poorly controlled diabetes (Additional file 6: Figure S5A).…”

Section: Low Mir-181b: Association With a Pro-thrombotic And Pro-inflmentioning

confidence: 65%

Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes

Witkowski

Saffarzadeh

et al. 2020

Cardiovasc Diabetol

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Background: Diabetes mellitus is characterized by chronic vascular inflammation leading to pathological expression of the thrombogenic full length (fl) tissue factor (TF) and its isoform alternatively-spliced (as) TF. Blood-borne TF promotes factor (F) Xa generation resulting in a pro-thrombotic state and cardiovascular complications. MicroRNA (miR)s impact gene expression on the post-transcriptional level and contribute to vascular homeostasis. Their distinct role in the control of the diabetes-related procoagulant state remains poorly understood. Methods: In a cohort of patients with poorly controlled type 2 diabetes (n = 46) plasma levels of miR-181b were correlated with TF pathway activity and markers for vascular inflammation. In vitro, human microvascular endothelial cells (HMEC)-1 and human monocytes (THP-1) were transfected with miR-181b or anti-miR-181b and exposed to tumor necrosis factor (TNF) α or lipopolysaccharides (LPS). Expression of TF isoforms, vascular adhesion molecule (VCAM) 1 and nuclear factor (NF) κB nuclear translocation was assessed. Moreover, aortas, spleen, plasma, and bone marrowderived macrophage (BMDM)s of mice carrying a deletion of the first miR-181b locus were analyzed with respect to TF expression and activity. Results: In patients with type 2 diabetes, plasma miR-181b negatively correlated with the procoagulant state as evidenced by TF protein, TF activity, d-dimer levels as well as markers for vascular inflammation. In HMEC-1, miR-181b abrogated TNFα-induced expression of flTF, asTF, and VCAM1. These results were validated using the anti-miR-181b. Mechanistically, we confirmed a miR-181b-mediated inhibition of importin-α3 (KPNA4) leading to reduced nuclear translocation of the TF transcription factor NFκB. In THP-1, miR-181b reduced both TF isoforms and FXa generation in response to LPS due to targeting phosphatase and tensin homolog (PTEN), a principal inducer for TF in monocytes. Moreover, in miR-181−/− animals, we found that reduced levels of miR-181b were accompanied by increased TF, VCAM1, and KPNA4 expression in aortic tissue as well as increased TF and PTEN expression in spleen. Finally, BMDMs of miR-181−/− mice showed increased TF expression and FXa generation upon stimulation with LPS. Conclusions: miR-181b epigenetically controls the procoagulant state in diabetes. Reduced miR-181b levels contribute to increased thrombogenicity and may help to identify individuals at particular risk for thrombosis.

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Section: Low Mir-181b: Association With a Pro-thrombotic And Pro-inflmentioning

confidence: 65%

Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes

Witkowski

Saffarzadeh

et al. 2020

Cardiovasc Diabetol

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“…The SOCS family of endogenous regulators sits at the crossroad of multiple signaling mechanisms, making them attractive targets for the treatment of inflammatory diseases [18,19]. In diabetes-mediated pathologies, alterations of SOCS1 expression associate with cardiovascular risk and progressive renal disease in patients [32,33]. Animal studies performed by a number of groups, including ours, have shown convincingly that SOCS1 gene absence, leading to sustained STAT activation, aggravates immune and inflammatory responses [23,25,34,35].…”

Section: Discussionmentioning

confidence: 88%

SOCS1-targeted therapy ameliorates renal and vascular oxidative stress in diabetes via STAT1 and PI3K inhibition

López-Sanz

Bernal

Recio

et al. 2018

Laboratory Investigation

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Oxidative stress resulting from excessive production of reactive oxygen species (ROS) or impaired antioxidant defenses is closely related to the development of diabetic vascular complications, including nephropathy and atherosclerosis. Chronic activation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathway contributes to diabetic complications by inducing expression of genes involved in cell proliferation, fibrosis, inflammation, and oxidative stress. Suppressors of cytokine signaling (SOCS) family of endogenous JAK/STAT regulators is an attractive target for therapeutic intervention. We investigated the beneficial effect of two different SOCS1-targeted therapies (adenovirus-mediated gene transfer and kinase-inhibitory region peptidomimetic) to combat oxidative stress injury in an experimental diabetes model of concomitant renal and macrovascular disease (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Diabetes resulted in progressive alteration of redox balance in mice, as demonstrated by increased ROS levels and decreased antioxidant activity, which ultimately led to renal dysfunction and vascular injury. The molecular and pathological alterations in early diabetes were partially reversed by preventive intervention with SOCS1-targeted therapies. Importantly, SOCS1 peptidomimetic provided reno- and atheroprotection in diabetic mice even in a setting of established disease. Compared with untreated controls, kidney and aorta from SOCS1-treated mice exhibited significantly lower levels of superoxide anion, DNA oxidation marker and NADPH oxidase (Nox) subunits, along with higher expression of antioxidant enzymes. These trends correlated with a reduction in parameters of renal damage (albuminuria, creatinine and tubular injury), atherosclerosis (lesion size) and inflammation (leukocytes and chemokines). Mechanistic studies in renal, vascular and phagocytic cells exposed to cytokines and high-glucose showed that SOCS1 blocked ROS generation by inhibiting both Nox complex assembly and Nox subunit expression, an effect mediated by inactivation of JAK2, STAT1, and PI3K signaling pathways. This study provides evidence for SOCS1-targeted therapies, especially SOCS1 peptidomimetic, as an alternative antioxidant strategy to limit the progression of diabetic micro- and macrovascular complications.

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“…In agreement with these findings, we unveil that METTL3 maintains pluripotency of piPSCs by sustaining JAK2 expression, inhibiting SOCS3 expression and activating STAT3/KLF4/SOX2 signal axis. The JAK2–STAT3 pathway plays important roles in a variety of biological processes, and dysfunctional JAK2–STAT3 pathway may contribute to diseases such as cancer, heart disease and obesity 35–37 . The regulation of JAK2–STAT3 signal pathway by m 6 A methylation could be a common mechanism that affects a range of other biological processes, which should be further investigated.…”

Section: Discussionmentioning

confidence: 99%

m6A methylation controls pluripotency of porcine induced pluripotent stem cells by targeting SOCS3/JAK2/STAT3 pathway in a YTHDF1/YTHDF2-orchestrated manner

Liu

Zhao

et al. 2019

Cell Death Dis

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Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine, disease treatment, and organ transplantation. As the ethical issue of human ESCs and similarity of pig in human genome and physiological characteristics, the porcine iPSCs (piPSCs) have become an ideal alternative study model. N6-methyladenosine (m6A) methylation is the most prevalent modification in eukaryotic mRNAs, regulating the self-renewal and differentiation of pluripotency stem cells. However, the explicit m6A-regulating machinery remains controversial. Here, we demonstrate that m6A modification and its modulators play a crucial role in mediating piPSCs pluripotency. In brief, loss of METTL3 significantly impairs self-renewal and triggers differentiation of piPSCs by interfering JAK2 and SOCS3 expression, further inactivating JAK2–STAT3 pathway, which then blocks the transcription of KLF4 and SOX2. We identify that both of JAK2 and SOSC3 have m6A modification at 3′UTR by m6A-seq analysis. Dual-luciferase assay shows that METTL3 regulates JAK2 and SOCS3 expression in an m6A-dependent way. RIP-qPCR validates JAK2 and SOCS3 are the targets of YTHDF1 and YTHDF2, respectively. SiMETTL3 induced lower m6A levels of JAK2 and SOCS3 lead to the inhibition of YTHDF1-mediated JAK2 translation and the block of YTHDF2-dependent SOCS3 mRNA decay. Subsequently, the altered protein expressions of JAK2 and SOCS3 inhibit JAK2–STAT3 pathway and then the pluripotency of piPSCs. Collectively, our work uncovers the critical role of m6A modification and its modulators in regulating piPSCs pluripotency and provides insight into an orchestrated network linking the m6A methylation and SOCS3/JAK2/STAT3 pathway in pluripotency regulation.

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Role of the JAK2/STAT3 signaling pathway in the pathogenesis of type 2 diabetes mellitus with macrovascular complications

Cited by 23 publications

References 24 publications

Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes

Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes

SOCS1-targeted therapy ameliorates renal and vascular oxidative stress in diabetes via STAT1 and PI3K inhibition

m6A methylation controls pluripotency of porcine induced pluripotent stem cells by targeting SOCS3/JAK2/STAT3 pathway in a YTHDF1/YTHDF2-orchestrated manner

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