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Adiponectin-mediated promotion of CD44 suppresses diabetic vascular inflammatory effects.

ABSTRACT: While adiponectin (APN) was known to significantly abolish the diabetic endothelial inflammatory response, the specific mechanisms have yet to be elucidated. Aortic vascular tissues from mice fed normal and high-fat diets (HFD) were analyzed by transcriptome analysis. GO functional annotation showed that APN inhibited vascular endothelial inflammation in an APPL1-dependent manner. We confirmed that activation of the Wnt/β-catenin signaling plays a key role in APN-mediated anti-inflammation. Mechanistically, APN promoted APPL1/reptin complex formation and β-catenin nuclear translocation. Simultaneously, we identified APN promoted the expression of CD44 by activating TCF/LEF in an APPL1-mediated manner. Clinically, the serum levels of APN and CD44 were decreased in diabetes; the levels of these two proteins were positively correlated. Functionally, treatment with CD44 C-terminal polypeptides protected diabetes-induced vascular endothelial inflammation in vivo. Collectively, we provided a roadmap for APN-inhibited vascular inflammatory effects and CD44 might represent potential targets against the diabetic endothelial inflammatory effect.

SUBMITTER: Duan Y

PROVIDER: S-EPMC10067764 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Adiponectin-mediated promotion of CD44 suppresses diabetic vascular inflammatory effects.

Duan Yanru Y Zhang Shihan S Xing Yuanyuan Y Wu Ye Y Zhao Wen W Xie Pinxue P Zhang Huina H Gao Xinxiao X Qin Yanwen Y Wang Yajing Y Ma Xinliang X Du Yunhui Y Liu Huirong H

iScience 20230320 4

While adiponectin (APN) was known to significantly abolish the diabetic endothelial inflammatory response, the specific mechanisms have yet to be elucidated. Aortic vascular tissues from mice fed normal and high-fat diets (HFD) were analyzed by transcriptome analysis. GO functional annotation showed that APN inhibited vascular endothelial inflammation in an APPL1-dependent manner. We confirmed that activation of the Wnt/β-catenin signaling plays a key role in APN-mediated anti-inflammation. Mech ...[more]

PMID: 37020952

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Project description:There is limited and discordant evidence on the role of nicotine in diabetic vascular disease. Exacerbated endothelial cell dysregulation in smokers with diabetes is associated with the disrupted adipose function. Adipokines possess vascular protective, anti-inflammatory, and anti-diabetic properties. However, whether and how nicotine primes and aggravates diabetic vascular disorders remain uncertain. In this study, we evaluated the alteration of adiponectin (APN) level in high-fat diet (HFD) mice with nicotine (NIC) administration. The vascular pathophysiological response was evaluated with vascular ring assay. Confocal and co-immunoprecipitation analysis were applied to identify the signal interaction and transduction. These results indicated that the circulating APN level in nicotine-administrated diabetic Apolipoprotein E-deficient (ApoE-/-) mice was elevated in advance of 2 weeks of diabetic ApoE-/- mice. NIC and NIC addition in HFD groups (NIC + HFD) reduced the vascular relaxation and signaling response to APN at 6 weeks. Mechanistically, APN receptor 1 (AdipoR1) level was decreased in NIC and further significantly reduced in NIC + HFD group at 6 weeks, while elevated suppressor of cytokine signaling 3 (SOCS3) expression was induced by NIC and further augmented in NIC + HFD group. Additionally, nicotine provoked SOCS3, degraded AdipoR1, and attenuated APN-activated ERK1/2 in the presence of high glucose and high lipid (HG/HL) in human umbilical vein endothelial cells (HUVECs). MG132 (proteasome inhibitor) administration manifested that AdipoR1 was ubiquitinated, while inhibited SOCS3 rescued the reduced AdipoR1. In summary, this study demonstrated for the first time that nicotine primed vascular APN resistance via SOCS3-mediated degradation of ubiquitinated AdipoR1, accelerating diabetic endothelial dysfunction. This discovery provides a potential therapeutic target for preventing nicotine-accelerated diabetic vascular dysfunction.

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Project description:BackgroundMedial calcification in diabetes contributes to the arterial occlusive process occurring below the knee level. Adiponectin is an adipokine with atheroprotective properties and possible protective role against arterial calcification. The aim of the study was to investigate, in type 2 diabetes, the link between vascular expression and serum concentration of adiponectin and (1) peripheral arterial calcification and (2) lower limb occlusive arterial disease.MethodsScoring of peripheral vascular calcification and peripheral arterial occlusive disease, using CT-scan and color-duplex ultrasonography respectively, were conducted and explored in relation to serum adiponectin level in a cross sectional study of 197 patients with type 2 diabetes. Vascular adiponectin expression in the arterial wall of diabetic patients with and without medial calcification was evaluated by immunohistochemistry.ResultsPeripheral arterial calcification score was higher in patients with the highest adiponectin concentration. In a multivariate logistic regression analysis, an increase of 1 µg/mL of adiponectin was associated with a 22% increase of arterial calcification (adjusted OR = 1.22; 95% CI 1.03-1.44; p = 0.02). Arterial occlusive score was also higher in patients with adiponectin concentration > median (2.8 ± 4.8 vs 4.2 ± 5.7, p = 0.034). Immunohistochemical analyses showed a strong and specific staining of adiponectin in smooth muscle cells in calcified arteries, with a more pronounced expression of adiponectin in early stages of medial calcification.ConclusionsPeripheral arterial calcification is positively associated with circulating adiponectin levels in patients with type 2 diabetes, but vascular adiponectin expression is already observed at early stages of calcification. Adiponectin secretion could be a compensatory mechanism against the calcification process.Trial registration DIACART NCT number: NCT02431234. Registered 30 April 2015.

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Adiponectin-mediated promotion of CD44 suppresses diabetic vascular inflammatory effects.

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Adiponectin-mediated promotion of CD44 suppresses diabetic vascular inflammatory effects.

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