Increased dipeptidyl peptidase-4 accelerates diet-related vascular aging and atherosclerosis in ApoE-deficient mice under chronic stress

Lei, Yanna; Guang, Yang; Hu, Lina; Piao, Limei; Inoue, Akira; Jiang, Haiying; Sasaki, Takeshi; Zhao, Guangxian; Yisireyili, Maimaiti; Yu, Chen; Wei, Xu; Takeshita, Kyosuke; Okumura, Kenji; Kuzuya, Masafumi; Cheng, Xian Wu

doi:10.1016/j.ijcard.2017.05.062

Cited by 60 publications

(88 citation statements)

References 45 publications

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“…We have shown that chronic stress markedly suppressed the plasma corticosterone level; this effect was restored by the treatment with anagliptin and exenatide. Recently, we have demonstrated that chronic stress also increased plasma adrenaline and noradrenaline levels, and these changes were reversed by both drugs . In addition, our observations here show that pharmacological interventions targeted toward DPP4 activity and GLP‐1R activation ameliorated the levels of plasma glucose and adipose insulin receptor substrate 1 and glucose transporter 4 genes in the stressed mice.…”

Section: Discussionsupporting

confidence: 67%

“…Both the thoracic aorta and aortic arch from mice and rats were used for a vascular cellular senescence assay by β‐galactosidase (β‐Gal) staining set in accordance with the manufacturer's instructions. The degree of vascular cellular senescence for each aorta was quantified with the positive area of activated β‐Gal as previously described …”

Section: Methodsmentioning

confidence: 99%

“…A recent study reported a close link between increased plasma DPP4 activities and inflammatory and metabolic disorders . Moreover, chronic stress increased plasma and tissue DPP4 activities in mice and rats …”

Section: Introductionmentioning

confidence: 94%

“…Dipeptidyl peptidase 4 (DPP4) is a complex enzyme that acts as a membrane‐anchored cell surface exopeptidase that transmits intracellular signals through a small intracellular tail . DPP4 has gained considerable interest as a therapeutic target, and a variety of DPP4 inhibitors that prolong the insulinotropic effects of glucagon‐like peptide‐1 (GLP‐1) are widely used in clinical settings as a new class of antidiabetic drugs . In addition to GLP‐1‐dependent effects on the cardiometabolic risk profile, DPP4 inhibition exhibits vascular protective benefits via the regulation of several substrate factor activities (eg, stromal cell–derived factor‐1α and granulocyte colony‐stimulating factor) .…”

Section: Introductionmentioning

confidence: 99%

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Chronic Psychological Stress Accelerates Vascular Senescence and Impairs Ischemia‐Induced Neovascularization: The Role of Dipeptidyl Peptidase‐4/Glucagon‐Like Peptide‐1‐Adiponectin Axis

Piao

Zhao

Zhu

et al. 2017

JAHA

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BackgroundExposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Given that dipeptidyl peptidase‐4 (DPP4) regulates several intracellular signaling pathways associated with the glucagon‐like peptide‐1 (GLP‐1) metabolism, we investigated the role of DPP4/GLP‐1 axis in vascular senescence and ischemia‐induced neovascularization in mice under chronic stress, with a special focus on adiponectin ‐mediated peroxisome proliferator activated receptor‐γ/its co‐activator 1α (PGC‐1α) activation.Methods and ResultsSeven‐week‐old mice subjected to restraint stress for 4 weeks underwent ischemic surgery and were kept under immobilization stress conditions. Mice that underwent ischemic surgery alone served as controls. We demonstrated that stress impaired the recovery of the ischemic/normal blood‐flow ratio throughout the follow‐up period and capillary formation. On postoperative day 4, stressed mice showed the following: increased levels of plasma and ischemic muscle DPP4 and decreased levels of GLP‐1 and adiponectin in plasma and phospho‐AMP‐activated protein kinase α (p‐AMPKα), vascular endothelial growth factor, peroxisome proliferator activated receptor‐γ, PGC‐1α, and Sirt1 proteins and insulin receptor 1 and glucose transporter 4 genes in the ischemic tissues, vessels, and/or adipose tissues and numbers of circulating endothelial CD31+/c‐Kit+ progenitor cells. Chronic stress accelerated aortic senescence and impaired aortic endothelial sprouting. DPP4 inhibition and GLP‐1 receptor activation improved these changes; these benefits were abrogated by adiponectin blocking and genetic depletion.ConclusionsThese results indicate that the DPP4/GLP‐1‐adiponectin axis is a novel therapeutic target for the treatment of vascular aging and cardiovascular disease under chronic stress conditions.

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Section: Discussionsupporting

confidence: 67%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Chronic Psychological Stress Accelerates Vascular Senescence and Impairs Ischemia‐Induced Neovascularization: The Role of Dipeptidyl Peptidase‐4/Glucagon‐Like Peptide‐1‐Adiponectin Axis

Piao

Zhao

Zhu

et al. 2017

JAHA

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“…Increased aldosterone levels might account for the previously observed association of higher‐leptin concentrations with endothelial dysfunction and cardiac fibrosis, as well as with cardiovascular events and unfavourable prognosis . In apolipoprotein E‐deficient mice, chronic psychological stress decreased the levels of leptin and adiponectin in atherosclerotic plaque . However, in our study, no relationship between leptin and clinical endpoints was observed.…”

Section: Discussionmentioning

confidence: 99%

Resistin is a prognostic factor for death in type 2 diabetes

Kapłon‐Cieślicka

Tymińska

Rosiak

et al. 2018

Diabetes Metabolism Res

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Purpose To investigate the association of leptin, resistin, and tumour necrosis factor α (TNF‐α) with prognosis in type 2 diabetes (T2D). Methods Analysis included 284 T2D patients. Apart from routine laboratory parameters, baseline leptin, resistin, and TNF‐α concentrations were measured. Patients were followed for a median of 5.4 years. The primary endpoint was all‐cause death at follow‐up. The secondary endpoint was a composite of death, acute coronary syndrome, and stroke or transient ischemic attack. Results At baseline, median age was 68 years, and 48% of patients were female. Data on the primary endpoint were obtained for all patients: 32 (11%) died during follow‐up. Data on the secondary endpoint were available for 230 patients, of whom 45 (20%) reached the secondary endpoint. In univariate analyses, older age, heart failure, lower‐glomerular filtration rate, and higher resistin, TNF‐α and NT‐proBNP concentrations were predictors of the study endpoints. Of these variables, only resistin remained an independent predictor of both study endpoints in multivariate models. In receiver‐operating characteristic analysis, area under the curve for resistin was 0.7. Resistin concentration of greater than or equal to 11.4 ng/mL had sensitivity of 41% and specificity of 91% for prediction of death at follow‐up (Youden's index). Conclusions Higher resistin is associated with reduced survival in T2D, irrespectively of TNF‐α. Resistin concentration of above 11 ng/mL indicates T2D patients at an increased risk of unfavourable outcomes. Leptin was not a prognostic factor. These results suggest that in T2D, association of resistin with unfavourable outcomes might, at least in part, result from its pro‐inflammatory properties.

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Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

Tomovic

Lazarević

Kocić

et al. 2018

Medicinal Research Reviews

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Dipeptidyl peptidase-4 (DPP-4) cleaves N-terminal dipeptides, with Pro, Ala or Ser at the penultimate position, and, in that way, modulates biological activity of certain polypeptides. Due to its ubiquitous distribution, many pathological processes are associated with altered DPP-4 expression and activity. Besides the regulation of glucose metabolism, DPP-4 also exhibits many other systemic effects, and the inhibition of its activity might lead to cardiovascular and renal protection. Mechanisms underlying these protective effects of DPP-4 inhibition are ascribed to elevated bioavailability of its substrates, to impacts on mediators and signaling pathways that ameliorate cardiovascular and renal function through the suppression of oxidative stress, inflammation, fibrosis and apoptosis, improved endothelial function and tissue reparation. Inflammation contributes to and promotes progression of cardiovascular and renal disorders. Herein, we discuss cellular and molecular mechanisms mediating the anti-inflammatory activity of clinically used DPP-4 inhibitors in cardiovascular and renal protection.

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Increased dipeptidyl peptidase-4 accelerates diet-related vascular aging and atherosclerosis in ApoE-deficient mice under chronic stress

Cited by 60 publications

References 45 publications

Chronic Psychological Stress Accelerates Vascular Senescence and Impairs Ischemia‐Induced Neovascularization: The Role of Dipeptidyl Peptidase‐4/Glucagon‐Like Peptide‐1‐Adiponectin Axis

Chronic Psychological Stress Accelerates Vascular Senescence and Impairs Ischemia‐Induced Neovascularization: The Role of Dipeptidyl Peptidase‐4/Glucagon‐Like Peptide‐1‐Adiponectin Axis

Resistin is a prognostic factor for death in type 2 diabetes

Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

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