Soluble dipeptidyl peptidase-4 induces microvascular endothelial dysfunction through proteinase-activated receptor-2 and thromboxane A2 release

Romacho, Tania; Vallejo, Susana; Villalobos, Laura A.; Wronkowitz, Nina; Indrakusuma, Ira; Sell, Henrike; Eckel, Jürgen; Sánchez‐Ferrer, Carlos F.; Peiró, Concepción

doi:10.1097/hjh.0000000000000886

Cited by 43 publications

(44 citation statements)

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“…As a consequence, induction of vascular inflammation, endothelial dysfunction and smooth muscle cell proliferation takes place. These processes are hallmarks of vascular diseases and have been linked to PAR2 (Hirano and Kanaide, 2003; Wronkowitz et al, 2014; Romacho et al, 2016). To our knowledge, there are scarce reports about a direct connection between obesity and PAR2 in the vasculature.…”

Section: Discussionmentioning

confidence: 99%

“…In this study we have focused on the effects of CM on inflammation and proliferation as two key processes in atherogenesis, since the role of PAR2 in adipokine-induced impairment of vascular reactivity (Romacho et al, 2016) and the effect of CM on endothelial migration has already been proven (Hu et al, 2013). CM contains numerous molecules derived from adipocytes, which serve as potential ligands for PAR2, thereby contributing to promote PAR2-mediated effects, such as proliferation.…”

Section: Discussionmentioning

confidence: 99%

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Protease-Activated Receptor 2 Promotes Pro-Atherogenic Effects through Transactivation of the VEGF Receptor 2 in Human Vascular Smooth Muscle Cells

2017

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Background: Obesity is associated with impaired vascular function. In the cardiovascular system, protease-activated receptor 2 (PAR2) exerts multiple functions such as the control of the vascular tone. In pathological conditions, PAR2 is related to vascular inflammation. However, little is known about the impact of obesity on PAR2 in the vasculature. Therefore, we explored the role of PAR2 as a potential link between obesity and cardiovascular diseases.Methods: C57BL/6 mice were fed with either a chow or a 60% high fat diet for 24 weeks prior to isolation of aortas. Furthermore, human coronary artery endothelial cells (HCAEC) and human coronary smooth muscle cells (HCSMC) were treated with conditioned medium obtained from in vitro differentiated primary human adipocytes. To investigate receptor interaction vascular endothelial growth factor receptor 2 (VEGFR2) was blocked by exposure to calcium dobesilate and a VEGFR2 neutralization antibody, before treatment with PAR2 activating peptide. Student's t-test or one-way were used to determine statistical significance.Results: Both, high fat diet and exposure to conditioned medium increased PAR2 expression in aortas and human vascular cells, respectively. In HCSMC, conditioned medium elicited proliferation as well as cyclooxygenase 2 induction, which was suppressed by the PAR2 antagonist GB83. Specific activation of PAR2 by the PAR2 activating peptide induced proliferation and cyclooxygenase 2 expression which were abolished by blocking the VEGFR2. Additionally, treatment of HCSMC with the PAR2 activating peptide triggered VEGFR2 phosphorylation.Conclusion: Under obesogenic conditions, where circulating levels of pro-inflammatory adipokines are elevated, PAR2 arises as an important player linking obesity-related adipose tissue inflammation to atherogenesis. We show for the first time that the underlying mechanisms of these pro-atherogenic effects involve a potential transactivation of the VEGFR2 by PAR2.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor 2 Promotes Pro-Atherogenic Effects through Transactivation of the VEGF Receptor 2 in Human Vascular Smooth Muscle Cells

2017

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“…Indeed, increased plasma DPP-4 activity accompanies adipose tissue expansion in humans, rats, and mice (Kirino et al, 2009;Lamers et al, 2011;Mulvihill et al, 2017;Zhuge et al, 2016). Moreover, small interfering RNA-mediated depletion of Dpp4 from human primary adipocytes improved adipocyte insulin sensitivity (Rohrborn et al, 2016), whereas treatment with sDPP4 directly activated inflammatory signaling pathways ex vivo (Lee et al, 2016;Romacho et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Circulating Levels of Soluble Dipeptidyl Peptidase-4 Are Dissociated from Inflammation and Induced by Enzymatic DPP4 Inhibition

et al. 2019

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“…Circulating form of DPP‐4 can impair vascular reactivity by causing defective endothelium‐dependent vasodilation, which contributes to endothelial dysfunction. Soluble DPP‐4 is agonist for protease‐activated receptor 2 on vascular cells, activator of downstream cyclooxygenase and promoter of endothelial release of vasoconstrictor thromboxane A2 . It was shown that soluble DPP‐4 in concentration‐dependent manner activates extracellular signal‐regulated kinase (ERK) 1/2, induces phosphorylation of the nuclear factor kappa B (NF‐κB) subunit p65, increases inducible nitric oxide synthase (iNOS) activity, expression and secretion of proinflammatory cytokines, interleukin (IL)‐6, ‐8, monocyte chemoattractant protein‐1 (MCP‐1), and stimulates proliferation of human vascular smooth muscle cells.…”

Section: Introductionmentioning

confidence: 99%

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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Soluble dipeptidyl peptidase-4 induces microvascular endothelial dysfunction through proteinase-activated receptor-2 and thromboxane A2 release

Cited by 43 publications

References 30 publications

Protease-Activated Receptor 2 Promotes Pro-Atherogenic Effects through Transactivation of the VEGF Receptor 2 in Human Vascular Smooth Muscle Cells

Protease-Activated Receptor 2 Promotes Pro-Atherogenic Effects through Transactivation of the VEGF Receptor 2 in Human Vascular Smooth Muscle Cells

Circulating Levels of Soluble Dipeptidyl Peptidase-4 Are Dissociated from Inflammation and Induced by Enzymatic DPP4 Inhibition

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

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