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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2017

Open Access 01-12-2017 | Original investigation

T-cadherin deficiency increases vascular vulnerability in T2DM through impaired NO bioactivity

Authors: Han Wang, Ling Tao, Anastasia Ambrosio, Wenjun Yan, Ross Summer, Wayne Bond Lau, Yajing Wang, Xinliang Ma

Published in: Cardiovascular Diabetology | Issue 1/2017

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Abstract

Background

Endothelial dysfunction plays a critical role in the development of type 2 diabetes (T2DM). T-cadherin (T-cad) has gained recognition as a regulator of endothelial cell (EC) function. The present study examined whether T-cad deficiency increases vascular vulnerability in T2DM.

Methods

Vascular segments were isolated from WT or T-cad knockout mice. Endothelial function, total NO accumulation, and the expression of T-cad related proteins were determined.

Results

Ach and acidified NaNO2 induced similar vasorelaxation in WT groups. T-cad KO mice exhibited normal response to acidified NaNO2, but manifested markedly reduced response to Ach. NO accumulation was also decreased in T-cad KO group. T-cad expression was reduced in WT mice fed 8 weeks of high fat diet (HFD). Furthermore, exacerbated reduction of vasorelaxation was observed in T-cad KO mice fed 8 weeks of HFD.

Conclusions

In the current study, we provide the first in vivo evidence that T-cadherin deficiency causes endothelial dysfunction in T2DM vascular segments, suggesting the involvement of T-cad deficiency in T2DM pathogenesis.
Literature
1.
Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives. Nat Rev Endocrinol. 2011;8(4):228–36.CrossRefPubMed
2.
Creager MA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Circulation. 2003;108(12):1527–32.CrossRefPubMed
3.
Pieper GM, Meier DA, Hager SR. Endothelial dysfunction in a model of hyperglycemia and hyperinsulinemia. Am J Physiol. 1995;269(3 Pt 2):H845–50.PubMed
4.
Bohlen HG, Lash JM. Topical hyperglycemia rapidly suppresses EDRF-mediated vasodilation of normal rat arterioles. Am J Physiol. 1993;265(1 Pt 2):H219–25.PubMed
5.
Tesfamariam B, Brown ML, Deykin D, Cohen RA. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest. 1990;85(3):929–32.CrossRefPubMedPubMedCentral
6.
Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J. Endothelium-derived nitric oxide and vascular physiology and pathology. Cell Mol Life Sci. 1999;55(8–9):1078–87.CrossRefPubMed
7.
Cosentino F, Hishikawa K, Katusic ZS, Luscher TF. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation. 1997;96(1):25–8.CrossRefPubMed
8.
McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR, Andrews JW, Hayes JR. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1992;35(8):771–6.PubMed
9.
Philippova M, Joshi MB, Pfaff D, Kyriakakis E, Maslova K, Erne P, Resink TJ. T-cadherin attenuates insulin-dependent signalling, eNOS activation, and angiogenesis in vascular endothelial cells. Cardiovasc Res. 2012;93(3):498–507.CrossRefPubMed
10.
Philippova M, Ivanov D, Joshi MB, Kyriakakis E, Rupp K, Afonyushkin T, Bochkov V, Erne P, Resink TJ. Identification of proteins associating with glycosylphosphatidylinositol-anchored T-cadherin on the surface of vascular endothelial cells: role for Grp78/BiP in T-Cadherin-dependent cell survival. Mol Cell Biol. 2008;28(12):4004–17.CrossRefPubMedPubMedCentral
11.
Ivanov D, Philippova M, Antropova J, Gubaeva F, Iljinskaya O, Tararak E, Bochkov V, Erne P, Resink T, Tkachuk V. Expression of cell adhesion molecule T-cadherin in the human vasculature. Histochem Cell Biol. 2001;115(3):231–42.PubMed
12.
Kuzmenko YS, Kern F, Bochkov VN, Tkachuk VA, Resink TJ. Density- and proliferation status-dependent expression of T-cadherin, a novel lipoprotein-binding glycoprotein: a function in negative regulation of smooth muscle cell growth? FEBS Lett. 1998;434(1–2):183–7.CrossRefPubMed
13.
Pfaff D, Schoenenberger AW, Dasen B, Erne P, Resink TJ, Philippova M. Plasma T-cadherin negatively associates with coronary lesion severity and acute coronary syndrome. Eur Heart J Acute Cardiovasc Care. 2015;4(5):410–8.CrossRefPubMed
14.
Matsuda K, Fujishima Y, Maeda N, Mori T, Hirata A, Sekimoto R, Tsushima Y, Masuda S, Yamaoka M, Inoue K, et al. Positive feedback regulation between adiponectin and T-cadherin impacts adiponectin levels in tissue and plasma of male mice. Endocrinology. 2015;156(3):934–46.CrossRefPubMed
15.
Cao Y, Tao L, Yuan Y, Jiao X, Lau WB, Wang Y, Christopher T, Lopez B, Chan L, Goldstein B, et al. Endothelial dysfunction in adiponectin deficiency and its mechanisms involved. J Mol Cell Cardiol. 2009;46(3):413–9.CrossRefPubMed
16.
Zheng Q, Yuan Y, Yi W, Lau WB, Wang Y, Wang X, Sun Y, Lopez BL, Christopher TA, Peterson JM, et al. C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway. Arterioscler Thromb Vasc Biol. 2011;31(11):2616–23.CrossRefPubMedPubMedCentral
17.
Yan W, Zhang H, Liu P, Wang H, Liu J, Gao C, Liu Y, Lian K, Yang L, Sun L, et al. Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1alpha signaling contributing to increased vulnerability in diabetic heart. Basic Res Cardiol. 2013;108(3):329.CrossRefPubMed
18.
Sheng T, Yang K. Adiponectin and its association with insulin resistance and type 2 diabetes. J Genet Genom. 2008;35(6):321–6.CrossRef
19.
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116(7):1784–92.CrossRefPubMedPubMedCentral
20.
Fukuda S, Hirata A, Nishizawa H, Nagao H, Kashine S, Kimura T, Inoue K, Fujishima Y, Yamaoka M, Kozawa J, et al. Systemic arteriosclerosis and eating behavior in Japanese type 2 diabetic patients with visceral fat accumulation. Cardiovasc Diabetol. 2015;14(1):8.CrossRefPubMedPubMedCentral
21.
Hartge MM, Kintscher U, Unger T. Endothelial dysfunction and its role in diabetic vascular disease. Endocrinol Metab Clin North Am. 2006;35(3):551–60.CrossRefPubMed
22.
Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, Lodish HF. T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc Natl Acad Sci USA. 2004;101(28):10308–13.CrossRefPubMedPubMedCentral
23.
Kostopoulos CG, Spiroglou SG, Varakis JN, Apostolakis E, Papadaki HH. Adiponectin/T-cadherin and apelin/APJ expression in human arteries and periadventitial fat: implication of local adipokine signaling in atherosclerosis? Cardiovasc Pathol. 2014;23(3):131–8.CrossRefPubMed
24.
Parker-Duffen JL, Nakamura K, Silver M, Kikuchi R, Tigges U, Yoshida S, Denzel MS, Ranscht B, Walsh K. T-cadherin is essential for adiponectin-mediated revascularization. J Biol Chem. 2013;288(34):24886–97.CrossRefPubMedPubMedCentral
25.
Nicolas A, Aubert R, Bellili-Munoz N, Balkau B, Bonnet F, Tichet J, Velho G, Marre M, Roussel R, Fumeron F. T-cadherin gene variants are associated with type 2 diabetes and the fatty liver index in the French population. Diabetes Metab. 2016;1262–3636(16):30408–16.
26.
Tyrberg B, Miles P, Azizian KT, Denzel MS, Nieves ML, Monosov EZ, Levine F, Ranscht B. T-cadherin (Cdh13) in association with pancreatic beta-cell granules contributes to second phase insulin secretion. Islets. 2011;3(6):327–37.CrossRefPubMedPubMedCentral
27.
28.
Capellini VK, Celotto AC, Baldo CF, Olivon VC, Viaro F, Rodrigues AJ, Evora PR. Diabetes and vascular disease: basic concepts of nitric oxide physiology, endothelial dysfunction, oxidative stress and therapeutic possibilities. Curr Vasc Pharmacol. 2010;8(4):526–44.CrossRefPubMed
29.
Shimabukuro M, Higa N, Masuzaki H, Sata M, Ueda S. Impact of individual metabolic risk components or its clustering on endothelial and smooth muscle cell function in men. Cardiovasc Diabetol. 2016;15(1):77.CrossRefPubMedPubMedCentral
30.
Semina EV, Rubina KA, Sysoeva VY, Rutkevich PN, Kashirina NM, Tkachuk VA. Novel mechanism regulating endothelial permeability via T-cadherin-dependent VE-cadherin phosphorylation and clathrin-mediated endocytosis. Mol Cell Biochem. 2014;387(1–2):39–53.CrossRefPubMed
31.
Andreeva AV, Han J, Kutuzov MA, Profirovic J, Tkachuk VA, Voyno-Yasenetskaya TA. T-cadherin modulates endothelial barrier function. J Cell Physiol. 2009;223(1):94–102.
32.
Semina EV, Rubina KA, Rutkevich PN, Voyno-Yasenetskaya TA, Parfyonova YV, Tkachuk VA. T-cadherin activates Rac1 and Cdc42 and changes endothelial permeability. Biochemistry (Mosc). 2009;74(4):362–70.CrossRefPubMed
33.
Ivanov D, Philippova M, Allenspach R, Erne P, Resink T. T-cadherin upregulation correlates with cell-cycle progression and promotes proliferation of vascular cells. Cardiovasc Res. 2004;64(1):132–43.CrossRefPubMed
34.
Andreeva AV, Kutuzov MA, Tkachuk VA, Voyno-Yasenetskaya TA. T-cadherin is located in the nucleus and centrosomes in endothelial cells. Am J Physiol Cell Physiol. 2009;297(5):C1168–77.CrossRefPubMed
35.
Joshi MB, Ivanov D, Philippova M, Erne P, Resink TJ. Integrin-linked kinase is an essential mediator for T-cadherin-dependent signaling via Akt and GSK3 in endothelial cells. FASEB J. 2007;21(12):3083–95.CrossRefPubMed
36.
Joshi MB. T-cadherin protects endothelial cells from oxidative stress-induced apoptosis. FASEB J. 2005;19(12):1737–9.PubMed
37.
Vanhoutte PM, Shimokawa H, Tang EHC, Feletou M. Endothelial dysfunction and vascular disease. Acta Physiol. 2009;196(2):193–222.CrossRef
38.
Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011;1813(11):1978–86.CrossRefPubMed
39.
Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol. 1996;271(5 Pt 1):C1424–37.PubMed
Metadata
Title
T-cadherin deficiency increases vascular vulnerability in T2DM through impaired NO bioactivity
Authors
Han Wang
Ling Tao
Anastasia Ambrosio
Wenjun Yan
Ross Summer
Wayne Bond Lau
Yajing Wang
Xinliang Ma
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2017
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-016-0488-0

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