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Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide

Insufficient hydrogen sulfide (H(2)S) has been implicated in Type 2 diabetic mellitus (T2DM) and hyperhomocysteinemia (HHcy)-related cardiovascular complications. We investigated the role of H(2)S in T2DM and HHcy-induced endothelial dysfunction in small mesenteric artery (SMA) of db/db mice fed a h...

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Autores principales: Cheng, Zhongjian, Shen, Xinggui, Jiang, Xiaohua, Shan, Huimin, Cimini, Maria, Fang, Pu, Ji, Yong, Park, Joon Young, Drosatos, Konstantinos, Yang, Xiaofeng, Kevil, Christopher G., Kishore, Raj, Wang, Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854893/
https://www.ncbi.nlm.nih.gov/pubmed/29524844
http://dx.doi.org/10.1016/j.redox.2018.02.006
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author Cheng, Zhongjian
Shen, Xinggui
Jiang, Xiaohua
Shan, Huimin
Cimini, Maria
Fang, Pu
Ji, Yong
Park, Joon Young
Drosatos, Konstantinos
Yang, Xiaofeng
Kevil, Christopher G.
Kishore, Raj
Wang, Hong
author_facet Cheng, Zhongjian
Shen, Xinggui
Jiang, Xiaohua
Shan, Huimin
Cimini, Maria
Fang, Pu
Ji, Yong
Park, Joon Young
Drosatos, Konstantinos
Yang, Xiaofeng
Kevil, Christopher G.
Kishore, Raj
Wang, Hong
author_sort Cheng, Zhongjian
collection PubMed
description Insufficient hydrogen sulfide (H(2)S) has been implicated in Type 2 diabetic mellitus (T2DM) and hyperhomocysteinemia (HHcy)-related cardiovascular complications. We investigated the role of H(2)S in T2DM and HHcy-induced endothelial dysfunction in small mesenteric artery (SMA) of db/db mice fed a high methionine (HM) diet. HM diet (8 weeks) induced HHcy in both T2DM db/db mice and non-diabetic db/+ mice (total plasma Hcy: 48.4 and 31.3 µM, respectively), and aggravated the impaired endothelium-derived hyperpolarization factor (EDHF)-induced endothelium-dependent relaxation to acetylcholine (ACh), determined by the presence of eNOS inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) and prostacyclin (PGI(2)) inhibitor indomethacin (INDO), in SMA from db/db mice but not that from db/+ mice. A non-selective Ca(2+)-active potassium channel (K(Ca)) opener NS309 rescued T2DM/HHcy-impaired EDHF-mediated vascular relaxation to ACh. EDHF-induced relaxation to ACh was inhibited by a non-selective K(Ca) blocker TEA and intermediate-conductance K(Ca) blocker (IK(Ca)) Tram-34, but not by small-conductance K(Ca) (SK(Ca)) blocker Apamin. HHcy potentiated the reduction of free sulfide, H(2)S and cystathionine γ-lyase protein, which converts L-cysteine to H(2)S, in SMA of db/db mice. Importantly, a stable H(2)S donor DATS diminished the enhanced O(2)(-) production in SMAs and lung endothelial cells of T2DM/HHcy mice. Antioxidant PEG-SOD and DATS improved T2DM/HHcy impaired relaxation to ACh. Moreover, HHcy increased hyperglycemia-induced IK(Ca) tyrosine nitration in human micro-vascular endothelial cells. EDHF-induced vascular relaxation to L-cysteine was not altered, whereas such relaxation to NaHS was potentiated by HHcy in SMA of db/db mice which was abolished by ATP-sensitive potassium channel blocker Glycolamide but not by K(Ca) blockers. CONCLUSIONS: Intermediate HHcy potentiated H(2)S reduction via CSE-downregulation in microvasculature of T2DM mice. H(2)S is justified as an EDHF. Insufficient H(2)S impaired EDHF-induced vascular relaxation via oxidative stress and IK(Ca) inactivation in T2DM/HHcy mice. H(2)S therapy may be beneficial for prevention and treatment of micro-vascular complications in patients with T2DM and HHcy.
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spelling pubmed-58548932018-03-19 Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide Cheng, Zhongjian Shen, Xinggui Jiang, Xiaohua Shan, Huimin Cimini, Maria Fang, Pu Ji, Yong Park, Joon Young Drosatos, Konstantinos Yang, Xiaofeng Kevil, Christopher G. Kishore, Raj Wang, Hong Redox Biol Research Paper Insufficient hydrogen sulfide (H(2)S) has been implicated in Type 2 diabetic mellitus (T2DM) and hyperhomocysteinemia (HHcy)-related cardiovascular complications. We investigated the role of H(2)S in T2DM and HHcy-induced endothelial dysfunction in small mesenteric artery (SMA) of db/db mice fed a high methionine (HM) diet. HM diet (8 weeks) induced HHcy in both T2DM db/db mice and non-diabetic db/+ mice (total plasma Hcy: 48.4 and 31.3 µM, respectively), and aggravated the impaired endothelium-derived hyperpolarization factor (EDHF)-induced endothelium-dependent relaxation to acetylcholine (ACh), determined by the presence of eNOS inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) and prostacyclin (PGI(2)) inhibitor indomethacin (INDO), in SMA from db/db mice but not that from db/+ mice. A non-selective Ca(2+)-active potassium channel (K(Ca)) opener NS309 rescued T2DM/HHcy-impaired EDHF-mediated vascular relaxation to ACh. EDHF-induced relaxation to ACh was inhibited by a non-selective K(Ca) blocker TEA and intermediate-conductance K(Ca) blocker (IK(Ca)) Tram-34, but not by small-conductance K(Ca) (SK(Ca)) blocker Apamin. HHcy potentiated the reduction of free sulfide, H(2)S and cystathionine γ-lyase protein, which converts L-cysteine to H(2)S, in SMA of db/db mice. Importantly, a stable H(2)S donor DATS diminished the enhanced O(2)(-) production in SMAs and lung endothelial cells of T2DM/HHcy mice. Antioxidant PEG-SOD and DATS improved T2DM/HHcy impaired relaxation to ACh. Moreover, HHcy increased hyperglycemia-induced IK(Ca) tyrosine nitration in human micro-vascular endothelial cells. EDHF-induced vascular relaxation to L-cysteine was not altered, whereas such relaxation to NaHS was potentiated by HHcy in SMA of db/db mice which was abolished by ATP-sensitive potassium channel blocker Glycolamide but not by K(Ca) blockers. CONCLUSIONS: Intermediate HHcy potentiated H(2)S reduction via CSE-downregulation in microvasculature of T2DM mice. H(2)S is justified as an EDHF. Insufficient H(2)S impaired EDHF-induced vascular relaxation via oxidative stress and IK(Ca) inactivation in T2DM/HHcy mice. H(2)S therapy may be beneficial for prevention and treatment of micro-vascular complications in patients with T2DM and HHcy. Elsevier 2018-02-14 /pmc/articles/PMC5854893/ /pubmed/29524844 http://dx.doi.org/10.1016/j.redox.2018.02.006 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Cheng, Zhongjian
Shen, Xinggui
Jiang, Xiaohua
Shan, Huimin
Cimini, Maria
Fang, Pu
Ji, Yong
Park, Joon Young
Drosatos, Konstantinos
Yang, Xiaofeng
Kevil, Christopher G.
Kishore, Raj
Wang, Hong
Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide
title Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide
title_full Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide
title_fullStr Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide
title_full_unstemmed Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide
title_short Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide
title_sort hyperhomocysteinemia potentiates diabetes-impaired edhf-induced vascular relaxation: role of insufficient hydrogen sulfide
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854893/
https://www.ncbi.nlm.nih.gov/pubmed/29524844
http://dx.doi.org/10.1016/j.redox.2018.02.006
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