Increased endogenous H2S generation by CBS, CSE, and 3MST gene therapy improves ex vivo renovascular relaxation in hyperhomocysteinemia

Utpal Sen , Pushpakumar B. Sathnur , Sourav Kundu , Srikanth Givvimani , Denise M. Coley , Paras K. Mishra , Natia Qipshidze , Neetu Tyagi , Naira Metreveli , and Suresh C. Tyagi

doi:10.1152/ajpcell.00398.2011

$Hydrogen sulfide (H 2 S) has recently been identified as a regulator of various physiological events, including vasodilation, angiogenesis, antiapoptotic, and cellular signaling. Endogenously, H 2 S is produced as a metabolite of homocysteine (Hcy) by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST). Although Hcy is recognized as vascular risk factor at an elevated level (hyperhomocysteinemia (HHcy)) and contributes to vascular injury leading to renovascular dysfunction, the exact mechanism is unclear. The goal of the current study was to investigate whether conversion of Hcy to H 2 S improves renovascular function. Ex vivo renal artery culture with CBS, CSE, and 3MST triple gene therapy generated more H 2 S in the presence of Hcy, and these arteries were more responsive to endothelial-dependent vasodilation compared with nontransfected arteries treated with high Hcy. Cross section of triple gene-delivered renal arteries immunostaining suggested increased expression of CD31 and VEGF and diminished expression of the antiangiogenic factor endostatin. In vitro endothelial cell culture demonstrated increased mitophagy during high levels of Hcy and was mitigated by triple gene delivery. Also, dephosphorylated Akt and phosphorylated FoxO3 in HHcy were reversed by H 2 S or triple gene delivery. Upregulated matrix metalloproteinases-13 and downregulated tissue inhibitor of metalloproteinase-1 in HHcy were normalized by overexpression of triple genes. Together, these results suggest that H 2 S plays a key role in renovasculopathy during HHcy and is mediated through Akt/FoxO3 pathways. We conclude that conversion of Hcy to H 2 S by CBS, CSE, or 3MST triple gene therapy improves renovascular function in HHcy. homocysteine hydrogen sulfide 3-mercaptopyruvate sulfurtransferase cystathionine β-synthase cystathionine γ-lyase mitophagy Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print April 18, 2012 , doi: 10.1152/ajpcell.00398.2011 Am J Physiol Cell Physiol July 1, 2012 vol. 303 no. 1 C41-C51 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpcell.00398.2011v1 303/1/C41 most recent Classifications Article Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Sen, U. Articles by Tyagi, S. C. PubMed PubMed citation Articles by Sen, U. Articles by Tyagi, S. C. Related Content Load related web page information Current Content July 1, 2012 Alert me to new issues of Am J Physiol Cell Physiol About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0363-6143 Online ISSN: 1522-1563 var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E")); try { var pageTracker = _gat._getTracker("UA-2924550-1"); pageTracker._trackPageview(); } catch(err) {} var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E")); try { var pageTracker = _gat._getTracker("UA-189672-30"); pageTracker._setDomainName(".physiology.org"); pageTracker._trackPageview(); } catch(err) {}$

Increased endogenous H2S generation by CBS, CSE, and 3MST gene therapy improves ex vivo renovascular relaxation in hyperhomocysteinemia

Utpal Sen , Pushpakumar B. Sathnur , Sourav Kundu , Srikanth Givvimani , Denise M. Coley , Paras K. Mishra , Natia Qipshidze , Neetu Tyagi , Naira Metreveli , and Suresh C. Tyagi

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