Qiuxia Li1, Young-Rae Kim1, Ajit Vikram1, Santosh Kumar1, Modar Kassan1, Mohanad Gabani1, Sang Ki Lee1, Julia S Jacobs1, Kaikobad Irani2. 1. From the Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City (Q.L., Y.-R.K., A.V., S.K., M.K., M.G., J.S.J., K.I.); and Department of Sports Science, Chungnam National University, Daejeon, Korea (S.K.L.). 2. From the Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City (Q.L., Y.-R.K., A.V., S.K., M.K., M.G., J.S.J., K.I.); and Department of Sports Science, Chungnam National University, Daejeon, Korea (S.K.L.). kaikobad-irani@uiowa.edu qiuxia-li@uiowa.edu.
Abstract
OBJECTIVE: Diabetes mellitus causes vascular endothelial dysfunction and alters vascular microRNA expression. We investigated whether endothelial microRNA-34a (miR-34a) leads to diabetic vascular dysfunction by targeting endothelial sirtuin1 (Sirt1) and asked whether the oxidative stress protein p66Shc governs miR-34a expression in the diabetic endothelium. APPROACH AND RESULTS: MiR-34a is upregulated, and Sirt1 downregulated, in aortic endothelium of db/db and streptozotocin-induced diabetic mice. Systemic administration of miR-34a inhibitor, or endothelium-specific knockout of miR-34a, prevents downregulation of aortic Sirt1 and rescues impaired endothelium-dependent aortic vasorelaxation induced by diabetes mellitus. Moreover, overexpression of Sirt1 mitigates impaired endothelium-dependent vasorelaxation caused by miR-34a mimic ex vivo. Systemic infusion of miR-34a inhibitor or genetic ablation of endothelial miR-34a prevents downregulation of endothelial Sirt1 by high glucose. MiR-34a is upregulated, Sirt1 is downregulated, and oxidative stress (hydrogen peroxide) is induced in endothelial cells incubated with high glucose or the free fatty acid palmitate in vitro. Increase of hydrogen peroxide and induction of endothelial miR-34a by high glucose or palmitate in vitro is suppressed by knockdown of p66shc. In addition, overexpression of wild-type but not redox-deficient p66Shc upregulates miR-34a in endothelial cells. P66Shc-stimulated upregulation of endothelial miR-34a is suppressed by cell-permeable antioxidants. Finally, mice with global knockdown of p66Shc are protected from diabetes mellitus-induced upregulation of miR-34a and downregulation of Sirt1 in the endothelium. CONCLUSIONS: These data show that hyperglycemia and elevated free fatty acids in the diabetic milieu recruit p66Shc to upregulate endothelial miR-34a via an oxidant-sensitive mechanism, which leads to endothelial dysfunction by targeting Sirt1.
OBJECTIVE: Diabetes mellitus causes vascular endothelial dysfunction and alters vascular microRNA expression. We investigated whether endothelial microRNA-34a (miR-34a) leads to diabetic vascular dysfunction by targeting endothelial sirtuin1 (Sirt1) and asked whether the oxidative stress protein p66Shc governs miR-34a expression in the diabetic endothelium. APPROACH AND RESULTS: MiR-34a is upregulated, and Sirt1 downregulated, in aortic endothelium of db/db and streptozotocin-induced diabetic mice. Systemic administration of miR-34a inhibitor, or endothelium-specific knockout of miR-34a, prevents downregulation of aortic Sirt1 and rescues impaired endothelium-dependent aortic vasorelaxation induced by diabetes mellitus. Moreover, overexpression of Sirt1 mitigates impaired endothelium-dependent vasorelaxation caused by miR-34a mimic ex vivo. Systemic infusion of miR-34a inhibitor or genetic ablation of endothelial miR-34a prevents downregulation of endothelial Sirt1 by high glucose. MiR-34a is upregulated, Sirt1 is downregulated, and oxidative stress (hydrogen peroxide) is induced in endothelial cells incubated with high glucose or the free fatty acid palmitate in vitro. Increase of hydrogen peroxide and induction of endothelial miR-34a by high glucose or palmitate in vitro is suppressed by knockdown of p66shc. In addition, overexpression of wild-type but not redox-deficient p66Shc upregulates miR-34a in endothelial cells. P66Shc-stimulated upregulation of endothelial miR-34a is suppressed by cell-permeable antioxidants. Finally, mice with global knockdown of p66Shc are protected from diabetes mellitus-induced upregulation of miR-34a and downregulation of Sirt1 in the endothelium. CONCLUSIONS: These data show that hyperglycemia and elevated free fatty acids in the diabetic milieu recruit p66Shc to upregulate endothelial miR-34a via an oxidant-sensitive mechanism, which leads to endothelial dysfunction by targeting Sirt1.
Authors: Giovanni G Camici; Marzia Schiavoni; Pietro Francia; Markus Bachschmid; Ines Martin-Padura; Martin Hersberger; Felix C Tanner; Piergiuseppe Pelicci; Massimo Volpe; Piero Anversa; Thomas F Lüscher; Francesco Cosentino Journal: Proc Natl Acad Sci U S A Date: 2007-03-14 Impact factor: 11.205
Authors: Tsung-Cheng Chang; Erik A Wentzel; Oliver A Kent; Kalyani Ramachandran; Michael Mullendore; Kwang Hyuck Lee; Georg Feldmann; Munekazu Yamakuchi; Marcella Ferlito; Charles J Lowenstein; Dan E Arking; Michael A Beer; Anirban Maitra; Joshua T Mendell Journal: Mol Cell Date: 2007-05-31 Impact factor: 17.970
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Teresa Vezza; Aranzazu M de Marañón; Francisco Canet; Pedro Díaz-Pozo; Miguel Marti; Pilar D'Ocon; Nadezda Apostolova; Milagros Rocha; Víctor M Víctor Journal: Antioxidants (Basel) Date: 2021-05-19