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Molecular Interplay Between Microrna-34A and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin S

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Molecular Interplay Between Microrna-34A and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin S Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2015/11/18/jpet.115.226894.DC1 1521-0103/356/2/314–323$25.00 http://dx.doi.org/10.1124/jpet.115.226894 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 356:314–323, February 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin s Gnanapragasam Arunachalam, Arun Prasath Lakshmanan, Samson Mathews Samuel, Chris R. Triggle, and Hong Ding Departments of Pharmacology (G.A., A.P.L., S.M.S.) and Medical Education (C.R.T., H.D.), Weill Cornell Medicine-Qatar, Education City, Doha, Qatar (C.T.) Received June 22, 2015; accepted November 10, 2015 Downloaded from ABSTRACT Impaired angiogenesis is a prominent risk factor that contributes sirtuin1, and their signaling targets was evaluated. miR-34a to the development of diabetes-associated cardiovascular expression is upregulated in a hyperglycemic milieu and parallels disease. MicroRNAs (miRNAs), small noncoding RNAs, are changes in the expression of sirtuin1, post-translational modifi- implicated as important regulators of vascular function, including cation of endothelial nitric oxide synthase (phospho/acetylation), endothelial cell differentiation, proliferation, and angiogenesis. In as well as an impairment in angiogenesis. The presence of jpet.aspetjournals.org silico analysis and in vitro studies indicate that silent informa- metformin, or the inhibition of miR-34a using an anti–miR-34a tion regulator 1 (SIRT1) is a potential target for endothelial inhibitor, increases the expression of sirtuin1 and attenuates the cell–specific miRNAs. In this study, we investigated the mo- impairment in angiogenesis in HG-exposed MMECs. In contrast, lecular crosstalk between miR-34a, the protein product of overexpression of a miR-34a mimic prevents metformin-mediated SIRT1 (sirtuin1), and the antidiabetic drug, metformin, in protection. These data indicate that miR-34a, via the regulation of hyperglycemia-mediated impaired angiogenesis in mouse sirtuin1 expression, has an anti-angiogenic action in MMECs, microvascular endothelial cells (MMECs). MMECs were cul- which can be modulated by metformin. In summary, miR-34a at ASPET Journals on October 2, 2021 tured, transfected with either a miR-34a inhibitor or mimic in represents both a target whereby metformin mediates its vascu- normal glucose (11 mM) or high glucose (HG, 40 mM) in the loprotective actions and also a potential therapeutic target for the presence or absence of metformin. The expression of miR-34a, prevention/treatment of diabetic vascular disease. Introduction inflammation, and impaired angiogenesis (Avogaro et al., 2011; Roberts and Porter, 2013; Sena et al., 2013). Despite The global increase in the prevalence of type 2 diabetes the known high risk for patients with diabetes to develop (T2DM) and the link to an elevated risk for both cardiovascu- CVD, the pathogenesis underlying the relationship between lar disease (CVD) and cancer are major concerns that heighten T2DM and CVD is not fully understood. Therefore, the the need for improved approaches for the early detection, identification of new molecular targets that are associated prevention, and treatment of T2DM (Tremblay and Hamet, with the development of vascular dysfunction in diabetes is of 2015). Vascular endothelial cells (ECs) play a major role in high scientific interest. maintaining normal cardiovascular homeostasis, and endo- MicroRNAs (miRNAs) are short (∼22 nucleotides) noncod- thelial dysfunction is recognized as an early indicator of ing RNAs that typically bind to 39 untranslated regions of diabetes-associated CVD (Ding and Triggle, 2010; Eelen mRNAs, acting principally at the post-transcriptional level et al., 2015). The diabetic milieu, namely hyperglycemia, and repressing the mRNA translation and stability (Olson, excess free fatty acid release, and insulin resistance, initiates 2014). miRNAs have been implicated as key elements playing a sequence of events in the vasculature that includes crucial roles in the pathogenesis of diabetes-associated CVD, oxidative stress, impaired endothelial function, increased including endothelial dysfunction, angiogenesis, hypertrophy, and heart failure (Urbich et al., 2008; Leeper and Cooke, 2011; Hata, 2013; Beltrami et al., 2014; Arunachalam et al., 2015; The work was supported by National Priorities Research Program grants [4- Zhu and Leung, 2015). Several endothelial-specific miRNAs 910-3-244, 5-149-3-040, 6-428-3-113] from Qatar National Research Fund (a member of Qatar Foundation) and a Biomedical Research Program establish- have been identified as regulators of cardiac and endothelial ment grant. The statements made herein are solely the responsibility of the function and linked to the regulation of angiogenesis and the author(s). dx.doi.org/10.1124/jpet.115.226894. development of senescence and inflammation (Suárez and s This article has supplemental material available at jpet.aspetjournals.org. Sessa, 2009; Caporali et al., 2011; Staszel et al., 2011; ABBREVIATIONS: AMPK, AMP-activated protein kinase; Ang-1, angiopoetin-1; Ang-2, angiopoetin-2; CVD, cardiovascular disease; DMEM, Dulbecco’s modified Eagle’s medium; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; HG, high glucose; miRNA, microRNA; MMEC, mouse microvascular EC; NG, normal glucose; SIRT1, silent information regulator 1; T2DM, type 2 diabetes; TSP-1, thrombospondin-1. 314 Metformin Modulates miR-34a Expression during Hyperglycemia 315 Zampetaki and Mayr, 2012; Arunachalam et al., 2015). humidified atmosphere containing 5% CO2, as previously described MicroRNA-34a (miR-34a) is highly expressed in ECs and (Arunachalam et al., 2014). Glucose concentrations were chosen on the has been reported to play a key role in the regulation of EC basis of random glucose measurements taken from normoglycaemic proliferation, inflammation, senescence, and apoptosis mice that approximates 11 mM, and for type 2 diabetic, db/db mice, (Qin et al., 2012; Badi et al., 2014; Fan et al., 2015). Elevated which, for the latter, have been reported to range from 30 to 55 mM and as also detailed in The Jackson Laboratory (Bar Harbor, ME) miR-34a expression has been reported in senescent human Phenome Data Summary for mice (Pannirselvam et al., 2002; umbilical vein ECs as well as in the heart and spleen of aged Semeniuk et al., 2002). For the studies comparing the effects of mice (Ito et al., 2010). mannitol, MMECs were incubated with media that consisted of 11 mM Silent information regulator 1 (SIRT1), referred to as an D-glucose plus 29 mM D-mannitol. anti-ageing gene, has been described as a novel regulatory miR-34a Inhibition and Overexpression. MMECs were grown switch in vascular EC homoeostasis (Potente et al., 2007; in antibiotic-free DMEM for 24 hours. For the protocols involving miR- Potente and Dimmeler, 2008). Furthermore, sirtuin1, the 34a inhibition, MMECs at 30–50% confluence were transfected with a protein product of SIRT1, via the deacetylation of endothelial miR-34a inhibitor (small, synthetic, and chemically modified single- nitric oxide synthase (eNOS), increases the generation of stranded RNA molecules designed to specifically bind to and inhibit nitric oxide and enhances endothelium-dependent vasodila- the mature miRNAs from functioning) or a miRNA inhibitor negative control (25 nmol/l, mirVana; Life Technologies Waltham, MA) for 12 tation (Mattagajasingh et al., 2007; Arunachalam et al., 2010). hours using Opti-MEM reduced serum media and lipofectamine-2000 miR-34a directly binds to SIRT1 through a miR-34a binding according to the manufacturer’s instructions (Invitrogen, Waltham, 9 site within the 3 untranslated regions of SIRT1, inhibits the MA). After 12 hours of transfection, the transfection media was Downloaded from expression of the protein sirtuin1, and regulates apoptosis via changed into media consisting of either NG or HG for another the sirtuin1-p53 pathway (Yamakuchi et al., 2008). In human 48 hours (media was changed at 24 hours). To overexpress miR-34a in umbilical vein ECs, the overexpression of miR-34a down- MMECs, cells were transfected with the miR-34a mimic (small, regulates sirtuin1 expression and induces EC senescence, synthetic, and chemically modified double-stranded RNAs that mimic whereas the knockdown of miR-34a enhances the expression particular endogenous miRNAs and enable miRNA functional anal- of sirtuin1 and attenuates endothelial senescence (Ito et al., ysis by upregulation of miRNA activity) or the negative control mimic jpet.aspetjournals.org 2010). In addition, several studies have highlighted miR-34a (50 nmol/l, mirVana; Life Technologies) for 12 hours using Opti-MEM reduced serum media and lipofectamine-2000, according to the as an important mediator of ageing-related cardiac dysfunc- manufacturer’s instructions (Invitrogen). After 12 hours of trans- tion by modulating the expression of sirtuin1 (Tabuchi et al., fection, the media was changed into a media consisting of either NG 2012; Boon et al., 2013; Han et al., 2015). Furthermore, the or HG for another 48 hours (media was changed at 24 hours). At the end overexpression of miR-34a in endothelial progenitor cells of the experimental period, lysates were taken for further analysis. reduces the expression of sirtuin1 expression, resulting in Treatment
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