Hyperglycaemic impairment of PAR2-mediated vasodilation: Prevention by inhibition of aortic endothelial sodium-glucose-co-Transporter-2 and minimizing oxidative stress

Vascular Pharmacology

Volumn 109, Issue , 2018, Pages 56-71

  El Daly, Mahmoud ^a,c   Pulakazhi Venu, Vivek Krishna ^a   Saifeddine, Mahmoud ^a   Mihara, Koichiro ^a   Kang, Sean ^a   Fedak, Paul W M ^a   Alston, Laurie A ^a   Hirota, Simon A ^a   Ding, Hong ^b   Triggle, Chris R ^a,b   Hollenberg, Morley D ^a  

^a UNIVERSITY OF CALGARY   (Canada)

^b WEILL CORNELL MEDICAL COLLEGE   (Qatar)

^c Minia University   (Egypt)

Author keywords

Hyperglycaemia; Oxidative vascular dysfunction; Proteinase activated receptor 2; SGLT2 inhibitor; Sulforaphane

Indexed keywords

ACETYLCHOLINE; CANAGLIFLOZIN; CATALASE; DAPAGLIFLOZIN; EMPAGLIFLOZIN; ENDOTHELIAL NITRIC OXIDE SYNTHASE; EPIDERMAL GROWTH FACTOR RECEPTOR; GLUCOSE; MESSENGER RNA; MUSCARINIC RECEPTOR; NITRIC OXIDE; PROTEIN KINASE C; PROTEIN TYROSINE KINASE; PROTEINASE ACTIVATED RECEPTOR 2; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; RHO KINASE; SODIUM GLUCOSE COTRANSPORTER 2; SULFORAPHANE; SUPEROXIDE DISMUTASE; TATA BINDING PROTEIN; TETRAHYDROBIOPTERIN; TRANSCRIPTION FACTOR NRF2; ANTIDIABETIC AGENT; ANTIOXIDANT; EGFR PROTEIN, MOUSE; INDUCIBLE NITRIC OXIDE SYNTHASE; NOS2 PROTEIN, MOUSE; SLC5A2 PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIOXIDANT ACTIVITY; AORTIC ENDOTHELIAL CELL; AORTIC RING (SLICE); AORTIC TISSUE; ARTICLE; CONCENTRATION RESPONSE; CONTROLLED STUDY; ENDOTHELIAL DYSFUNCTION; ENZYME INHIBITION; GENE INDUCTION; GLUCOSE BLOOD LEVEL; HYPERGLYCEMIA; MALE; MOUSE; MRNA EXPRESSION LEVEL; NONHUMAN; ORGAN CULTURE; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN FUNCTION; SIGNAL TRANSDUCTION; VASCULAR TISSUE; VASODILATATION; ANIMAL; ANTAGONISTS AND INHIBITORS; AORTA; BLOOD; C57BL MOUSE; COMPARATIVE STUDY; DOSE RESPONSE; DRUG EFFECT; ENDOTHELIUM CELL; METABOLISM; MITOCHONDRION; ORGAN CULTURE TECHNIQUE; PATHOLOGY; PATHOPHYSIOLOGY; VASCULAR ENDOTHELIUM;

ANIMALS; ANTIOXIDANTS; AORTA; DOSE-RESPONSE RELATIONSHIP, DRUG; ENDOTHELIAL CELLS; ENDOTHELIUM, VASCULAR; HYPERGLYCEMIA; HYPOGLYCEMIC AGENTS; MALE; MICE, INBRED C57BL; MITOCHONDRIA; NITRIC OXIDE; NITRIC OXIDE SYNTHASE TYPE II; ORGAN CULTURE TECHNIQUES; OXIDATIVE STRESS; PROTEIN KINASE C; RECEPTOR, EPIDERMAL GROWTH FACTOR; RECEPTOR, PAR-2; RHO-ASSOCIATED KINASES; SIGNAL TRANSDUCTION; SODIUM-GLUCOSE TRANSPORTER 2; SRC-FAMILY KINASES; VASODILATION;

EID: 85048895435     PISSN: 15371891     EISSN: 18793649     Source Type: Journal    
DOI: 10.1016/j.vph.2018.06.006     Document Type: Article

References (76)

1. Brownlee, M., Biochemistry and molecular cell biology of diabetic complications. Nature 414:6865 (2001), 813–820.
2. Ding, H., Aljofan, M., Triggle, C.R., Oxidative stress and increased eNOS and NADPH oxidase expression in mouse microvessel endothelial cells. J. Cell. Physiol. 212:3 (2007), 682–689.
3. Forbes, J.M., Cooper, M.E., Mechanisms of diabetic complications. Physiol. Rev. 93:1 (2013), 137–188.
4. Triggle, C.R., The early effects of elevated glucose on endothelial function as a target in the treatment of type 2 diabetes. Timely topics in medicine. Cardiovasc. Dis., 12, 2008, E3.
5. De Vriese, A.S., Verbeuren, T.J., Van de Voorde, J., Lameire, N.H., Vanhoutte, P.M., Endothelial dysfunction in diabetes. Br. J. Pharmacol. 130:5 (2000), 963–974.
6. Ding, H., Triggle, C.R., Endothelial dysfunction in diabetes: multiple targets for treatment. Pflugers Arch. - Eur. J. Physiol. 459:6 (2010), 977–994.
7. Clar, C., Gill, J.A., Court, R., Waugh, N., Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open, 2(5), 2012.
8. Zinman, B., Wanner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., Devins, T., Johansen, O.E., Woerle, H.J., Broedl, U.C., Inzucchi, S.E., Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373:22 (2015), 2117–2128.
9. Wu, J.H., Foote, C., Blomster, J., Toyama, T., Perkovic, V., Sundstrom, J., Neal, B., Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. The Lancet. Diab. Endocrinol. 4:5 (2016), 411–419.
10. Ihlemann, N., Rask-Madsen, C., Perner, A., Dominguez, H., Hermann, T., Kober, L., Torp-Pedersen, C., Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects. Am. J. Physiol. Heart Circ. Physiol. 285:2 (2003), H875–H882.
11. Pannirselvam, M., Simon, V., Verma, S., Anderson, T., Triggle, C.R., Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small mesenteric arteries from diabetic (db/db) mice. Br. J. Pharmacol. 140:4 (2003), 701–706.
12. Pannirselvam, M., Verma, S., Anderson, T.J., Triggle, C.R., Cellular basis of endothelial dysfunction in small mesenteric arteries from spontaneously diabetic (db/db −/−) mice: role of decreased tetrahydrobiopterin bioavailability. Br. J. Pharmacol. 136:2 (2002), 255–263.
13. Coughlin, S.R., Thrombin signalling and protease-activated receptors. Nature 407:6801 (2000), 258–264.
14. Cicala, C., Protease activated receptor 2 and the cardiovascular system. Br. J. Pharmacol. 135:1 (2002), 14–20.
15. Ramachandran, R., Noorbakhsh, F., Defea, K., Hollenberg, M.D., Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat. Rev. Drug Discov. 11:1 (2012), 69–86.
16. Alberelli, M.A., De Candia, E., Functional role of protease activated receptors in vascular biology. Vasc. Pharmacol. 62:2 (2014), 72–81.
17. Robin, J., Kharbanda, R., Mclean, P., Campbell, R., Vallance, P., Protease-activated receptor 2-mediated vasodilatation in humans in vivo: role of nitric oxide and prostanoids. Circulation 107:7 (2003), 954–959.
18. al-Ani, B., Saifeddine, M., Hollenberg, M.D., Detection of functional receptors for the proteinase-activated-receptor-2-activating polypeptide, SLIGRL-NH2, in rat vascular and gastric smooth muscle. Can. J. Physiol. Pharmacol. 73:8 (1995), 1203–1207.
19. De Mey, J.G., Claeys, M., Vanhoutte, P.M., Endothelium-dependent inhibitory effects of acetylcholine, adenosine triphosphate, thrombin and arachidonic acid in the canine femoral artery. J. Pharmacol. Exp. Ther. 222:1 (1982), 166–173.
20. Kagota, S., Maruyama, K., Mcguire, J.J., Characterization and functions of protease-activated receptor 2 in obesity, diabetes, and metabolic syndrome: a systematic review. Biomed. Res. Int., 2016, 2016, 3130496.
21. Aman, M., Hirano, M., Kanaide, H., Hirano, K., Upregulation of proteinase-activated receptor-2 and increased response to trypsin in endothelial cells after exposure to oxidative stress in rat aortas. J. Vasc. Res. 47:6 (2010), 494–506.
22. Lee, H., Hamilton, J.R., Physiology, pharmacology, and therapeutic potential of protease-activated receptors in vascular disease. Pharmacol. Ther. 134:2 (2012), 246–259.
23. Gao, X., Dinkova-Kostova, A.T., Talalay, P., Powerful and prolonged protection of human retinal pigment epithelial cells, keratinocytes, and mouse leukemia cells against oxidative damage: the indirect antioxidant effects of sulforaphane. Proc. Natl. Acad. Sci. U. S. A. 98:26 (2001), 15221–15226.
24. Wakabayashi, N., Dinkova-Kostova, A.T., Holtzclaw, W.D., Kang, M.I., Kobayashi, A., Yamamoto, M., Kensler, T.W., Talalay, P., Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc. Natl. Acad. Sci. U. S. A. 101:7 (2004), 2040–2045.
25. Dinkova-Kostova, A.T., Holtzclaw, W.D., Cole, R.N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., Talalay, P., Direct evidence that sulfhydryl groups of keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc. Natl. Acad. Sci. U. S. A. 99:18 (2002), 11908–11913.
26. Ma, Q., Role of nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 53 (2013), 401–426.
27. Dranka, B.P., Benavides, G.A., Diers, A.R., Giordano, S., Zelickson, B.R., Reily, C., Zou, L., Chatham, J.C., Hill, B.G., Zhang, J., Landar, A., Darley-Usmar, V.M., Assessing bioenergetic function in response to oxidative stress by metabolic profiling. Free Radic. Biol. Med. 51:9 (2011), 1621–1635.
28. Feeley, K.P., Westbrook, D.G., Bray, A.W., Ballinger, S.W., An ex-vivo model for evaluating bioenergetics in aortic rings. Redox Biol. 2 (2014), 1003–1007.
29. Bustin, S.A., Benes, V., Garson, J.A., Hellemans, J., Huggett, J., Kubista, M., Mueller, R., Nolan, T., Pfaffl, M.W., Shipley, G.L., Vandesompele, J., Wittwer, C.T., The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 55:4 (2009), 611–622.
30. Pulakazhi Venu, V.K., Uboldi, P., Dhyani, A., Patrini, A., Baetta, R., Ferri, N., Corsini, A., Muro, A.F., Catapano, A.L., Norata, G.D., Fibronectin extra domain a stabilises atherosclerotic plaques in apolipoprotein E and in LDL-receptor-deficient mice. Thromb. Haemost. 114:1 (2015), 186–197.
31. Au-Wang, J.-M., Au-Chen, A.F., Au-Zhang, K., Isolation and primary culture of mouse aortic endothelial cells. JoVE(118), 2016, e52965.
32. Garg, A., Zhao, A., Erickson, S.L., Mukherjee, S., Lau, A.J., Alston, L., Chang, T.K., Mani, S., Hirota, S.A., Pregnane X receptor activation attenuates inflammation-associated intestinal epithelial barrier dysfunction by inhibiting cytokine-induced myosin light-chain kinase expression and c-Jun N-terminal kinase 1/2 activation. J. Pharmacol. Exp. Ther. 359:1 (2016), 91–101.
33. Kanwal, A., Singh, S.P., Grover, P., Banerjee, S.K., Development of a cell-based nonradioactive glucose uptake assay system for SGLT1 and SGLT2. Anal. Biochem. 429:1 (2012), 70–75.
34. Kilkenny, C., Browne, W., Cuthill, I.C., Emerson, M., Altman, D.G., Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br. J. Pharmacol. 160:7 (2010), 1577–1579.
35. Schini, V.B., Vanhoutte, P.M., L-arginine evokes both endothelium-dependent and -independent relaxations in L-arginine-depleted aortas of the rat. Circ. Res. 68:1 (1991), 209–216.
36. Gui, Y., Zheng, X.L., Hollenberg, M.D., Interleukin-1beta, Src- and non-Src tyrosine kinases, and nitric oxide synthase induction in rat aorta in vitro. Am. J. Physiol. Heart Circ. Physiol. 279:2 (2000), H566–H576.
37. Griendling, K.K., Alexander, R.W., Oxidative stress and cardiovascular disease. Circulation 96:10 (1997), 3264–3265.
38. Cosentino, F., Eto, M., De Paolis, P., van der Loo, B., Bachschmid, M., Ullrich, V., Kouroedov, A., Delli Gatti, C., Joch, H., Volpe, M., Luscher, T.F., High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation 107:7 (2003), 1017–1023.
39. Jay, D., Hitomi, H., Griendling, K.K., Oxidative stress and diabetic cardiovascular complications. Free Radic. Biol. Med. 40:2 (2006), 183–192.
40. Giacco, F., Brownlee, M., Oxidative stress and diabetic complications. Circ. Res. 107:9 (2010), 1058–1070.
41. Shi, Y., Vanhoutte, P.M., Macro- and microvascular endothelial dysfunction in diabetes. J. Diab. 9:5 (2017), 434–449.
42. Landmesser, U., Dikalov, S., Price, S.R., McCann, L., Fukai, T., Holland, S.M., Mitch, W.E., Harrison, D.G., Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J. Clin. Invest. 111:8 (2003), 1201–1209.
43. Chuaiphichai, S., Crabtree, M.J., Mcneill, E., Hale, A.B., Trelfa, L., Channon, K.M., Douglas, G., A key role for tetrahydrobiopterin-dependent endothelial NOS regulation in resistance arteries: studies in endothelial cell tetrahydrobiopterin-deficient mice. Br. J. Pharmacol. 174:8 (2017), 657–671.
44. Brown, D.I., Griendling, K.K., Regulation of signal transduction by reactive oxygen species in the cardiovascular system. Circ. Res. 116:3 (2015), 531–549.
45. Chen, C.H., Cheng, T.H., Lin, H., Shih, N.L., Chen, Y.L., Chen, Y.S., Cheng, C.F., Lian, W.S., Meng, T.C., Chiu, W.T., Chen, J.J., Reactive oxygen species generation is involved in epidermal growth factor receptor transactivation through the transient oxidization of Src homology 2-containing tyrosine phosphatase in endothelin-1 signaling pathway in rat cardiac fibroblasts. Mol. Pharmacol. 69:4 (2006), 1347–1355.
46. Chen, K., Vita, J.A., Berk, B.C., Keaney, J.F. Jr., c-Jun N-terminal kinase activation by hydrogen peroxide in endothelial cells involves SRC-dependent epidermal growth factor receptor transactivation. J. Biol. Chem. 276:19 (2001), 16045–16050.
47. Sarashina, A., Koiwai, K., Seman, L.J., Yamamura, N., Taniguchi, A., Negishi, T., Sesoko, S., Woerle, H.J., Dugi, K.A., Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects. Drug Metab. Pharmacokinet. 28:3 (2013), 213–219.
48. Heise, T., Seman, L., Macha, S., Jones, P., Marquart, A., Pinnetti, S., Woerle, H.J., Dugi, K., Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diab. Ther.: Res. Treat. Educ. Diab. Relat. Disord. 4:2 (2013), 331–345.
49. Shah, M.S., Brownlee, M., Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ. Res. 118:11 (2016), 1808–1829.
50. Li, Y., Pagano, P.J., Microvascular NADPH oxidase in health and disease. Free Radic. Biol. Med. 109 (2017), 33–47.
51. Zhang, Q., Malik, P., Pandey, D., Gupta, S., Jagnandan, D., Belin De Chantemele, E., Banfi, B., Marrero, M.B., Rudic, R.D., Stepp, D.W., Fulton, D.J., Paradoxical activation of endothelial nitric oxide synthase by NADPH oxidase. Arterioscler. Thromb. Vasc. Biol. 28:9 (2008), 1627–1633.
52. Liang, C.F., Liu, J.T., Wang, Y., Xu, A., Vanhoutte, P.M., Toll-like receptor 4 mutation protects obese mice against endothelial dysfunction by decreasing NADPH oxidase isoforms 1 and 4. Arterioscler. Thromb. Vasc. Biol. 33:4 (2013), 777–784.
53. Reinehr, R., Becker, S., Eberle, A., Grether-Beck, S., Haussinger, D., Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. J. Biol. Chem. 280:29 (2005), 27179–27194.
54. Xi, G., Shen, X.C., Wai, C., Clemmons, D.R., Recruitment of Nox4 to a plasma membrane scaffold is required for localized reactive oxygen species generation and sustained Src activation in response to insulin-like growth factor-I. J. Biol. Chem. 288:22 (2013), 15641–15653.
55. Xi, G., Shen, X., Maile, L.A., Wai, C., Gollahon, K., Clemmons, D.R., Hyperglycemia enhances IGF-I-stimulated Src activation via increasing Nox4-derived reactive oxygen species in a PKCzeta-dependent manner in vascular smooth muscle cells. Diabetes 61:1 (2012), 104–113.
56. Maier, W., Cosentino, F., Lutolf, R.B., Fleisch, M., Seiler, C., Hess, O.M., Meier, B., Luscher, T.F., Tetrahydrobiopterin improves endothelial function in patients with coronary artery disease. J. Cardiovasc. Pharmacol. 35:2 (2000), 173–178.
57. Verma, S., Lovren, F., Dumont, A.S., Mather, K.J., Maitland, A., Kieser, T.M., Triggle, C.R., Anderson, T.J., Tetrahydrobiopterin improves endothelial function in human saphenous veins. J. Thorac. Cardiovasc. Surg. 120:4 (2000), 668–671.
58. Cosentino, F., Luscher, T.F., Tetrahydrobiopterin and endothelial nitric oxide synthase activity. Cardiovasc. Res. 43:2 (1999), 274–278.
59. Oelze, M., Kroller-Schon, S., Welschof, P., Jansen, T., Hausding, M., Mikhed, Y., Stamm, P., Mader, M., Zinssius, E., Agdauletova, S., Gottschlich, A., Steven, S., Schulz, E., Bottari, S.P., Mayoux, E., Munzel, T., Daiber, A., The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS One, 9(11), 2014, e112394.
60. Salim, H.M., Fukuda, D., Yagi, S., Soeki, T., Shimabukuro, M., Sata, M., Glycemic control with ipragliflozin, a novel selective SGLT2 inhibitor, ameliorated endothelial dysfunction in Streptozotocin-induced diabetic mouse. Front. Cardiovasc. Med., 3, 2016, 43.
61. Zhou, H., Wang, S., Zhu, P., Hu, S., Chen, Y., Ren, J., Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol. 15 (2017), 335–346.
62. Davies, M.J., Merton, K.W., Vijapurkar, U., Balis, D.A., Desai, M., Canagliflozin improves risk factors of metabolic syndrome in patients with type 2 diabetes mellitus and metabolic syndrome. Diab. Metab. Syndr. Obesity: Targets Ther. 10 (2017), 47–55.
63. Martens, P., Mathieu, C., Verbrugge, F.H., Promise of SGLT2 inhibitors in heart failure: diabetes and beyond. Curr. Treat. Opt. Cardiovasc. Med., 19(3), 2017, 23.
64. Ott, C., Jumar, A., Striepe, K., Friedrich, S., Karg, M.V., Bramlage, P., Schmieder, R.E., A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc. Diabetol., 16(1), 2017, 26.
65. Fitchett, D., Inzucchi, S.E., Lachin, J.M., Wanner, C., van de Borne, P., Mattheus, M., Johansen, O.E., Woerle, H.J., Broedl, U.C., George, J.T., Zinman, B., Cardiovascular mortality reduction with Empagliflozin in patients with type 2 diabetes and cardiovascular disease. J. Am. Coll. Cardiol. 71:3 (2018), 364–367.
66. Inzucchi, S.E., Zinman, B., Fitchett, D., Wanner, C., Ferrannini, E., Schumacher, M., Schmoor, C., Ohneberg, K., Johansen, O.E., George, J.T., Hantel, S., Bluhmki, E., Lachin, J.M., How does Empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 41:2 (2018), 356–363.
67. Hawley, S.A., Ford, R.J., Smith, B.K., Gowans, G.J., Mancini, S.J., Pitt, R.D., Day, E.A., Salt, I.P., Steinberg, G.R., Hardie, D.G., The Na+/glucose cotransporter inhibitor canagliflozin activates AMPK by inhibiting mitochondrial function and increasing cellular AMP levels. Diabetes 65:9 (2016), 2784–2794.
68. Daiber, A., Steven, S., Weber, A., Shuvaev, V.V., Muzykantov, V.R., Laher, I., Li, H., Lamas, S., Munzel, T., Targeting vascular (endothelial) dysfunction. Br. J. Pharmacol. 174:12 (2017), 1591–1619.
69. Sesso, H.D., Buring, J.E., Christen, W.G., Kurth, T., Belanger, C., Macfadyen, J., Bubes, V., Manson, J.E., Glynn, R.J., Gaziano, J.M., Vitamins E and C in the prevention of cardiovascular disease in men: the physicians’ health study II randomized controlled trial. JAMA 300:18 (2008), 2123–2133.
70. Salonen, R.M., Nyyssonen, K., Kaikkonen, J., Porkkala-Sarataho, E., Voutilainen, S., Rissanen, T.H., Tuomainen, T.P., Valkonen, V.P., Ristonmaa, U., Lakka, H.M., Vanharanta, M., Salonen, J.T., Poulsen, H.E., Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the antioxidant supplementation in atherosclerosis prevention (ASAP) study. Circulation 107:7 (2003), 947–953.
71. Axelsson, A.S., Tubbs, E., Mecham, B., Chacko, S., Nenonen, H.A., Tang, Y., Fahey, J.W., Derry, J.M.J., Wollheim, C.B., Wierup, N., Haymond, M.W., Friend, S.H., Mulder, H., Rosengren, A.H., Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes. Sci. Transl. Med., 9(394), 2017.
72. Thompson, J.A., Larion, S., Mintz, J.D., Belin De Chantemele, E.J., Fulton, D.J., Stepp, D.W., Genetic deletion of NADPH oxidase 1 rescues microvascular function in mice with metabolic disease. Circ. Res. 121:5 (2017), 502–511.
73. Kagota, S., Chia, E., Mcguire, J.J., Preserved arterial vasodilatation via endothelial protease-activated receptor-2 in obese type 2 diabetic mice. Br. J. Pharmacol. 164:2 (2011), 358–371.
74. Schaffer, S.W., Jong, C.J., Mozaffari, M., Role of oxidative stress in diabetes-mediated vascular dysfunction: unifying hypothesis of diabetes revisited. Vasc. Pharmacol. 57:5–6 (2012), 139–149.
75. Siti, H.N., Kamisah, Y., Kamsia, J., The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vasc. Pharmacol. 71 (2015), 40–56.
76. Lemmey, H.A.L., Ye, X., Ding, H.C., Triggle, C.R., Garland, C.J., Dora, K.A., Hyperglycaemia disrupts conducted vasodilation in the resistance vasculature of db/db mice. Vasc. Pharmacol. 103-105 (2018), 29–35.