Table 2.
Evidence Implicating Nitrosative Stress and Peroxynitrite Formation in Diabetes and Diabetic Complications
| Organ/Tissue, function Investigated | Species/ cells | Disease Model, trigger | Main Finding | Reference |
|---|---|---|---|---|
| Plasma | Human | T2DM | Cardiopulmonary bypass induced greater oxidative and nitrosative stress in diabetic patients. | 7 |
| Plasma | Human | T2DM | Increased plasma nitrotyrosine levels in diabetic patients | 8 |
| Plasma | Human | T2DM | Increased plasma nitrite/nitrate levels in diabetic patients. | 9 |
| Plasma | Human | T2DM | Postprandial hypertriglyceridemia and hyperglycemia induced endothelial dysfunction in diabetic patients and increased plasma nitrotyrosine levels, which was attenuated by simvastatin treatment. | 10 |
| Plasma | Human | T2DM | Increased plasma nitrotyrosine levels in diabetic patients, which correlate with postprandial hyperglycemia. | 11 |
| Plasma | Human | T1DM | Increased plasma nitrite, nitrate and nitrotyrosine , which correlate with the insulin requirements of the diabetic patients. | 12 |
| Plasma | Human | T1DM | Increased plasma nitrite/nitrate, nitrotyrosine and elevated blood pressure in diabetic patients. | 13 |
| LDL | Human | T1DM | Incubation of human aortic endothelial cells with LDL from T1DM patients increased Na+/K+-ATPase and Ca2+- ATPase activities, NOS activity and peroxynitrite production. | 14 |
| Platelets | Human | T1DM, T2DM | Increased iNOS derived peroxynitrite formation in diabetic platelets | 15 |
| Aorta, vascular function | Mouse | Mouse STZ-induced diabetes | Increased eNOS expression, nitrotyrosine formation and PARP activation in endothelium and vascular smooth muscle. | 16 |
| Skin microvasculature | Human | T2DM and prediabetic | Increased nitrotyrosine formation and PARP activation in endothelial cells of diabetic and prediabetic patients. | 17 |
| Aorta, cardiac and vascular function, pancreatic islet beta- cells | Mouse | STZ-induced diabetes. | A peroxynitrite decomposition catalyst improved vascular and cardiac function and protected against diabetes. | 18 |
| Human aortic endothelial cells | Human | High glucose | Increased ONOO- formation, tyrosine nitration and inhibition of prostacycline synthase. | 19 |
| Human umbilical vein endothelial cells | Human | Stable or intermittent high glucose | Stable or intermittent high glucose stimulated nitrotyrosine formation through PKC-dependent activation of NAD(P)H oxidase. | 20 |
| Human aortic endothelial cells | Human | High glucose | Glucose-induced activation of PKC resulted in Peroxynitrite formation and nitration of prostacyclin synthase. | 21 |
| Bovine endothelial cells | Bovine | Hyperglycemia (HG) | HG induced increased lipid peroxidation, increased superoxide and peroxynitrite formation, and PKC activity. | 22 |
| Aorta, liver, kidney | Rat | STZ-induced diabetes | Increased free radical and NO concentrations in the liver, kidney and aorta; increased ONOO− formation in aorta. | 23 |
| Aorta, vascular function | Rat | Zucker diabetic rats | Age-dependent increase of nitrotyrosine formation in the vasculature and development of endothelial dysfunction, which is attenuated by a peroxynitrite scavenger, ebselen. | 24 |
| Cardiac myocytes | Human | T2DM, hypertension | Increased apoptosis, necrosis, angiotensine II and nitrotyrosine formation in myocytes. | 25 |
| Cardiac myocytes | Mouse | STZ-induced diabetes | Increased apoptosis, H2O2, .OH, angiotensine II and nitrotyrosine formation in myocytes, which is decreased by IGF-1 overexpression. | 26 |
| Heart mitochondria | Rat | STZ-induced diabetes | Increased nitration and inactivation of succinyl-CoA:3- oxoacid CoA-transferase (SCOT). | 27 |
| Heart | Rat | High glucose | Perfusion of isolated hearts with high glucose increased superoxide generation, NO, nitrotyrosine formation and iNOS expression. | 28 |
| Heart | Mouse | Alloxan-induced diabtes | Tyrosine nitration of mitochondrial proteins. | 29 |
| Pancreatic islet beta-cells | Mouse | NOD mice | Increased nitrotyrosine formation in pancreatic islet beta-cells. | 30 |
| Placenta | Human | T1DM | Increased nitration in vascular endothelium and villous stroma. | 31 |
| Placental vasculature | Human | T1DM, preeclampsia | Increased nitrotyrosine formation, attenuated vasoconstrictor and vasodilatory responses in diabetes and preeclampsia. | 32 |
| Kidney | Human | Patients with diabetic nephropathy | Increased nitrotyrosine immunostaining in renal tubuli of diabetic patients. | 33 |
| Kidney | Rat | STZ-induced diabetes | Increased superoxide and nitrotyrosine formation in renal cortex. | 34 |
| Kidney | Mouse | STZ-induced diabetes | Increased renal nitrotyrosine and advanced glycation end product formation, which is attenuated by ramipril or aminoguanidine. | 35 |
| Kidney | Rat | STZ-induced diabetes | Increased renal expression of p47phox, hydrogen peroxide production and nitrotyrosine formation. | 36 |
| Retina | Rat | STZ-induced diabetes | Increased nitrosative stress, which is attenuated by aminoguanidine. | 37 |
| Retina | Rat | BBZ/Wor rat model of NIDDM | Increased iNOS and nitrotyrosine immunoreactivity in diabetic retinas. | 38 |
| Retina | Rat | STZ-induced diabetes | Increased retinal lipid peroxidation and nitrotyrosine formation, which was only slightly attenuated by reinstitution of good glycemic control. | 39 |
| Retina | Rat | STZ-induced diabetes | Increased tyrosine nitration and expression of vascular endothelial growth factor contribute to the breakdown of the blood-retina barrier in diabetes. | 40 |
| Retinal endothelial cells | High glucose | High glucose induced increased nitrotyrosine formation in retinal endothelial cells, which was blocked by superoxide or peroxynitrite scavengers, NOS or aldose reductase inhibitors. | 41 | |
| Peripheral nerves, epineurial arterioles, endoneurial blood flow | Rat | STZ-induced diabetes | Antioxidants reduced the production of superoxide and peroxynitrite in epineurial arterioles and improved endoneural blood flow. | 42 |
| Epineurial arterioles, endoneurial blood flow | Rat | STZ-induced diabetes | Antioxidant (M40403) reduced the production of superoxide and peroxynitrite in epineurial arterioles and improved endoneural blood flow. | 43 |
| Peripheral motor nerve function | Human | T1DM | Decreased motor nerve function in diabetic patients correlates with increased nitrosative stress. | 44 |
| Peripheral sensory neurons | Rat | STZ-induced diabetes | Rise in cytoplasmic labeling of nitrotyrosine, PARP activation. | 45 |
| Peripheral nerves, epineurial arterioles, endoneurial blood flow | Rat | STZ-induced diabetes | Antioxidants reduced the production of superoxide and peroxynitrite in epineurial arterioles and improved endoneural blood flow. | 46 |
| Bladder | Rat | STZ-induced diabetes | Increased proteasomal activation and nitrotyrosine formation during diabetic cystopathy. | 47 |