TABLE 5.
Evidence implicating endogenous peroxynitrite formation and/or protein nitration in diabetes and diabetic complications
| Disease Model, Trigger | Tissue, Function Investigated | Main Findings | Reference Nos. |
|---|---|---|---|
| General | |||
| T2DM | Human plasma | Cardiopulmonary bypass induced greater oxidative and nitrosative stress in diabetic patients. | 850 |
| T2DM | Human plasma | Increased plasma nitrite/nitrate and NT levels in diabetic patients. Postprandial hypertriglyceridemia and hyperglycemia induces endothelial dysfunction in diabetic patients and increased plasma NT levels. Plasma NT levels in diabetic patients correlate with postprandial hyperglycemia. | 36, 186, 188, 190 |
| T1DM | Human plasma | Increased plasma nitrite, nitrate, and NT, which correlate with the insulin requirements of the diabetic patients. | 553, 555 |
| T1DM, T2DM | Human platelets | Increased iNOS-derived peroxynitrite formation in diabetic platelets. | 1265 |
| Primary diabetes | |||
| NOD mice, STZ- induced diabetes | Mouse pancreatic islet β-cells | Increased NT formation in pancreatic islet β-cells. Inhibitors of iNOS and/or scavengers or peroxynitrite prevent development of diabetes and reduce NT staining in the islets in various experimental models. | 822, 1209, 1210, 1234 |
| Diabetic vascular dysfunction | |||
| High glucose | Human aortic endothelial cells | Increased peroxynitrite formation, tyrosine nitration, and inhibition of prostacyclin synthase. | 1473 |
| Stable or intermittent high glucose | Human umbilical vein endothelial cells | Stable or intermittent high glucose stimulated NT formation through PKC-dependent activation of NAD(P)H oxidase. | 1049 |
| High glucose | Human aortic endothelial cells | Glucose-induced activation of PKC resulted in peroxynitrite formation and nitration of prostacyclin synthase. | 236 |
| High glucose | Bovine endothelial cells | HG induced increased lipid peroxidation, increased superoxide and peroxynitrite formation, and PKC activity. | 1040 |
| STZ-induced diabetes | Mouse aorta, vascular and cardiac function pancreatic islet β-cells | Increased eNOS expression, NT formation, and PARP activation in endothelium and vascular smooth muscle. A peroxynitrite decomposition catalyst improved vascular and cardiac function and protected against diabetes. | 1186, 1234 |
| STZ-induced diabetes | Rat aorta, liver, kidney | Increased free radical and NO concentrations in the liver, kidney, and aorta; increased peroxynitrite formation in aorta. | 1198 |
| Zucker diabetic rats | Rat aorta, vascular function | Age-dependent increase of NT formation in the vasculature and development of endothelial dysfunction, which is attenuated by a peroxynitrite scavenger, ebselen. | 138 |
| LDL from T1DM patients | Human aortic endothelial cells | Incubation of human aortic endothelial cells with LDL from T1DM patients increased Na+ K+-ATPase and Ca2+-ATPase activities, NOS activity, and peroxynitrite production. | 1050 |
| T2DM and prediabetes | Human skin microvasculature | Increased NT formation and PARP activation in endothelial cells of diabetic and prediabetic patients. | 1242 |
| T1DM, preeclampsia | Human placental vasculature | Increased NT formation in vascular endothelium and villous stroma, attenuated vasoconstrictor and vasodilatory responses in diabetes and preeclampsia. | 711, 807 |
| Diabetic cardiomyopathy | |||
| Alloxan-induced diabetes | Mouse heart mitochondria | Tyrosine nitration of mitochondrial proteins. | 1298 |
| STZ-induced diabetes | Mouse cardiac myocytes | Increased apoptosis, H2O2, superoxide, angiotensin II and NT formation in myocytes, which is decreased by IGF-I overexpression. | 646 |
| STZ-induced diabetes | Rat heart mitochondria | Increased nitration and inactivation of succinyl-CoA:3-oxoacid CoA-transferase (SCOT). | 1299 |
| High glucose | Rat heart | Perfusion of isolated hearts with high glucose increased superoxide generation, NO, NT formation, and iNOS expression. | 189 |
| High glucose | Rat heart | M40403 (SOD) mimetic decreases Q–T interval prolongation, coronary perfusion pressure and lipid peroxidation, NT formation, and PARP activation. | 316 |
| T2DM, hypertension | Human cardiac myocytes | Increased apoptosis, necrosis, angiotensin II, and NT formation in myocytes. | 413 |
| Diabetic nephropathy | |||
| STZ-induced diabetes | Mouse kidney | Increased renal NT and advanced glycation end product formation, which is attenuated by ramipril or aminoguanidine. | 402 |
| STZ-induced diabetes | Rat kidney | Increased superoxide and nitrotyrosine formation in renal cortex. | 615 |
| STZ-induced diabetes | Rat kidney | Increased renal expression of p47phox, hydrogen peroxide production, and NT formation. | 974 |
| Diabetic nephropathy | Human kidney | Increased staining NT formation in tubuli of diabetic patients. | 1277 |
| Diabetic retinopathy | |||
| High glucose | Retinal endothelial cells | High glucose induced increased NT formation in retinal endothelial cells, which was blocked by superoxide or peroxynitrite scavengers, NOS, or aldose reductase inhibitors. | 352 |
| BBZ/Wor rat model of NIDDM | Rat retina | Increased iNOS and nitrotyrosine immunoreactivity in diabetic retinas. | 351 |
| STZ-induced diabetes | Rat retina | Increased NT, which is attenuated by aminoguanidine or by an aldose reductase inhibitor fidarestat. | 333, 963 |
| STZ-induced diabetes | Rat retina | Increased retinal lipid peroxidation and NT formation, which was only slightly attenuated by reinstitution of good glycemic control. | 712 |
| STZ-induced diabetes | Rat retina | Increased tyrosine nitration and expression of vascular endothelial growth factor contribute to the breakdown of the blood-retina barrier in diabetes. | 354 |
| Diabetic neuropathy | |||
| STZ-induced diabetes | Rat peripheral nerves, epineurial arterioles, endoneurial blood flow | Antioxidants reduced the production of superoxide and peroxynitrite in epineurial arterioles and improved endoneural blood flow. | 230–232 |
| STZ-induced diabetes | Rat peripheral sensory neurons | Rise in cytoplasmic labeling of nitrotyrosine, PARP activation. | 209 |
| STZ-induced diabetes, NOD mice | Mouse sciatic motor and hindlimb digital sensory nerve | A peroxynitrite scavenger FP-15 normalizes diabetes-associated decreased sciatic motor nerve and digital sensory nerve conduction velocity, and ameliorated the NT formation and poly(ADP-ribose) accumulation in diabetic nerves. | 961 |
| T1DM | Human peripheral motor nerve function | Decreased motor nerve function in diabetic patients correlates with increased nitrosative stress. | 554 |
| Diabetic cystopathy | |||
| STZ-induced diabetes | Rat bladder | Increased proteasomal activation and NT formation during diabetic cystopathy. | 1034 |
T2DM, type 2 diabetes mellitus; T1DM, type 1 diabetes mellitus; NT/3-NT, nitrotyrosine/3-nitrotyrosine; iNOS, inducible nitric oxide synthase; NOD, non-obese diabetic; STZ, streptozotocin; SOD, superoxide dismutase; PARP, poly(ADP-ribose) polymerase.