Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies.
Macro- and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP.
Pacher
Pál
P
Laboratory of Physiologic Studies, National Institutes of Health, NIAAA, Bethesda, MD 20892-9413, USA. ppacher@lycos.com
Obrosova
Irina G
IG
Mabley
Jon G
JG
Szabó
Csaba
C
D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism; D048909:Diabetes Complications / Q000209:etiology / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000209:etiology; D003928:Diabetic Nephropathies / Q000209:etiology; D003929:Diabetic Neuropathies / Q000209:etiology; D003930:Diabetic Retinopathy / Q000209:etiology; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D011065:Poly(ADP-ribose) Polymerases
Circulation. 2003 Feb 18;107(6):896-904
12591762
Curr Diab Rep. 2003 Dec;3(6):439-45
14611738
Toxicol Lett. 2003 Apr 11;140-141:113-24
12676457
Clin Investig. 1992 May;70(5):403-10
1600350
J Cardiovasc Pharmacol. 2000 Aug;36(2):182-7
10942159
Diabetologia. 1999 May;42(5):539-44
10333045
Circ Res. 2000 Dec 8;87(12):1123-32
11110769
FEBS Lett. 1997 Jul 14;411(2-3):157-60
9271196
Diabetes. 2002 Nov;51(11):3274-82
12401719
Nitric Oxide. 2002 May;6(3):295-304
12009847
Diabetes. 2003 Mar;52(3):818-23
12606525
Br J Pharmacol. 2001 Sep;134(1):21-9
11522593
J Pharmacol Exp Ther. 2000 Jul;294(1):396-401
10871338
Nature. 2000 Apr 13;404(6779):787-90
10783895
J Am Coll Cardiol. 2002 Sep 4;40(5):1006-16
12225730
Free Radic Biol Med. 2003 Sep 15;35(6):683-94
12957660
Am J Physiol. 1996 Nov;271(5 Pt 1):C1424-37
8944624
FASEB J. 1992 Aug;6(11):2905-14
1644256
Diabetes. 2002 Apr;51(4):1076-82
11916928
J Biol Chem. 2003 Sep 5;278(36):33972-7
12821649
Circ Res. 2002 Jan 11;90(1):107-11
11786526
Trends Pharmacol Sci. 2003 Sep;24(9):471-8
12967772
Nat Med. 2001 Jan;7(1):108-13
11135624
Diabetes Care. 2003 May;26(5):1589-96
12716823
Diabetes. 2005 Jan;54(1):234-42
15616034
J Clin Invest. 2003 Oct;112(7):986-8
14523035
Circ Res. 2004 Feb 20;94(3):377-84
14670841
Kidney Int. 2000 May;57(5):1968-72
10792615
Oncol Rep. 2004 Feb;11(2):505-8
14719091
Diabetes. 2002 Sep;51(9):2817-25
12196476
J Thorac Cardiovasc Surg. 2000 Jul;120(1):1-11
10884648
Diabetes. 2002 Jan;51(1):198-203
11756341
FASEB J. 2005 Mar;19(3):401-3
15611153
J Neurochem. 2002 Mar;80(5):771-9
11948240
Diabetologia. 2004 Apr;47(4):710-7
15298348
J Am Coll Cardiol. 1999 Dec;34(7):2111-9
10588232
Diabetes. 2003 Nov;52(11):2795-804
14578299
Diabetes Care. 1996 Mar;19(3):257-67
8742574
J Autoimmun. 2001 Jun;16(4):449-55
11437493
Diabetes Care. 2002 Aug;25(8):1439-43
12145247
Invest Ophthalmol Vis Sci. 2003 Jul;44(7):3135-43
12824263
J Cardiovasc Pharmacol. 1998;32 Suppl 3:S54-61
9883749
Clin Auton Res. 2003 Dec;13(6):406-21
14673690
Diabetologia. 2003 Oct;46(10):1419-27
12898015
Nature. 2001 Dec 13;414(6865):813-20
11742414
Clin Exp Nephrol. 2003 Mar;7(1):1-8
14586737
Clin Biochem. 2001 Feb;34(1):65-70
11239518
Mol Med. 2004 Jan-Jun;10(1-6):28-35
15502880
Diabetes Metab Res Rev. 2003 Jul-Aug;19(4):313-9
12879409
Diabetologia. 2001 Jul;44(7):834-8
11508267
Diabetes. 2004 Mar;53(3):711-20
14988256
Diabetes Care. 1990 Nov;13(11):1169-79
2261838
Cardiovasc Res. 1999 Sep;43(4):1018-28
10615429
Am J Pathol. 2003 Jun;162(6):1995-2004
12759255
Am J Physiol Heart Circ Physiol. 2000 Apr;278(4):H1311-9
10749729
J Mol Med (Berl). 2001 Aug;79(8):437-48
11511974
Biochem Pharmacol. 2003 Apr 1;65(7):1189-97
12663054
Circ Res. 2001 Oct 12;89(8):684-91
11597991
Diabetes. 2003 Sep;52(9):2363-71
12941777
Circulation. 2002 Sep 3;106(10):1211-8
12208795
Circ Res. 2000 Nov 10;87(10):840-4
11073878
Circ Res. 2000 May 12;86(9):1008
10807875
Mol Med. 2002 Oct;8(10):571-80
12477967
Pharmacol Rev. 2002 Sep;54(3):375-429
12223530
Kidney Int. 2002 Jan;61(1):186-94
11786100
Diabetes. 1997 May;46(5):907-11
9133563
J Clin Endocrinol Metab. 2003 Apr;88(4):1624-8
12679448
Biochimie. 2002 Oct;84(10):1013-9
12504281
FASEB J. 2003 Aug;17(11):1514-6
12824290
N J Med. 1994 Nov;91(11):776-8
7808691
Free Radic Biol Med. 2003 Nov 15;35(10):1240-51
14607523
Diabetes. 2002 Sep;51(9):2833-9
12196478
Nature. 1998 Jan 22;391(6665):393-7
9450756
Toxicol Lett. 2003 Apr 11;140-141:105-12
12676456
Diabetes. 1999 Sep;48(9):1856-62
10480619
Diabetes Care. 1995 May;18(5):708-14
8586013
Circulation. 2002 Nov 19;106(21):2680-6
12438293
Circulation. 2002 Apr 9;105(14):1656-62
11940543
Diabetologia. 2003 Mar;46(3):401-8
12687339
Diabetologia. 2002 Apr;45(4):476-94
12032623
Biosci Rep. 1999 Aug;19(4):235-51
10589989
Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1568-80
16356120
Diabetes. 2001 Aug;50(8):1927-37
11473057
Cardiovasc Res. 2001 Mar;49(4):798-807
11230979
Int J Mol Med. 2004 Jul;14(1):55-64
15202016
Cardiovasc Res. 1998 Nov;40(2):239-47
9893715
Endocr Rev. 2001 Feb;22(1):36-52
11159815
Diabetes. 2002 Feb;51(2):514-21
11812763
Circulation. 1997 Jul 1;96(1):25-8
9236411
Acta Physiol Scand. 2000 Jul;169(3):183-7
10886032
Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2289-94
11709394
Free Radic Res. 2003 Jan;37(1):33-40
12653215
Diabetes. 2001 Jun;50(6):1414-24
11375343
Am J Hypertens. 2003 Sep;16(9 Pt 1):761-6
12944035
Br J Pharmacol. 2000 Jul;130(5):963-74
10882379
Diabetes Care. 1998 Oct;21(10):1753-8
9773743
Atherosclerosis. 2002 Nov;165(1):69-77
12208472
Diabetes Care. 2003 Aug;26(8):2433-41
12882875
J Pharmacol Exp Ther. 2002 Mar;300(3):862-7
11861791
J Am Soc Nephrol. 2001 Aug;12(8):1630-1639
11461935
Ann Thorac Surg. 2002 Oct;74(4):1201-7
12400769
J Clin Invest. 2001 Apr;107(7):853-60
11285304
J Clin Invest. 2003 Oct;112(7):1049-57
14523042
Circulation. 2003 Feb 25;107(7):1017-23
12600916