Matrix metalloproteinases (MMPs) are proteolytic enzymes related to a proinflammatory environment in several diseases, including diabetes, which can be activated by reactive nitrogen species. This work aimed to determine MMP-2 and MMP-9 activities and nitration in term placentas from type 2 diabetic patients and verify the hypothesis that peroxynitrites are positive regulators of placental MMP-2 and MMP-9 activities. For this purpose, term placentas from healthy and type 2 diabetic patients were analyzed for MMP-2 and MMP-9 levels and activities, protein nitration, and nitration of MMP-2 and MMP-9. Villous explants were cultured in the presence of peroxynitrites for further evaluation of MMP-2 and MMP-9 activities. We found that MMP-2 and MMP-9 activities were increased in term placentas from diabetic patients. These changes were found even when MMP-2 protein concentrations were diminished and MMP-9 protein concentrations were not changed in the diabetic group. Increased protein nitration and specific nitration of MMP-2 and MMP-9 were found in term placentas from diabetic patients. Peroxynitrites were able to increase the activity of placental MMP-2 and MMP-9. Taken together, this study has shown for first time that peroxynitrites can nitrate and activate MMP-2 and MMP-9 in the placenta, a nitrative pathway possibly related to MMPs overactivity in the placentas from type 2 diabetic patients.
BalsellsMGarcia-PattersonAGichICorcoyR. Maternal and fetal outcome in women with type 2 versus type 1 diabetes mellitus: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2009;94(11):4284โ4291.
2.
Michael WeindlingA. Offspring of diabetic pregnancy: short-term outcomes. Semin Fetal Neonatal Med. 2009;14(2):111โ118.
3.
MelamedNHodM. Perinatal mortality in pregestational diabetes. Int J Gynaecol Obstet. 2009;104(suppl 1):S20โS24.
4.
PlagemannAHarderTDudenhausenJW. The diabetic pregnancy, macrosomia, and perinatal nutritional programming. Nestle Nutr Workshop Ser Pediatr Program. 2008;61:91โ102.
5.
ThornburgKLO'TierneyPLoueyS. The placenta is a programming agent in cardiovascular disease. Placenta. 2010;31(suppl):54โ59.
6.
JanssonTMyattLPowellTL. The role of trophoblast nutrient and ion transporters in the development of pregnancy complications and adult disease. Curr Vasc Pharmacol. 2009;7(4):521โ533.
7.
OmuAEAl-AzemiMKOmuFE. Butyrylcholinesterase activity in women with diabetes mellitus in pregnancy: correlation with antioxidant activity. J Obstet Gynaecol. 2010;30(2):122โ126.
8.
PacherPObrosovaIGMableyJGSzaboC.Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. Curr Med Chem. 2005;12(3):267โ275.
9.
LyallFGibsonJLGreerIABrockmanDEEisALMyattL. Increased nitrotyrosine in the diabetic placenta: evidence for oxidative stress. Diabetes Care. 1998;21(10):1753โ1758.
10.
HorvathEMMagenheimRKuglerE. Nitrative stress and poly(ADP-ribose) polymerase activation in healthy and gestational diabetic pregnancies. Diabetologia. 2009;52(9):1935โ1943.
11.
San MartinRSobreviaL. Gestational diabetes and the adenosine/L-arginine/nitric oxide (ALANO) pathway in human umbilical vein endothelium. Placenta. 2006;27(1):1โ10.
12.
LappasMHidenUFroehlichJDesoyeGHaugel-De MouzonSJawerbaumA. The role of oxidative stress in the pathophysiology of gestational diabetes mellitus. Antioxid Redox Signal. 2011;15(12):3061โ3100.
13.
PustovrhMCJawerbaumACapobiancoE. Oxidative stress promotes the increase of matrix metalloproteinases-2 and -9 activities in the feto-placental unit of diabetic rats. Free Radic Res. 2005;39(12):1285โ1293.
14.
PustovrhCJawerbaumASinnerD. Membrane-type matrix metalloproteinase-9 activity in placental tissue from patients with pre-existing and gestational diabetes mellitus. Reprod Fertil Dev. 2000;12(5-6):269โ275.
15.
VuTHWerbZ. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev. 2000;14(17):2123โ2133.
16.
HuangSCSheuBCChangWCChengCYWangPHLinS. Extracellular matrix proteases-cytokine regulation role in cancer and pregnancy. Front Biosci. 2009;14:1571โ1588.
17.
CockleJVGopichandranNWalkerJJLeveneMIOrsiNM. Matrix metalloproteinases and their tissue inhibitors in preterm perinatal complications. Reprod Sci. 2007;14(7):629โ645.
ValdesGCorthornJ. Review: the angiogenic and vasodilatory utero-placental network. Placenta. 2011;32(suppl 2):S170โS175.
20.
WangWSawickiGSchulzR. Peroxynitrite-induced myocardial injury is mediated through matrix metalloproteinase-2. Cardiovasc Res. 2002;53(1):165โ174.
21.
GuZKaulMYanB. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science. 2002;297(5584):1186โ1190.
22.
HarrisLKMccormickJCartwrightJEWhitleyGSDashPR. S-nitrosylation of proteins at the leading edge of migrating trophoblasts by inducible nitric oxide synthase promotes trophoblast invasion. Exp Cell Res. 2008;314(8):1765โ1776.
23.
MandalMMandalADasSChakrabortiTSajalC. Clinical implications of matrix metalloproteinases. Mol Cell Biochem. 2003;252(1-2):305โ329.
24.
DerosaGD'angeloATinelliC. Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in diabetic and healthy subjects. Diabetes Metab. 2007;33(2):129โ134.
25.
ThrailkillKMBunnRCMoreauCS. Matrix metalloproteinase-2 dysregulation in type 1 diabetes. Diabetes Care. 2007;30(9):2321โ2326.
26.
PustovrhMCJawerbaumACapobiancoEWhiteVLopez-CostaJJGonzalezE. Increased matrix metalloproteinases 2 and 9 in placenta of diabetic rats at midgestation. Placenta. 2005;26(4):339โ348.
27.
PustovrhCJawerbaumASinnerDWhiteVCapobiancoEGonzalezE. Metalloproteinase 2 activity and modulation in uterus from neonatal streptozotocin-induced diabetic rats during embryo implantation. Reprod Fertil Dev. 2002;14(7-8):479โ485.
28.
BradfordMM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248โ254.
29.
WhiteVCapobiancoEHigaR. Increased nitration and diminished activity of copper/zinc superoxide dismutase in placentas from diabetic rats. Free Radic Res. 2010;44(12):1407โ1415.
30.
RaHJParksWC. Control of matrix metalloproteinase catalytic activity. Matrix Biol. 2007;26(8):587โ596.
31.
OhkawaHOhishiNYagiK. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351โ358.
32.
SzaboC. Multiple pathways of peroxynitrite cytotoxicity. Toxicol Lett. 2003;140โ141:105โ112.
33.
PustovrhMCJawerbaumAWhiteV. The role of nitric oxide on matrix metalloproteinase 2 (MMP2) and MMP9 in placenta and fetus from diabetic rats. Reproduction(Cambridge, England). 2007;134(4):605โ613.
34.
Macmillan-CrowLAThompsonJA. Immunoprecipitation of nitrotyrosine-containing proteins. Methods Enzymol. 1999;301:135โ145.
35.
JawerbaumAWhiteV. Animal models in diabetes and pregnancy. Endocr Rev. 2010;31(5):680โ701.
36.
JawerbaumAGonzalezE. Diabetic pregnancies: the challenge of developing in a pro-inflammatory environment. Curr Med Chem. 2006;13(18):2127โ2138.
37.
MottJDWerbZ. Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol. 2004;16(5):558โ564.
38.
DeanRAOverallCM. Proteomics discovery of metalloproteinase substrates in the cellular context by iTRAQ labeling reveals a diverse MMP-2 substrate degradome. Mol Cell Proteomics. 2007;6(4):611โ623.
39.
Demir-WeustenAYSevalYKaufmannPDemirRYucelGHuppertzB. Matrix metalloproteinases-2, -3 and -9 in human term placenta. Acta Histochem. 2007;109(5):403โ412.
40.
WeissAGoldmanSShalevE. The matrix metalloproteinases (MMPS) in the decidua and fetal membranes. Front Biosci. 2007;12:649โ659.
41.
SchulzR. Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol. 2007;47:211โ242.
42.
FreiseCErbenUMucheM. The alpha 2 chain of collagen type VI sequesters latent proforms of matrix-metalloproteinases and modulates their activation and activity. Matrix Biol. 2009;28(8):480โ489.
NelsonKKMelendezJA. Mitochondrial redox control of matrix metalloproteinases. Free Radic Biol Med. 2004;37(6):768โ784.
45.
HuJVan Den SteenPESangQXOpdenakkerG. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov. 2007;6(6):480โ498.
46.
ManiconeAMMcguireJK. Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol. 2008;19(1):34โ41.
47.
WebsterRPRobertsVHMyattL. Protein nitration in placenta-functional significance. Placenta. 2008;29(12):985โ994.
48.
WebsterRPBrockmanDMyattL. Nitration of p38 MAPK in the placenta: association of nitration with reduced catalytic activity of p38 MAPK in pre-eclampsia. Mol Hum Reprod. 2006;12(11):677โ685.
