Role of matrix metalloproteinase 9 and its tissue inhibitor 1 in development and prognosis of diabetic retinopathy
S.V. Ziablitsev1, A.V. Korobova2, O.V. Petrenko3, V.N. Serduk4, S.U. Mogilevsky3
- Ukranian science-practical center of endocrine surgery, transplantation of endocrine organs and tis- sue Health Ministry of Ukraine, Kyiv;
- M. Gorky Donetsk National Medical University, Krasny Liman;
- L.M. Shupik National medical academy of postgradual education, Kyiv;
- SE «Dnepropetrovsk Medical Academy Health Ministry of Ukraine», Dnipro
DOI: https://doi.org/10.15407/fz62.05.037

Abstract
The article presents the results of investigation of violations in the proteolysis system in patients with type 2
diabetes and diabetic retinopathy (DR). We studied the levels of matrix metalloproteinase-9 (MMP-9) and
tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in the blood and in the intraocular fluid of patients
with type 2 diabetes depending upon the stage of DR. We have established that the level of MMP-9 and
TIMP-1 in the blood and in the intraocular fluid increased in patients with type 2 diabetes without signs
of DR and with any stage of DR compared to the levels of these parameters in patients without diabetes.
Increasing the levels of MMP-9 and TIMP-1 took place with increasing of DR severity and reached its
maximum levels at the proliferative stage of DR. It was found that the levels of MMP-9 in the intraocular
fluid and type 2 diabetes duration affected the probability of developing diabetic macular edema. At the level
of MMP-9 ≥ 105 ng/ml and 2 diabetes duration ≥ 10 years, the probability of developing macular edema
was 100%. As a result of the construction of predictive models it was found that the level of MMP-9 in the
intraocular fluid, stage of DR at the beginning of observation and type 2 diabetes duration had influence
on the probability of the development of proliferative DR over 4 years of follow-up. If the level of MMP-9
≥ 100 ng/ml, type 2 diabetes duration ≥ 10 years and absence of DR at the beginning of observation were
observed the probability of developing proliferative DR would compose 85.9%.
Keywords:
proteolysis system; metalloproteinase-9; tissue inhibitor of matrix metalloproteinase-1; intraocular fluid; diabetic retinopathy.
References
- Evrosimovska B, Velickovski B, Dimova C, VeleskaStefkovska D. Matrix metalloproteinases (with accent to collagenases). J Cell Anim Biol. 2011; 5(7). 113-20.
- Raffetto JD, Khalil RA. Matrix Metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol. 2008; 75(2): 346-59..
- Nagase H, Woessner JF. Matrix metalloproteinases. J Biol Chem. 1999; 274: 21491-4..
- Giebel SJ, Menicucci G, McGuire PG. Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood-retinal barrier. Lab Invest. 2005; 85(5): 597-607.
CrossRef
PubMed
- Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosc. 2006; 11. 1696-701.
- Rogowicz A, Zozulińska D, Wierusz-Wysocka B. Role of matrix metalloproteinases in the development of vascular complications of diabetes mellitus – clinical implications. Pol Arch Med Wewn. 2007; 117 (3): 1-7.
- Bhatt LK, Addepalli V. Attenuation of diabetic retinopathy by enhanced inhibition of MMP-2 and MMP-9 using aspirin and minocycline in streptozotocin-diabetic rats. Amer J Translat Res. 2010; 2(2): 181-9.
- Kowluru RA, Mohammad G, dos Santos JM, Zhong Q. Abrogation of MMP-9 gene protects against the development of retinopathy in diabetic mice by preventing mitochondrial damage. Diabetes. 2011; 60(11): 3023-33.
CrossRef
PubMed PubMedCentral
- Derosa G, D'Angelo A, Tinelli C, Devangelio E, Consoli A, Miccoli R, Penno G, Del Prato S, Paniga S, Cicero AFG. Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in diabetic and healthy subjects. Diabet Metabol. 2007; 33(2): 129-34.
CrossRef
PubMed
- Rangasamy S, McGuire PG, Das A. Diabetic retinopathy and inflammation: novel therapeutic targets. Middle East Afr J Ophthalmol. 2012; 19 (1): 52-9.
CrossRef
PubMed PubMedCentral
- Kowluru RA. Role of Matrix Metalloproteinase-9 in the development of diabetic retinopathy and its regulation by H-Ras. Invest Ophthalmol Visual Sci. 2010; 51(8): 4320-26.
CrossRef
PubMed PubMedCentral
- Zheng Y, He M, Congdon N. The worldwide epidemic of diabetic retinopathy. Ind J Ophthalmol. 2012; 60(5): 428–31.
CrossRef
PubMed PubMedCentral
- El-Azab MF, Mysona BA, El-Remessy AB. Statins for prevention of diabetic-related blindness: a new treatment option? Exp Rev Ophthalmol. 2011; 6(3): 269-72.
CrossRef
PubMed PubMedCentral
- Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010; 87(1): 4-14.
CrossRef
PubMed
- International Diabetes Federation. IDF Diabetes Atlas, 7 ed. Brussels, Belgium: International Diabetes Federation, 2015.
- Wilkinson-Berka JL. Angiotensin and diabetic retinopathy. Int J Biochem Cell Biol. 2006; 38: 752-65.
CrossRef
PubMed
- Cheung N, Mitchell P, Wong TY. Diabetic retinopath. Lancet. 2010; 376(9735): 124-36.
CrossRef
- Tronko MD, Sokolova LK, Vlasenko NV, Kostukevich AA., 2015. Achieving the goals in treatment of patients with diabetes mellitus in Ukraine. Results Diabetes Management Practices Study (IDMPS). Endokrynologia. 20(4): 658-68. [Ukrainian].
- Kowluru RA, Zhong Q, Santos JM. Matrix metalloproteinases in diabetic retinopathy: potential role of MMP- 9. Exp Opin Invest Drugs. 2012; 21(6): 797-805.
CrossRef
PubMed PubMedCentral
- Demirel S, Argo C, Agarwal A, Parriott J, Sepah YJ, Do DV, Nguyen QD. Updates on the clinical trials in diabetic macular edema. Middle East Afr J Ophthalmol. 2016; 23(1): 3-12.
CrossRef
PubMed PubMedCentral
- Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology. 2003; 110(9): 1677-82.
CrossRef
- Tayebjee MH, Lim HS, Macfadyen RJ. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 and -2 in type 2 diabetes. Diabetes Care. 2004; 27(8): 2049-51.
CrossRef
PubMed
- Heo SH, Cho CH, Kim HO, Jo YH, Yoon KS, Lee JH, Park JC, Park KC, Ahn TB, Chung KC, Yoon SS, Chang DI. Plaque rupture is a determinant of vascular events in carotid artery atherosclerotic disease: involvement of Matrix Metalloproteinases 2 and 9. J Clin Neurol. 2011; 7(2): 69-76.
CrossRef
PubMed PubMedCentral
- Beránek M, Kolar P, Tschoplova S, Kankova K, Vasku A. Genetic variations and plasma levels of gelatinase A (matrix metalloproteinase-2) and gelatinase B (matrix metalloproteinase-9) in proliferative diabetic retinopathy. Mol Vis. 2008; 14: 1114-21.
- Abu El-Asrar AM, Mohammad G, Nawaz MI et al. Relationship between vitreous levels of Matrix Metalloproteinases and Vascular Endothelial Growth Factor in proliferative diabetic retinopathy. PLoS One. 2013; 8(12): e85857.
|