Loss of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) in the Diabetic Retina: Role of Matrix Metalloproteinases

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2019 Feb 23

PMID 30793207

Citations 21

Authors

Randa S Eshaq

Norman R Harris

Affiliations

Soon will be listed here.

Abstract

Purpose: To test the hypothesis that high glucose and matrix metalloproteinases (MMPs) contribute to the diabetes-induced loss of platelet endothelial cell adhesion molecule-1 (PECAM-1) in the retinal microvasculature.

Methods: PECAM-1 and MMP protein, activity, and interactions with PECAM-1 were assessed using western blotting, zymography, immunofluorescence, or coimmunoprecipitation assays. These assays were conducted using primary rat retinal microvascular endothelial cells (RRMECs) grown either in normal glucose (5 mM) or high glucose (25 mM) conditions and using retinas collected from streptozotocin-induced diabetic or control rats. The broad-spectrum MMP inhibitor GM6001 was administered in vivo and in vitro to ascertain the role of MMPs in the hyperglycemia-induced loss of PECAM-1.

Results: A dramatic decrease in PECAM-1 (western blotting, immunofluorescence) was observed in both the diabetic retina and in hyperglycemic RRMECs. The decrease in PECAM-1 was accompanied by a significant increase in the presence and activity of matrix metalloproteinase-2 (MMP-2) (but not matrix metalloproteinase-9 [MMP-9]) in the diabetic plasma (P < 0.05) and in hyperglycemic RRMECs (P < 0.05). Moreover, RRMEC PECAM-1 significantly decreased when treated with plasma collected from diabetic rats. Several MMP-2 cleavage sites on PECAM-1 were identified using in silico analysis. Moreover, PECAM-1/MMP-2 interactions were confirmed using coimmunoprecipitation. PECAM-1 was significantly decreased in RRMECs treated with MMP-2 (P < 0.05), but became comparable to controls with the MMP inhibitor GM6001 in both the diabetic retina and hyperglycemic RRMECs.

Conclusions: These results indicate a possible role of MMP-2 in hyperglycemia-induced PECAM-1 loss in retinal endothelial cells.

Citing Articles

Associations of Circulating Platelet Endothelial Cell Adhesion Molecule-1 Levels With Progression of Cerebral Small-Vessel Disease, Cognitive Decline, and Incident Dementia.

Sim M, Tan E, Chan S, Cai Y, Chai Y, Chong J J Am Heart Assoc. 2024; 13(22):e035133.

PMID: 39526361 PMC: 11681413. DOI: 10.1161/JAHA.124.035133.

Deep Immune and RNA Profiling Revealed Distinct Circulating CD163+ Monocytes in Diabetes-Related Complications.

Siwan E, Wong J, Brooks B, Shinko D, Baker C, Deshpande N Int J Mol Sci. 2024; 25(18).

PMID: 39337580 PMC: 11432403. DOI: 10.3390/ijms251810094.

Effects of Nox4 upregulation on PECAM-1 expression in a mouse model of diabetic retinopathy.

Wang J, Lai D, Wang J, Zhang S PLoS One. 2024; 19(5):e0303010.

PMID: 38748682 PMC: 11095704. DOI: 10.1371/journal.pone.0303010.

The Effects of Tissue Healing Factors in Wound Repair Involving Absorbable Meshes: A Narrative Review.

Vasalou V, Kotidis E, Tatsis D, Boulogeorgou K, Grivas I, Koliakos G J Clin Med. 2023; 12(17).

PMID: 37685753 PMC: 10488606. DOI: 10.3390/jcm12175683.

PECAM-1 drives β-catenin-mediated EndMT via internalization in colon cancer with diabetes mellitus.

Wu Q, Du X, Cheng J, Qi X, Liu H, Lv X Cell Commun Signal. 2023; 21(1):203.

PMID: 37580771 PMC: 10426208. DOI: 10.1186/s12964-023-01193-2.

References

Fujiwara K . Platelet endothelial cell adhesion molecule-1 and mechanotransduction in vascular endothelial cells. J Intern Med. 2006; 259(4):373-80. DOI: 10.1111/j.1365-2796.2006.01623.x. View

Hendrick A, Gibson M, Kulshreshtha A . Diabetic Retinopathy. Prim Care. 2015; 42(3):451-64. DOI: 10.1016/j.pop.2015.05.005. View

Kakei Y, Akashi M, Shigeta T, Hasegawa T, Komori T . Alteration of cell-cell junctions in cultured human lymphatic endothelial cells with inflammatory cytokine stimulation. Lymphat Res Biol. 2014; 12(3):136-43. PMC: 4170982. DOI: 10.1089/lrb.2013.0035. View

Gencer S, Cebeci A, Irmak-Yazicioglu M . Matrix metalloproteinase gene expressions might be oxidative stress targets in gastric cancer cell lines. Chin J Cancer Res. 2013; 25(3):322-33. PMC: 3696711. DOI: 10.3978/j.issn.1000-9604.2013.06.05. View

Fleming I, Fisslthaler B, Dixit M, Busse R . Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells. J Cell Sci. 2005; 118(Pt 18):4103-11. DOI: 10.1242/jcs.02541. View

Leskova W, Watts M, Carter P, Eshaq R, Harris N . Measurement of retinal blood flow rate in diabetic rats: disparity between techniques due to redistribution of flow. Invest Ophthalmol Vis Sci. 2013; 54(4):2992-9. PMC: 3638664. DOI: 10.1167/iovs.13-11915. View

Leasher J, Bourne R, Flaxman S, Jonas J, Keeffe J, Naidoo K . Global Estimates on the Number of People Blind or Visually Impaired by Diabetic Retinopathy: A Meta-analysis From 1990 to 2010. Diabetes Care. 2016; 39(9):1643-9. DOI: 10.2337/dc15-2171. View

Tzima E, Irani-Tehrani M, Kiosses W, Dejana E, Schultz D, Engelhardt B . A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature. 2005; 437(7057):426-31. DOI: 10.1038/nature03952. View

Madonna R, Giovannelli G, Confalone P, Renna F, Geng Y, De Caterina R . High glucose-induced hyperosmolarity contributes to COX-2 expression and angiogenesis: implications for diabetic retinopathy. Cardiovasc Diabetol. 2016; 15:18. PMC: 4731895. DOI: 10.1186/s12933-016-0342-4. View

10.

Wang W, Sawicki G, Schulz R . Peroxynitrite-induced myocardial injury is mediated through matrix metalloproteinase-2. Cardiovasc Res. 2001; 53(1):165-74. DOI: 10.1016/s0008-6363(01)00445-x. View

11.

Grobelny D, Poncz L, Galardy R . Inhibition of human skin fibroblast collagenase, thermolysin, and Pseudomonas aeruginosa elastase by peptide hydroxamic acids. Biochemistry. 1992; 31(31):7152-4. DOI: 10.1021/bi00146a017. View

12.

Meleth A, Agron E, Chan C, Reed G, Arora K, Byrnes G . Serum inflammatory markers in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2005; 46(11):4295-301. DOI: 10.1167/iovs.04-1057. View

13.

Fernandez-Martin L, Marcos-Ramiro B, Bigarella C, Graupera M, Cain R, Reglero-Real N . Crosstalk between reticular adherens junctions and platelet endothelial cell adhesion molecule-1 regulates endothelial barrier function. Arterioscler Thromb Vasc Biol. 2012; 32(8):e90-102. DOI: 10.1161/ATVBAHA.112.252080. View

14.

Kowluru R, Zhong Q, Santos J . Matrix metalloproteinases in diabetic retinopathy: potential role of MMP-9. Expert Opin Investig Drugs. 2012; 21(6):797-805. PMC: 3802521. DOI: 10.1517/13543784.2012.681043. View

15.

Sternlicht M, Werb Z . How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001; 17:463-516. PMC: 2792593. DOI: 10.1146/annurev.cellbio.17.1.463. View

16.

Duh E, Sun J, Stitt A . Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight. 2017; 2(14). PMC: 5518557. DOI: 10.1172/jci.insight.93751. View

17.

Wong M, Harbour S, Wee J, Lau L, Andrews R, Jackson D . Proteolytic cleavage of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) is regulated by a calmodulin-binding motif. FEBS Lett. 2004; 568(1-3):70-8. DOI: 10.1016/j.febslet.2004.04.094. View

18.

Cheung A, Fung M, Lo A, Lam T, So K, Chung S . Aldose reductase deficiency prevents diabetes-induced blood-retinal barrier breakdown, apoptosis, and glial reactivation in the retina of db/db mice. Diabetes. 2005; 54(11):3119-25. DOI: 10.2337/diabetes.54.11.3119. View

19.

McLeod D, Lefer D, Merges C, Lutty G . Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. Am J Pathol. 1995; 147(3):642-53. PMC: 1870979. View

20.

Adamis A . Is diabetic retinopathy an inflammatory disease?. Br J Ophthalmol. 2002; 86(4):363-5. PMC: 1771111. DOI: 10.1136/bjo.86.4.363. View