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303 OXIDIZED, GLYCATED LOW-DENSITY LIPOPROTEIN SELECTIVELY MODULATES TISSUE INHIBITOR OF METALLOPROTEINASE 3 EXPRESSION IN HUMAN RETINAL CAPILLARY PERICYTES.
  1. Y. Yu1,
  2. J. L. Barth4,
  3. W. Song1,
  4. K. Lu2,
  5. A. Dashti3,
  6. Y. Huang4,
  7. W. S. Argraves1
  1. University of Oklahoma Health Sciences Center, Oklahoma City, OK;
  2. 1Philadelphia, PA
  3. 2New Haven, CT
  4. 3San Diego, CA
  5. 4Charleston, SC

Abstract

Tissue inhibitor of metalloproteinase (TIMP)-3 can inhibit neovascularization, a key event in the progression of diabetic retinopathy. We examined the influences of modified LDL on retinal pericyte expression of TIMP-3 compared with other TIMPs and matrix metalloproteinases (MMPs) since low-density lipoproteins (LDLs) modified by oxidation/glycation are implicated in diabetic vascular complications. Quiescent human retinal pericytes were exposed for 24 hours to native LDL (N-LDL), glycated LDL (G-LDL), and heavily oxidized-glycated LDL (HOG-LDL). TIMP and MMP expression were assessed at the level of mRNA (meta-analysis of microarray data, quantitative PCR) and protein (immunoblotting, ELISA). By microarray analysis, TIMP-1, -2, -3, and -4 and MMP-1, -2, -11, -14, and -25 expression was detected, but only TIMP-3 mRNA showed a differential response, being expressed at significantly lower levels in response to HOG-LDL versus N-LDL, and this was confirmed by quantitative PCR and immunoblotting of cell/matrix proteins. In contrast to TIMP-3 in cells, analyses of secreted TIMP-1, TIMP-2, MMP-1, and collagenase activity indicated no changes in their production in response to modified LDL. Combined N-LDL and HOG-LDL treatment restored TIMP-3 mRNA expression to levels comparable to N-LDL alone. We conclude that among the TIMPs and MMPs expressed in retinal pericytes, expression of TIMP-3 is uniquely regulated by HOG-LDL. Reduced TIMP-3 expression may be implicated in neovascularization in diabetic retinopathy.

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