Premium
Proteinase Activity In The Spontaneously Hypertensive Rat: Free Radical Production, Receptor Cleavage, And Insulin Resistance
Author(s) -
DeLano Frank A,
SchmidSchonbein Geert W
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb90-b
Subject(s) - endocrinology , medicine , chemistry , receptor , insulin , insulin receptor , insulin resistance , biology
Arterial hypertension is associated with organ dysfunctions of unknown origin. We hypothesize that enhanced microvascular proteolytic activity of spontaneously hypertensive rats (SHR) may be pathophysiological, such that cell membrane receptors may be enzymatically cleaved. Immuno‐histochemistry of matrix‐degrading metalloproteinases (MMP‐9) protein showed enhanced levels in SHR microvessels, mast cells, and circulating leukocytes compared to normotensive Wistar‐Kyoto (WKY) rats. In‐vivo micro‐zymography revealed enhanced enzymatic activity in SHR. Plasma of the SHR also has enhanced protease activity. SHR leukocytes labeled with antibody to the extracellular domain have reduced membrane adhesion receptor CD18 and insulin receptor α density, in line with attenuated leukocyte adhesion and elevated blood glucose levels and glycated hemoglobin. Blockade of MMPs with a broad acting inhibitor reduces protease activity in plasma and microcirculation, blocks the proteolytic cleavage of CD18 and insulin receptor, normalizes glucose and glycated hemoglobin levels. It also reduces the blood pressure of the WKY and SHR. The results suggest that elevated microvascular MMP activity leads to proteolytic cleavage of CD18 and suppresses leukocyte‐endothelial adhesion and cleavage of insulin receptor to insulin resistance. Supported by HL 10881.