IGF-1 receptor cleavage in hypertension

Abstract

Increased protease activity causes receptor dysfunction due to extracellular cleavage of different membrane receptors in hypertension. The vasodilatory effects of insulin-like growth factor-1 (IGF-1) are decreased in hypertension. Therefore, in the present study the association of an enhanced protease activity and IGF-1 receptor cleavage was investigated using the spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto (WKY) controls (n = 4). Matrix metalloproteinase (MMP) activities were determined using gelatin zymography on plasma and different tissue samples. WKY aorta rings were incubated in WKY or SHR plasma with or without MMP inhibitors, and immunohistochemistry was used to quantify the densities of the alpha and beta IGF-1 receptor (IGF-1R) subunits and to determine receptor cleavage. The pAkt and peNOS levels in the aorta were investigated using immunoblotting as a measure of IGF-IR function. Increased MMP-2 and MMP-9 activities were detected in plasma and peripheral tissues of SHRs. IGF-1R beta labeling was similar in both groups without plasma incubation, but the fraction of immunolabeled area for IGF-1R alpha was lower in the endothelial layer of the SHR aorta (p < 0.05). A 24-h incubation of WKY aorta with SHR plasma did not affect the IGF-1R beta labeling density, but reduced the IGF-1R alpha labeling density in the endothelium (p < 0.05). MMP inhibitors prevented this decrease (p < 0.01). Western blot analyses revealed that the pAkt and peNOS levels under IGF-1-stimulated and -unstimulated conditions were lower in SHRs (p < 0.05). A reduced IGF-1 cellular response in the aorta was associated with the decrease in the IGF-1R alpha subunit in the SHR hypertension model. Our results indicate that MMP-dependent receptor cleavage contributed to the reduced IGF-1 response in SHRs.

Matrisome-Associated Gene Expression Patterns Correlating with TIMP2 in Cancer

“…Surprisingly, there have been few, if any, studies into the fate of these TIMP:MMP/ADAM12 complexes or whether combinations of these impart modulatory effects on TIMP2 function. To add further complexity to the system, many of TIMP2’s molecular targets can be proteolytically cleaved by metalloproteinase activity 62–64 . We focused our in-depth analyses on breast and lung tumors, since we have found that TIMP2 can deliver therapeutic effects in murine models of these cancers and that they formed the nucleus of our identified study cluster.…”

Pancreatic source of protease activity in the spontaneously hypertensive rat and its reduction during temporary food restriction

“…Cleavage of its insulin receptors leads to the insulin resistance in the SHR . The ectodomain of the insulin‐like growth factor‐1 is clipped in the SHR . Endothelial apoptosis and the resulting capillary rarefaction in the SHR are due to the degradation of the VEGFR2, and the deficient leukocyte adhesion in the SHR is due to cleavage of membrane adhesion molecules .…”

Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition

“…Consistent with these, most significant results for PP in our study (4 out of 5 DMRs) were related to average levels during early pregnancy. Regions specific to PP included TRH, a gene implicated in the reduction of blood pressure in rats [75], and IGF1R a growth factor receptor which also participates in the regulation of blood pressure [76]. The two other DMRs were common with SBP: overlapping RNF141 and C6orf138 (PTCHD4), a gene found to be sensitive to transmitted adaptation to stress and associated with chronic obstructive pulmonary disease (COPD) [77,78].…”