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Nuclear factor kappa B and matrix metalloproteinase induced receptor cleavage in the spontaneously hypertensive rat.

ABSTRACT: Recent evidence suggests that inflammation in the spontaneously hypertensive rat (SHR) is associated with an uncontrolled matrix metalloproteinase (MMP) activity. We hypothesize that the transcription factor nuclear factor kappa B (NFκB) is overexpressed in the SHR, enhancing its MMP activity and enzymatic cleavage of the β2 adrenergic receptor (β₂AR), thereby diminishing catecholamine-mediated arteriolar vasodilation. NFκB expression level and translocation were compared between Wistar Kyoto rat and SHR kidney, heart, and brain. The animals were treated with NFκB inhibitor, pyrrolidine dithiocarbamate, for 10 weeks and correlations between NFκB and MMP activity were determined. Immunohistochemistry showed that NFκB expression is increased in untreated SHR kidney (≈ 14%) and brain hypothalamus (≈ 22%) compared to that in Wistar Kyoto rats (P < 0.05), but not in myocardium and cerebral cortex. After pyrrolidine dithiocarbamate treatment, the SHR systolic blood pressure was reduced to close to Wistar Kyoto rat levels. NFκB expression level in treated SHR was also decreased in kidney and hypothalamus compared to nontreated animals (P < 0.05). Furthermore, MMP-2 and MMP-9 activities in SHR plasma were significantly reduced (≈ 41%) by pyrrolidine dithiocarbamate treatment. Additionally, zymographic analyses and in situ zymography showed decreased MMP-2 activity in kidney homogenates and decreased MMP-1 and MMP-9 activities in brain. The level of the β₂AR extracellular, but not intracellular, domain density was found to be reduced in kidney, showing a receptor cleavage process that can be blocked by pyrrolidine dithiocarbamate treatment. These results suggest NFκB is an important transcription factor in the SHR and may be involved in the enhanced MMP activity and, consequently, receptor cleavage.

SUBMITTER: Wu KI

PROVIDER: S-EPMC3077933 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Nuclear factor kappa B and matrix metalloproteinase induced receptor cleavage in the spontaneously hypertensive rat.

Wu Kwan-I Sharon KI Schmid-Schönbein Geert W GW

Hypertension (Dallas, Tex. : 1979) 20110110 2

Recent evidence suggests that inflammation in the spontaneously hypertensive rat (SHR) is associated with an uncontrolled matrix metalloproteinase (MMP) activity. We hypothesize that the transcription factor nuclear factor kappa B (NFκB) is overexpressed in the SHR, enhancing its MMP activity and enzymatic cleavage of the β2 adrenergic receptor (β₂AR), thereby diminishing catecholamine-mediated arteriolar vasodilation. NFκB expression level and translocation were compared between Wistar Kyoto ra ...[more]

PMID: 21220710

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Project description:Metabolic disease is accompanied by a range of cellular defects ("comorbidities") whose origin is uncertain. To investigate this pathophysiological phenomenon we used the Spontaneously Hypertensive Rat (SHR), which besides an elevated arterial blood pressure also has many other comorbidities, including a defective glucose and lipid metabolism. We have shown that this model of metabolic disease has elevated plasma matrix metalloproteinase (MMP) activity, which cleaves the extracellular domain of membrane receptors. We hypothesize here that the increased MMP activity also leads to abnormal cleavage of the scavenger receptor and fatty acid transporter CD36. To test this idea, chronic pharmaceutical MMP inhibition (CGS27023A) of the SHR and its normotensive control, the Wistar Kyoto Rat (WKY), was used to determine if inhibition of MMP activity serves to maintain CD36 receptor density and function. Surface density of CD36 on macrophages from the heart, spleen, and liver was determined in WKY, SHR, CGS-treated WKY (CGS WKY), and CGS-treated SHR (CGS SHR) by immunohistochemistry with an antibody against the CD36 ectodomain. The extracellular CD36 density was lower in SHR heart and spleen macrophages compared to that in the WKY. MMP inhibition by CGS served to restore the reduced CD36 density on SHR cardiac and splanchnic macrophages to levels of the WKY. To examine CD36 function, culture assays with murine macrophages (RAW 264.7) after incubation in fresh WKY or SHR plasma were used to test for adhesion of light-weight donor red blood cell (RBC) by CD36. This form of RBC adhesion to macrophages was reduced after incubation in SHR compared WKY plasma. Analysis of the supernatant macrophage media by Western blot shows a higher level of CD36 extracellular protein fragments following exposure to SHR plasma compared to WKY. MMP inhibition in the SHR plasma compared to untreated plasma, served to increase the RBC adhesion to macrophages and decrease the number of receptor fragments in the macrophage media. In conclusion, these studies bring to light that plasma in the SHR model of metabolic disease has an unchecked MMP degrading activity which causes cleavage of a variety of membrane receptors, including CD36, which attenuates several cellular functions typical for the metabolic disease, including RBC adhesion to the scavenger receptor CD36. In addition to other cell dysfunctions chronic MMP inhibition restores CD36 in the SHR.

Dataset Information

Nuclear factor kappa B and matrix metalloproteinase induced receptor cleavage in the spontaneously hypertensive rat.

Publications

Nuclear factor kappa B and matrix metalloproteinase induced receptor cleavage in the spontaneously hypertensive rat.

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