Nuclear Factor Kappa B and Matrix Metalloproteinase Induced Receptor Cleavage in the Spontaneously Hypertensive Rat

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 (NF kappa B) is overexpressed in the SHR, enhancing its MMP activity and enzymatic cleavage of the beta 2 adrenergic receptor (beta(2)AR), thereby diminishing catecholamine-mediated arteriolar vasodilation. NF kappa B expression level and translocation were compared between Wistar Kyoto rat and SHR kidney, heart, and brain. The animals were treated with NF kappa B inhibitor, pyrrolidine dithiocarbamate, for 10 weeks and correlations between NF kappa B and MMP activity were determined. Immunohistochemistry showed that NF kappa B expression is increased in untreated SHR kidney (approximate to 14%) and brain hypothalamus (approximate to 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. NF kappa B 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 (approximate to 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 beta(2)AR 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 NF kappa B is an important transcription factor in the SHR and may be involved in the enhanced MMP activity and, consequently, receptor cleavage. (Hypertension. 2011; 57:261-268.). Online Data Supplement