期刊
HYPERTENSION
卷 57, 期 2, 页码 261-U247出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.110.158709
关键词
adrenergic receptor; matrix metalloproteinases; microcirculation; receptor cleavage; pyrrolidine dithiocarbamate
资金
- National Institutes of Health [HL-10881]
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
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