Key result
Salt-induced hypertensive disease promotes overexpression of matricellular genes like PAI-1 and OPN, which are stimulated by angiotensin II and selectively regulated by JunB and CREB.
Salt-induced hypertension alters cerebral artery gene expression (PAI-1, OPN) via ANG II, ERK, JunB, and CREB signaling pathways.
Identifies hypertension-altered genes and pathways in cerebral arteries; leaves open translation to human remodeling or therapy.
Although changes in gene expression are necessary for arterial remodeling during hypertension, the genes altered and their mechanisms of regulation remain uncertain. The goal of this study was to identify cerebral artery genes altered by hypertension and define signaling pathways important in their regulation. Intact cerebral arteries from Dahl salt-sensitive normotensive and hypertensive high-salt (HS) rats were examined by immunostaining, revealing an increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and expression of the proliferative marker Ki-67 in arteries from hypertensive animals. Arterial RNA analyzed by microarray and validated with RT-quantitative PCR revealed that jun family member junB and matricellular genes plasminogen activator inhibitor-1 (PAI-1) and osteopontin (OPN) were significantly overexpressed in HS arteries. Fisher exact test and annotation-based gene subsets showed that genes upregulated by Jun and Ca(2+)/cAMP-response element-binding protein (CREB) were overrepresented. A model of cultured rat cerebrovascular smooth muscle cells was used to test the hypothesis that angiotensin II (ANG II), JunB, and CREB are important in the regulation of genes identified in the rat hypertension model. ANG II induced a transient induction of junB and a delayed induction of PAI-1 and OPN mRNA levels, which were reduced by ERK inhibition with U-0126. Silencing junB using small-interfering RNA reduced mRNA levels of OPN but not PAI-1. The silencing of CREB reduced PAI-1 induction by ANG II but enhanced the transcription of OPN. Together, these results suggest that salt-induced hypertensive disease promotes changes in matricellular genes that are stimulated by ANG II, regulated by ERK, and selectively regulated by JunB and CREB.
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Rose et al. (2007) studied Salt-induced hypertensive disease. High-salt diet and Angiotensin II / gene silencing vs. Normotensive controls / untreated cells was evaluated on Gene expression changes (junB, PAI-1, OPN) and signaling pathway activation. Salt-induced hypertensive disease promotes overexpression of matricellular genes like PAI-1 and OPN, which are stimulated by angiotensin II and selectively regulated by JunB and CREB.
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