Role of Reactive Oxygen Species-Sensitive Extracellular Signal-Regulated Kinase Pathway in Angiotensin II-Induced Endothelin-1 Gene Expression in Vascular Endothelial Cells

Abstract

Background: Circulating angiotensin II (Ang II) increases vascular endothelin-1 (ET-1) tissue levels, which in turn mediate a major part of Ang II-stimulated vascular growth and hypertension in vivo. Ang II also stimulates the generation of reactive oxygen species (ROS) within vascular endothelial cells. However, whether ROS are involved in Ang II-induced ET-1 gene expression, and the related intracellular mechanisms occurring within vascular endothelial cells remain unclear. Methods: Cultured endothelial cells were stimulated with Ang II, and the thus elicited ET-1 gene expression was examined by Northern blotting and a promoter activity assay. Antioxidant pretreatment of endothelial cells was performed prior to Ang II-induced extracellular signal-regulated kinase (ERK) phosphorylation in order to elucidate the redox-sensitive pathway for ET-1 gene expression. Results: The ET-1 gene was induced with Ang II, which was inhibited with Ang II type 1 receptor antagonist (irbesartan). Ang II-enhanced intracellular ROS levels were inhibited by irbesartan and several antioxidants, and antioxidants also suppressed Ang II-induced ET-1 gene expression. Further, Ang II-activated ERK phosphorylation was also significantly inhibited by certain antioxidants. An ERK inhibitor, U0126, inhibited Ang II-induced ET-1 expression completely. Cotransfection of the dominant negative mutant of Ras, Raf and MEK1 (ERK kinase) attenuated the Ang II-enhanced ET-1 promoter activity, suggesting that the Ras/Raf/ERK pathway is required for Ang II-induced ET-1 gene expression. Ang II-induced activator protein-1 (AP-1) reporter activities were inhibited by antioxidants. Moreover, mutational analysis of the ET-1 gene promoter showed that the AP-1 binding site was an important cis element in Ang II-induced ET-1 gene expression. Conclusions: Our data suggest that ROS are involved in Ang II-induced ET-1 gene expression within endothelial cells. The redox-sensitive ERK-mediated AP-1 transcriptional pathway plays an important role in Ang II-induced ET-1 gene expression.

Angiotensin II Induces C-Reactive Protein Expression via AT1-ROS-MAPK-NF-κB Signal Pathway in Hepatocytes

“…The results of the present experiment exhibited that Ang II stimulated ROS production in hepatocytes mainly via AT1 and mitochondria-derived pathway, since AT1 receptor blocker losartan and mitochondrial respiratory complex II inhibitor TTFA markedly antagonized the stimulatory effect of Ang II on ROS production, while AT2 receptor blocker PD123319 and NAD (P) H oxidase inhibitor DPI slightly inhibited Ang II-stimulated ROS generation. These results are in line with other researches [30,31]. Additionally, antioxidant NAC completely inhibited Ang II-induced CRP protein expression.…”

Chronic stress impacts the cardiovascular system: animal models and clinical outcomes

“…Margination, adhesion, and translocation of leukocytes, all prerequisites for atherosclerosis, are enhanced by angiotensin II type 1 receptors (AT 1 Rs) (218,219,259,380). Angiotensin II also promotes the expression and production of adhesive and proinflammatory molecules (vascular cell adhesion protein 1, intercellular adhesion molecule 1, monocyte chemoattractant protein-1, macrophage inflammatory protein-1␣, and IL-8) on the endothelial and vascular smooth muscle cells (55,145,200,267,282,325). Angiotensin II affects vascular smooth muscle signal transduction and several growth factors (transforming growth factor-␤, platelet-derived growth factor, and basic fibroblast growth factor) that stimulate smooth muscle proliferation (165).…”

Contrast-Induced Nephropathy in Percutaneous Coronary Interventions: Pathogenesis, Risk Factors, Outcome, Prevention and Treatment

“…After the administration of CM, there is an increased responsiveness to angiotensin-II [42]. Moreover, ROS decrease the bioavailability of nitric oxide (NO) with subsequent formation of peroxynitrite and alteration of the microcirculation [43].…”