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

Once thought of as toxic by-products of cellular metabolism, reactive oxygen species (ROS) have been implicated in a large variety of cell-signaling processes. Several enzymatic systems contribute to ROS production in vascular endothelial cells, including NA(D)PH oxidase, xanthine oxidase, uncoupled endothelial nitric oxide synthase, and the mitochondrial electron transport chain. The respiratory chain is the major source of ROS in most mammalian cells, but the role of mitochondria-derived ROS in vascular cell signaling has received little attention. A new paradigm has evolved in recent years postulating that, in addition to producing ATP, mitochondria also play a key role in cell signaling and regulate a variety of cellular functions. This review focuses on the emerging role of mitochondrial ROS as signaling molecules in vascular endothelial cells. Specifically, we discuss some recent findings that indicate that mitochondrial ROS regulate vascular endothelial function, focusing on major sites of ROS production in endothelial mitochondria, factors modulating mitochondrial ROS production, the physiological and clinical implications of endothelial mitochondrial ROS, and methodological considerations in the study of mitochondrial contribution to vascular ROS generation.

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Lead induces dysregulation of iron regulatory protein 1 via the extracellular signal-regulated kinase pathway in human vascular endothelial cells

Brain Research ◽

10.1016/j.brainres.2012.03.052 ◽

2012 ◽

Vol 1455 ◽

pp. 19-27 ◽

Cited By ~ 6

Author(s):

Qiang Wang ◽

Yan Lin ◽

Wenbin Zhang ◽

Mingchao Liu ◽

Yaoming Chen ◽

...

Keyword(s):

Endothelial Cells ◽

Vascular Endothelial Cells ◽

Regulatory Protein ◽

Vascular Endothelial ◽

Iron Regulatory Protein ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Kinase Pathway ◽

Iron Regulatory Protein 1

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Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1 and HO-2 to cytoprotection

AJP Cell Physiology ◽

10.1152/ajpcell.00386.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. C1399-C1410 ◽

Cited By ~ 112

Author(s):

Helena Parfenova ◽

Shyamali Basuroy ◽

Sujoy Bhattacharya ◽

Dilyara Tcheranova ◽

Yan Qu ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Endothelial Cells ◽

Vascular Endothelium ◽

Vascular Endothelial Cells ◽

Glutamate Toxicity ◽

Vascular Endothelial ◽

Oxygen Species ◽

Apoptotic Effects ◽

Cerebral Vascular

In cerebral circulation, epileptic seizures associated with excessive release of the excitatory neurotransmitter glutamate cause endothelial injury. Heme oxygenase (HO), which metabolizes heme to a vasodilator, carbon monoxide (CO), and antioxidants, biliverdin/bilirubin, is highly expressed in cerebral microvessels as a constitutive isoform, HO-2, whereas the inducible form, HO-1, is not detectable. Using cerebral vascular endothelial cells from newborn pigs and HO-2-knockout mice, we addressed the hypotheses that 1) glutamate induces oxidative stress-related endothelial death by apoptosis, and 2) HO-1 and HO-2 are protective against glutamate cytotoxicity. In cerebral endothelial cells, glutamate (0.1–2.0 mM) increased formation of reactive oxygen species, including superoxide radicals, and induced major keystone events of apoptosis, such as NF-κB nuclear translocation, caspase-3 activation, DNA fragmentation, and cell detachment. Glutamate-induced apoptosis was greatly exacerbated in HO-2 gene-deleted murine cerebrovascular endothelial cells and in porcine cells with pharmacologically inhibited HO-2 activity. Glutamate toxicity was prevented by superoxide dismutase, suggesting apoptotic changes are oxidative stress related. When HO-1 was pharmacologically upregulated by cobalt protoporphyrin, apoptotic effects of glutamate in cerebral endothelial cells were completely prevented. Glutamate-induced reactive oxygen species production and apoptosis were blocked by a CO-releasing compound, CORM-A1 (50 μM), and by bilirubin (1 μM), consistent with the antioxidant and cytoprotective roles of the end products of HO activity. We conclude that both HO-1 and HO-2 have anti-apoptotic effects against oxidative stress-related glutamate toxicity in cerebral vascular endothelium. Although HO-1, when induced, provides powerful protection, HO-2 is an essential endogenous anti-apoptotic factor against glutamate toxicity in the cerebral vascular endothelium.

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