Abstract
SummaryEndothelial oxidative stress develops with aging and reactive oxygen species impair endothelium‐dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial KCa3.1, which contributes to EDR, is upregulated by H2O2. We investigated whether KCa3.1 upregulation compensates for diminished EDR to NO during aging‐related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1‐phosphate were increased in aged wild‐type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild‐type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age‐matched wild‐type mice. Increased H2O2 levels induced Fyn and extracellular signal‐regulated kinases (ERKs) phosphorylation and KCa3.1 upregulation. Catalase/GPX1 double knockout (catalase−/−/GPX1−/−) upregulated KCa3.1 in MAECs. NO production was decreased in aged wild‐type, CerS2 null, and catalase−/−/GPX1−/− MAECs. However, KCa3.1 activation‐induced, NG‐nitro‐l‐arginine‐, and indomethacin‐resistant EDR was increased without a change in acetylcholine‐induced EDR in aortic rings from aged wild‐type, CerS2 null, and catalase−/−/GPX1−/− mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1‐phosphate induced similar changes in levels of the antioxidant enzymes and upregulated KCa3.1. Our findings suggest that, during aging‐related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H2O2 and thereby upregulate KCa3.1 expression and function via a H2O2/Fyn‐mediated pathway. Altogether, enhanced KCa3.1 activity may compensate for decreased NO signaling during vascular aging.
Highlights
Endothelial oxidative stress develops with aging and thereby impairs endothelial function (Donato et al, 2007; Ungvari et al, 2010)
We investigated whether reactive oxygen species (ROS) generation is increased in mouse aortic endothelial cells (MAECs) from aged wild-type (Fig. 1) and young ceramide synthase 2 (CerS2) null (Fig. 2) mice using the H2O2-sensitive dye, 5-(and 6-) chloromethyl-20,70-dichlorofluorescin diacetate (CM-DCFH-DA) or peroxy-orange 1, or the superoxidesensitive dye, dihydroethidine
We examined whether levels of antioxidant enzymes are altered in CerS2 null MAECs
Summary
Endothelial oxidative stress develops with aging and thereby impairs endothelial function (Donato et al, 2007; Ungvari et al, 2010). Endothelial cells (ECs) contribute to the maintenance of vascular homeostasis by secreting nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor, thereby playing an important role in preventing the genesis and progression of cardiovascular diseases. Dysregulated redox signaling and increased ROS production with aging lead to endothelial dysfunction, thereby contributing to the pathogenesis of cardiovascular diseases, such as coronary artery diseases, hypertension, and atherosclerosis, in elderly patients (Ungvari et al, 2010). Little is known about the mechanism by which ECs preserve their function of relaxing vascular smooth muscle during aging-related oxidative stress
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