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Abstract

Recently, ALLHAT study clearly demonstrated the benefit of natriuretic-diuretic therapy. However, most diuretics promote not only sodium but potassium excretion, sometimes resulting in the systemic potassium deficiency. Many clinical studies, including SHEP study, suggest that potassium loss increases cardiovascular events and/or sudden death independent of blood pressure. Enhanced oxygen radical production is assumed to be one of the harmful effects of potassium depletion, which results in vascular dysfunction and impaired cardiac performance. However, the precise mechanism for this is so far unknown. In order to gain an insight into this, we focused on SOD which eliminates oxygen radicals in the vasculature. We investigated the direct effect of potassium depletion on SOD in rat vascular smooth muscle cells (VSMC). First, we determined total SOD activity by modulated NBT assay and analyzed expression of SOD families, Cu/Zn-SOD, Mn-SOD and EC-SOD by immunoblotting. Lowering ambient potassium concentration ( [K+]o ) of culture medium from 5 to 1 mEq/l for 24 hours decreased total SOD activity by 30%. This was accompanied with specific decrease of EC-SOD and Mn-SOD. We next focused on EC-SOD because it dominantly regulates SOD activity in the vascular system. To clarify the underlying mechanism of EC-SOD decrease, we examined its transcriptional and translational regulation. Potassium depletion did not affect EC-SOD mRNA level monitored by Northern blotting analysis. Surprisingly, EC-SOD protein level was regulated by translational mechanism. 35S-metabolic labeling revealed that potassium depletion attenuated EC-SOD protein synthesis in a [K+]o-dependent manner. In contrast, pulse-and chase-35S-metabolic labeling did not suggest its enhanced degradation by potassium loss. Complementary study demonstrated that global protein synthesis was strictly regulated by [K+]o. Collectively, we conclude that potassium depletion concentration-dependently causes the attenuation of EC-SOD protein synthesis followed by its protein decrease in VSMC. The same manner could be expected to Mn-SOD. Decrease of EC-SOD and Mn-SOD proteins would contribute to the decrease in total SOD activity, leading to the increase of oxygen radicals in the vasculature. These findings may have important implication for the missing link between potassium depletion and enhanced oxygen radicals in the vascular system.

Am J Hypertens (2004) 17, 97A–97A; doi: 10.1016/j.amjhyper.2004.03.249

Antioxidants, Risk Factors, Vasculature
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© American Journal of Hypertension, Ltd. 2004
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