Targeting the redox regulation of SERCA in vascular physiology and disease

The sarco/endoplasmic reticulum calcium ATPase (SERCA) is essential for the control of intracellular free Ca(2+) levels. Although the importance for this enzyme in cardiac myocytes is well recognized, it is only recently that SERCA has been identified as an important effector of nitric oxide (NO) action in vascular cells. NO can stimulate the uptake of cytosolic Ca(2+) via SERCA by adducting glutathione to the reactive cysteine-674. Mutation of this single amino acid prevents the stimulation of Ca(2+) uptake by NO, as well as its ability to inhibit smooth muscle cell functions including migration. NO function is impaired in a variety of cardiovascular diseases, including diabetes, hypercholesterolemia, and atherosclerosis, which are all associated with SERCA dysfunction caused by the increased oxidants in these diseases. Targeting the oxidant sources in vascular diseases to prevent SERCA from being oxidized and/or increasing the expression of SERCA may improve vascular disease development.