STIM1 Restores Coronary Endothelial Function in Type 1 Diabetic Mice

RATIONALE:The endoplasmic reticulum (ER) is a major intracellular Ca store in endothelial cells (ECs). The Ca concentration in the ER greatly contributes to the generation of Ca signals that regulate endothelial functions. Many proteins, including stromal interaction molecule 1/2 (STIM1/2), Orai1/2/3, and sarcoplasmic/endoplasmic reticulum Ca-ATPase 3 (SERCA3), are involved in the ER Ca refilling after store depletion in ECs. OBJECTIVE:This study is designed to examine the role of Ca in the ER in coronary endothelial dysfunction in diabetes. METHODS AND RESULTS:Mouse coronary ECs (MCECs) isolated from diabetic mice exhibited (1) a significant decrease in the Ca mobilization from the ER when the cells were treated by SERCA inhibitor, and (2) significant downregulation of STIM1 and SERCA3 protein expression in comparison to the controls. Overexpression of STIM1 restored (1) the increase in cytosolic Ca concentration due to Ca leak from the ER in diabetic MCECs, (2) the Ca concentration in the ER, and (3) endothelium-dependent relaxation that was attenuated in diabetic coronary arteries. CONCLUSIONS:Impaired ER Ca refilling in diabetic MCECs, due to the decrease in STIM1 protein expression, attenuates endothelium-dependent relaxation in diabetic coronary arteries, while STIM1 overexpression has a beneficial and therapeutic effect on coronary endothelial dysfunction in diabetes.