STIM1 restores coronary endothelial function in type 1 diabetic mice.
BACKGROUND
The endoplasmic reticulum (ER) is a major intracellular Ca(2+) store in endothelial cells (ECs). The Ca(2+) concentration in the ER greatly contributes to the generation of Ca(2+) signals that regulate endothelial functions. Many proteins, including stromal interaction molecule 1/2 (STIM1/2), Orai1/2/3, and sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 3 (SERCA3), are involved in the ER Ca(2+) refilling after store depletion in ECs.


OBJECTIVE
This study is designed to examine the role of Ca(2+) in the ER in coronary endothelial dysfunction in diabetes.


RESULTS
Mouse coronary ECs (MCECs) isolated from diabetic mice exhibited (1) a significant decrease in the Ca(2+) 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(2+) concentration due to Ca(2+) leak from the ER in diabetic MCECs, (2) the Ca(2+) concentration in the ER, and (3) endothelium-dependent relaxation that was attenuated in diabetic coronary arteries.


CONCLUSIONS
Impaired ER Ca(2+) 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.
Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Irene A
IA
Estrada
Reshma
R
Donthamsetty
Patryk
P
Debski
Meng-Hua
MH
Zhou
Shenyuan L
SL
Zhang
Jason X-J
JX
Yuan
Wenlong
W
Han
Ayako
A
Makino
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000494:pharmacology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D015220:Calcium Channels; D005230:Fatty Acids, Nonesterified; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506950:Atp2a3 protein, mouse; D002118:Calcium