Increased activation of stromal interaction molecule-1/Orai-1 in aorta from hypertensive rats: a novel insight into vascular dysfunction.
Disturbances in the regulation of cytosolic calcium (Ca(2+)) concentration play a key role in the vascular dysfunction associated with arterial hypertension. Stromal interaction molecules (STIMs) and Orai proteins represent a novel mechanism to control store-operated Ca(2+) entry. Although STIMs act as Ca(2+) sensors for the intracellular Ca(2+) stores, Orai is the putative pore-forming component of Ca(2+) release-activated Ca(2+) channels at the plasma membrane. We hypothesized that augmented activation of Ca(2+) release-activated Ca(2+)/Orai-1, through enhanced activity of STIM-1, plays a role in increased basal tonus and vascular reactivity in hypertensive animals. Endothelium-denuded aortic rings from Wistar-Kyoto and stroke-prone spontaneously hypertensive rats were used to evaluate contractions because of Ca(2+) influx. Depletion of intracellular Ca(2+) stores, which induces Ca(2+) release-activated Ca(2+) activation, was performed by placing arteries in Ca(2+) free-EGTA buffer. The addition of the Ca(2+) regular buffer produced greater contractions in aortas from stroke-prone spontaneously hypertensive rats versus Wistar-Kyoto rats. Thapsigargin (10 micromol/L), an inhibitor of the sarcoplasmic reticulum Ca(2+) ATPase, further increased these contractions, especially in stroke-prone spontaneously hypertensive rat aorta. Addition of the Ca(2+) release-activated Ca(2+) channel inhibitors 2-aminoethoxydiphenyl borate (100 micromol/L) or gadolinium (100 micromol/L), as well as neutralizing antibodies to STIM-1 or Orai-1, abolished thapsigargin-increased contraction and the differences in spontaneous tone between the groups. Expression of Orai-1 and STIM-1 proteins was increased in aorta from stroke-prone spontaneously hypertensive rats when compared with Wistar-Kyoto rats. These results support the hypothesis that both Orai-1 and STIM-1 contribute to abnormal vascular function in hypertension. Augmented activation of STIM-1/Orai-1 may represent the mechanism that leads to impaired control of intracellular Ca(2+) levels in hypertension.
Giachini
Fernanda R C
FR
Medical College of Georgia, Department of Physiology, 1120 15th St, CA-3141, Augusta, GA 30912-3000, USA. fgiachini@mcg.edu
Chiao
Chin-Wei
CW
Carneiro
Fernando S
FS
Lima
Victor V
VV
Carneiro
Zidonia N
ZN
Dorrance
Anne M
AM
Tostes
Rita C
RC
Webb
R Clinton
RC
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000502:physiology; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D000071740:ORAI1 Protein; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D000071737:Stromal Interaction Molecule 1; D019284:Thapsigargin / Q000494:pharmacology
D015220:Calcium Channels; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D000071740:ORAI1 Protein; C532493:Orai1 protein, rat; C518857:Stim1 protein, rat; D000071737:Stromal Interaction Molecule 1; D019284:Thapsigargin; D002118:Calcium