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(Hypertension. 2009;53:409.)
© 2009 American Heart Association, Inc.

Original Articles Part 2

Increased Activation of Stromal Interaction Molecule-1/Orai-1 in Aorta From Hypertensive Rats

A Novel Insight Into Vascular Dysfunction

Fernanda R.C. Giachini; Chin-Wei Chiao; Fernando S. Carneiro; Victor V. Lima; Zidonia N. Carneiro; Anne M. Dorrance; Rita C. Tostes; R. Clinton Webb

From the Department of Physiology (F.R.C.G., C.-W.C., F.S.C., V.V.L., Z.N.C., R.C.T., R.C.W.), Medical College of Georgia, Augusta; Department of Pharmacology (F.R.C.G., F.S.C., R.C.T.), University of Sao Paulo, Sao Paulo, Brazil; and the Department of Pharmacology and Toxicology (A.M.D.), Michigan State University, East Lansing.

Correspondence to Fernanda R.C. Giachini, Medical College of Georgia, Department of Physiology, 1120 15th St, CA-3141, Augusta, GA 30912-3000. E-mail fgiachini{at}mcg.edu

Disturbances in the regulation of cytosolic calcium (Ca²⁺) 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 Ca²⁺ entry. Although STIMs act as Ca²⁺ sensors for the intracellular Ca²⁺ stores, Orai is the putative pore-forming component of Ca²⁺ release–activated Ca²⁺ channels at the plasma membrane. We hypothesized that augmented activation of Ca²⁺ release–activated Ca²⁺/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 Ca²⁺ influx. Depletion of intracellular Ca²⁺ stores, which induces Ca²⁺ release–activated Ca²⁺ activation, was performed by placing arteries in Ca²⁺ free-EGTA buffer. The addition of the Ca²⁺ regular buffer produced greater contractions in aortas from stroke-prone spontaneously hypertensive rats versus Wistar-Kyoto rats. Thapsigargin (10 µmol/L), an inhibitor of the sarcoplasmic reticulum Ca²⁺ ATPase, further increased these contractions, especially in stroke-prone spontaneously hypertensive rat aorta. Addition of the Ca²⁺ release–activated Ca²⁺ channel inhibitors 2-aminoethoxydiphenyl borate (100 µmol/L) or gadolinium (100 µmol/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 Ca²⁺ levels in hypertension.

Key Words: Ca²⁺ regulation • STIM-1Orai-1 • SOC • CRAC channel • hypertension • vascular smooth muscle cell

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