Increased Activation of Stromal Interaction Molecule-1/Orai-1 in Aorta From Hypertensive Rats: A Novel Insight Into Vascular Dysfunction

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 53; no. 2, Part 2 Suppl; pp. 409 - 416
• Main Authors: Giachini, Fernanda R.C., Chiao, Chin-Wei, Carneiro, Fernando S., Lima, Victor V., Carneiro, Zidonia N., Dorrance, Anne M., Tostes, Rita C., Webb, R Clinton
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.02.2009; Lippincott Williams & Wilkins
• Subjects: Animals; Aorta - drug effects; Aorta - metabolism; Aorta - physiopathology; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - physiology; Body Weight - physiology; Calcium - metabolism; Calcium Channels - metabolism; Cardiology. Vascular system; Cytosol - metabolism; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Experimental diseases; Homeostasis - physiology; Hypertension - metabolism; Male; Medical sciences; Membrane Glycoproteins - metabolism; Muscle Contraction - drug effects; ORAI1 Protein; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stromal Interaction Molecule 1; Thapsigargin - pharmacology; Hypertension; Rat; SOC; Rodentia; Smooth muscle; Cardiovascular disease; Ca2+ regulation; CRAC channel; Orai-1; STIM-1; Vertebrata; Mammalia; Animal; Aorta; vascular smooth muscle cell
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.108.124404

Disturbances in the regulation of cytosolic calcium (Ca) 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 entry. Although STIMs act as Ca sensors for the intracellular Ca stores, Orai is the putative pore-forming component of Ca release–activated Ca channels at the plasma membrane. We hypothesized that augmented activation of Ca release–activated Ca/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 influx. Depletion of intracellular Ca stores, which induces Ca release–activated Ca activation, was performed by placing arteries in Ca free-EGTA buffer. The addition of the Ca 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 Ca ATPase, further increased these contractions, especially in stroke-prone spontaneously hypertensive rat aorta. Addition of the Ca release–activated Ca 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 Ca levels in hypertension.