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Resistance to Store Depletion–induced Endothelial Injury in Rat Lung after Chronic Heart Failure

Departments of Physiology and Pharmacology and Pathology, and Center for Lung Biology, University of South Alabama, Mobile, Alabama

Correspondence and requests for reprints should be addressed to Mary I. Townsley, Ph.D., Department of Physiology, MSB 3074, University of South Alabama, Mobile, AL 36688. E-mail: mtownsley{at}usouthal.edu

Rationale: In chronic heart failure, the lung endothelial permeability response to angiotensin II or thapsigargin-induced store depletion is ablated, although the mechanisms are not understood. Objectives: To determine whether the ablated permeability response to store depletion during heart failure was due to impaired expression of store operated Ca²⁺ channels in lung endothelium. Methods: Heart failure was induced by aortocaval fistula in rats. Permeability was measured in isolated lungs using the filtration coefficient and a low Ca²⁺/Ca²⁺ add-back strategy to identify the component of the permeability response dependent on Ca²⁺ entry. Main Results: In fistulas, right ventricular mass and left ventricular end diastolic pressure were increased and left ventricular shortening fraction decreased compared with shams. Thapsigargin-induced store depletion increased lung endothelial permeability in shams, but not in fistulas. Permeability increased in both groups after the Ca²⁺ ionophore A23187 or 14,15-epoxyeicosatrienoic acid, independent of store depletion. A diacylglycerol analog had no impact on permeability. Increased distance between the endoplasmic reticulum and the plasmalemmal membrane was ruled out as a mechanism for the loss of the permeability response to store depletion. Endothelial expression of the endoplasmic reticulum Ca²⁺ ATPase was not altered in fistulas compared with shams, whereas the store-operated canonical transient receptor potential channels 1, 3, and 4 were downregulated in extraalveolar vessel endothelium. Conclusions: We conclude that the adaptive mechanism limiting store depletion–induced endothelial lung injury in the aortocaval model of heart failure involves downregulation of store-operated Ca²⁺ channels.

Key Words: calcium channels • permeability • secondary pulmonary hypertension

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