Published ahead of print on July 28, 2005, doi:10.1164/rccm.200506-847OC Am. J. Respir. Crit. Care Med., Volume 172, Number 9, November 2005, 1153-1160 A more recent version of this article appeared on November 1, 2005
Submitted on June 2, 2005 Resistance to Store Depletion-induced Endothelial Injury in Rat Lung after Chronic Heart FailureDiego F Alvarez1,1 Department of Physiology, University of South Alabama, Mobile, AL, USA, 2 Department of Pharmacology and Pathology, University of South Alabama, Mobile, AL, USA; Center for Lung Biology, University of South Alabama, Mobile, AL, USA, 3 Department of Physiology, University of South Alabama, Mobile, AL, USA; Center for Lung Biology, University of South Alabama, Mobile, AL, USA * To whom correspondence should be addressed. 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, though 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 Ca++ 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 Ca++/Ca++ addback strategy to identify the component of the permeability response dependent upon Ca++ entry. Main Results: In fistulas, right ventricular mass and left ventricular end diastolic pressure were increased and left ventricular shortening fraction decreased compared to shams. Thapsigargin-induced store depletion increased lung endothelial permeability in shams, but not in fistulas. Permeability increased in both groups after the Ca++ ionophore A23187 or 14,15-epoxyeicosatrienoic acid, independent of store depletion. A diacylglycerol analogue 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 Ca++ ATPase was not altered in fistulas compared to shams, whereas the store-operated canonical transient receptor potential channels 1, 3 and 4 were down-regulated in extra-alveolar vessel endothelium. Conclusions: We conclude that the adaptive mechanism limiting store depletion-induced endothelial lung injury in the aortocaval model of heart failure involves down regulation of the store-operated Ca++ channels. Key words: permeability, secondary pulmonary hypertension, calcium channels
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