Lung Endothelial Dysfunction in Congestive Heart Failure: Role of Impaired Ca2+ Signaling and Cytoskeletal Reorganization

• Published in: Circulation research Vol. 106; no. 6; pp. 1103 - 1116
• Main Authors: Kerem, Alexander, Yin, Jun, Kaestle, Stephanie M, Hoffmann, Julia, Schoene, Axel M, Singh, Baljit, Kuppe, Hermann, Borst, Mathias M, Kuebler, Wolfgang M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 02.04.2010; Lippincott Williams & Wilkins
• Subjects: Acetylcholine - pharmacology; Actins - metabolism; Animals; Biological and medical sciences; Blood Pressure; Calcium Signaling - drug effects; Cardiology. Vascular system; Cholinergic Antagonists - pharmacology; Cytochalasin D - pharmacology; Cytoskeleton - drug effects; Cytoskeleton - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Endothelium, Vascular - physiopathology; Fundamental and applied biological sciences. Psychology; Heart; Heart Failure - complications; Heart Failure - metabolism; Heart Failure - pathology; Heart Failure - physiopathology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Histamine - pharmacology; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - physiopathology; Ionophores - pharmacology; Lung - blood supply; Male; Medical sciences; Microscopy, Fluorescence; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase - metabolism; Perfusion; Pneumology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Rats; Rats, Sprague-Dawley; Stress, Mechanical; Time Factors; Transient Receptor Potential Channels - metabolism; Vasodilation - drug effects; Vasodilator Agents - pharmacology; Vertebrates: cardiovascular system; Heart failure; cytoskeletal dynamics; Calcium; Respiratory disease; Lung; Cardiovascular disease; Respiratory system; Inorganic element; Pulmonary hypertension; Signal transduction; Vertebrata; Mammalia; regulation; Heart disease; Endothelial dysfunction; congestive heart failure; Circulatory system; Ca
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.210542

RATIONALE:Congestive heart failure (CHF) frequently results in remodeling and increased tone of pulmonary resistance vessels. This adaptive response, which aggravates pulmonary hypertension and thus, promotes right ventricular failure, has been attributed to lung endothelial dysfunction. OBJECTIVE:We applied real-time fluorescence imaging to identify endothelial dysfunction and underlying molecular mechanisms in an experimental model of CHF induced by supracoronary aortic banding in rats. METHODS AND RESULTS:Endothelial dysfunction was evident in lungs of CHF rats as impaired endothelium-dependent vasodilation and lack of endothelial NO synthesis in response to mechanical stress, acetylcholine, or histamine. This effect was not attributable to downregulation of endothelial NO synthase. Imaging of the cytosolic Ca concentration ([Ca]i) revealed a singular impairment of endothelial [Ca]i homeostasis and signaling characterized by a lack of [Ca]i oscillations and deficient or attenuated [Ca]i responses to mechanical stress, histamine, acetylcholine, or thapsigargin. Reconstitution of a [Ca]i signal by ionophore treatment restored endothelial NO production, but lack of endothelial responsiveness was not primarily attributable to downregulation of Ca influx channels in CHF. Rather, we identified a massive remodeling of the endothelial cytoskeleton in the form of an increased expression of β-actin and F-actin formation which contributed critically to endothelial dysfunction in CHF because cytoskeletal disruption by cytochalasin D largely reconstituted endothelial [Ca]i signaling and NO production. CONCLUSIONS:Our findings characterize a unique scenario of endothelial dysfunction in CHF that is caused by a singular impairment of [Ca]i signaling, and identify cytoskeletal reorganization as a major regulator of endothelial signaling and function.