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Lung endothelial dysfunction in congestive heart failure: role of impaired Ca2+ signaling and cytoskeletal reorganization.

Abstract：

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(2+) concentration ([Ca(2+)](i)) revealed a singular impairment of endothelial [Ca(2+)](i) homeostasis and signaling characterized by a lack of [Ca(2+)](i) oscillations and deficient or attenuated [Ca(2+)](i) responses to mechanical stress, histamine, acetylcholine, or thapsigargin. Reconstitution of a [Ca(2+)](i) signal by ionophore treatment restored endothelial NO production, but lack of endothelial responsiveness was not primarily attributable to downregulation of Ca(2+) influx channels in CHF. Rather, we identified a massive remodeling of the endothelial cytoskeleton in the form of an increased expression of beta-actin and F-actin formation which contributed critically to endothelial dysfunction in CHF because cytoskeletal disruption by cytochalasin D largely reconstituted endothelial [Ca(2+)](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(2+)](i) signaling, and identify cytoskeletal reorganization as a major regulator of endothelial signaling and function.

journal_name

Circ Res

journal_title

Circulation research

authors

Kerem A,Yin J,Kaestle SM,Hoffmann J,Schoene AM,Singh B,Kuppe H,Borst MM,Kuebler WM

doi

10.1161/CIRCRESAHA.109.210542

subject

Has Abstract

pub_date

2010-04-02 00:00:00

pages

1103-16

issue

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.109.210542

journal_volume

106

pub_type

杂志文章

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Lung endothelial dysfunction in congestive heart failure: role of impaired Ca2+ signaling and cytoskeletal reorganization.