Editors' ChoicePulmonary Arterial Hypertension

Too Much of a Good Channel in Pulmonary Arterial Hypertension

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Science Translational Medicine  19 Feb 2014:
Vol. 6, Issue 224, pp. 224ec34
DOI: 10.1126/scitranslmed.3008649

Great progress has been made in the management and treatment of pulmonary arterial hypertension (PAH) in the past two decades. PAH is a condition that affects the pulmonary arteries and leads to a progressive increase in vascular resistance, right ventricular failure, and death. It is accepted that patients with PAH have pulmonary endothelial dysfunction, impaired apoptosis, and disorganized angiogenesis, but the basis for these findings remains unidentified.

The chloride intracellular channel 4 (CLIC4) is a protein that is essential for normal angiogenesis. The CLIC4 knockout mouse is characterized by a reduced capacity to form collateral blood vessels. CLIC4 is highly expressed in the pulmonary vascular endothelium of patients with PAH, particularly in plexiform formations, which are distinct histopathological lesions that result from misguided angiogenesis. Wojciak-Stothard et al. tested whether the aberrant expression of CLIC4 contributes to the vascular alterations observed in PAH. The authors found higher concentrations of CLIC4 in plasma and circulating endothelial cells of PAH patients as compared with healthy controls. CLIC4 was predominantly localized in the cytoplasm of cultured human pulmonary artery endothelial cells (HPAEC), where it interacted with cytoskeletal proteins involved in cell motility. Overexpression of this protein was associated with increased HPAEC survival, enhanced angiogenic capacity, and endothelial permeability. CLIC4 was also increased in rat models of PAH, in which it predominantly localized in the pulmonary vascular endothelium. Interestingly, CLIC4 knockout mice did not have as many pulmonary hypertensive changes when exposed to hypoxia. Furthermore, CLIC4 activated the nuclear factor IB, stabilized the hypoxia-inducible factor-1I, and increased downstream production of vascular endothelial growth factor and endothelin-1, which are mediators involved in the pathobiology of PAH.

The extensive and thorough investigations performed by Wojciak-Stothard et al. demonstrate the critical role of CLIC4 in the pathobiology of PAH and regulation of pulmonary endothelial function. However, it remains unclear whether therapeutic interventions that decrease CLIC4 expression might be beneficial in human PAH, a condition that continues to be associated with a high morbidity and mortality.

B. Wojciak-Stothard et al., Aberrant chloride intracellular channel 4 expression contributes to endothelial dysfunction. Circulation, published online 6 February 2014 (10.1161/CIRCULATIONAHA.113.006797). [Abstract]

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