Chronic hypoxia inhibits K<sub>v</sub> channel gene expression in rat distal pulmonary artery

Wang, Jian; Weigand, Letitia A.; Wang, Wenqian; Sylvester, J. J.; Shimoda, Larissa A.

doi:10.1152/ajplung.00379.2004

Cited by 83 publications

(82 citation statements)

References 39 publications

(59 reference statements)

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“…12,18,21,22) Previous studies have shown that chronic hypoxia decreases Kv gene expression. 1,2,10) Here, we showed that Kv1.5 and Kv2.1, the channels that participate in determining membrane potential in rat PASMCs, were downregulated in PASMCs during simulated HA. These data support the concept that Kv channel inhibition and downregulation may be etiologically related to the development of PAH.…”

Section: Discussionmentioning

confidence: 60%

“…1 As shown in Fig. 3E and 3F, Kv1.5 and Kv2.1 mRNA expression was significantly downregulated in HA PASMCs compared to N PASMCs, and DCA partially reversed the downregulation of Kv1.5 and nearly restored normal Kv2.1 expression.…”

Section: Effect Of Dca On the [Ca 2+ ]I Of Pasmcs In Ha Ratsmentioning

confidence: 62%

“…The downregulation of Kv1.5 and Kv2.1 under hypoxic conditions confirmed previously published literatures. 1,11,12) Rozanski et al 26) showed that cultured cardiomyocytes from infarcted rat hearts exhibit an increase in delayed rectifier K + current (Ik) when incubated with DCA for 4 hr. This effect was mimicked by pyruvate and inhibited by a pyruvate dehydrogenase blocker, suggesting that the effects of DCA are due to metabolic changes.…”

Section: Discussionmentioning

confidence: 99%

“…This condition is an important pathological result of mountain sickness, and prolonged PAH results in right heart failure. 1 The mechanism of how PAH develops remains unknown, and the treatments for PAH are limited.…”

Section: Introductionmentioning

confidence: 99%

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Dichloroacetate Inhibits Vascular Remodeling and Increases Voltage-gate K+ Expression in a High-altitude-induced Pulmonary Artery Hypertension Rat Model

Peng

Sun

et al. 2011

JOURNAL OF HEALTH SCIENCE

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To investigate the effect of dichloroacetate (DCA) on the mean pulmonary artery pressure (mPAP), pulmonary artery (PA) remodeling and voltage-gate K + (Kv) channel expression in pulmonary arterial smooth muscle cells (PASMCs) in high altitude-induced pulmonary artery hypertension (HA-PAH) rats. Sprague-Dawley rats were randomly assigned to normal control (N), high altitude (HA), and HA+DCA (70 mg/kg DCA administration daily) groups (n = 8 each). Rats were housed in a hypobaric, hypoxic chamber to mimic an altitude of 5000 m for 21 days; then the mPAP and the wall thickness (WT) of the PA smooth muscle were measured. PASMCs apoptosis was examined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stain. Real-time PCR, immunohistochemistry and western blot analyses were carried out to detect Kv1.5 and Kv2.1 expression in PASMCs. The expression of Kv1.5 and Kv2.1 was decreased in HA rats. With DCA treatment, the expression of Kv1.5 and Kv2.1 was restored, and the established HA-PAH was ameliorated. Compared with the HA-PAH rats, the DCA-treated rats displayed a decreased mPAP, WT of the PAs, right ventricular hypertrophy and ([Ca 2+ ]i), and more PASMCs were apoptotic. DCA partially reversed the down-regulation of Kv1.5 and Kv2.1 in the PASMCs of HA-PAH rats. DCA can reverse the remodeling of the PA and upregulate Kv1.5 and Kv2.1 expression in the PASMCs of HA-PAH rats. This result suggests that DCA may be an effective drug for treating HA-PAH and that restoring Kv1.5 and Kv2.1 can partially decrease mPAP.

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Section: Discussionmentioning

confidence: 60%

Section: Effect Of Dca On the [Ca 2+ ]I Of Pasmcs In Ha Ratsmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dichloroacetate Inhibits Vascular Remodeling and Increases Voltage-gate K+ Expression in a High-altitude-induced Pulmonary Artery Hypertension Rat Model

Peng

Sun

et al. 2011

JOURNAL OF HEALTH SCIENCE

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“…These hypoxic responses greatly contribute to the pathogenesis and development of chronic hypoxic pulmonary hypertension (CHPH). [6][7][8] Although pulmonary veins also contain smooth muscle that is likely to be important in CHPH, the absence of reliable methods to culture pulmonary venous smooth muscle cells (PVSMCs) has greatly delayed the related research. Thus, there is a need for an easy, reliable and widely accepted method to obtain these cells.…”

mentioning

confidence: 99%

Isolation and primary culture of rat distal pulmonary venous smooth muscle cells

Peng

Wang

et al. 2010

Hypertens Res

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Primary culture of pulmonary arterial smooth muscle cells is used extensively for in vitro studies of the physiology and pathophysiology of numerous lung diseases, including chronic hypoxic pulmonary hypertension (CHPH). Despite the potentially important functions of pulmonary veins in CHPH, primary culturing of pulmonary venous smooth muscle cells (PVSMCs) has received very little attention to date. No efficient and widely accepted methods have been established. Consequently, related studies have been delayed, which inhibits progress in exploring the mechanisms of CHPH and other lung diseases. In this study, we describe a simple and efficient method of obtaining primary cultures of PVSMCs isolated from rat distal pulmonary veins. By following four steps, isolation of pulmonary veins, enzymatic digestion, concentration of resuspended pellets and incubation, we acquired purified PVSMCs (495%). PVSMCs were characterized by morphological activity and by immunoblotting and immunofluorescence staining for a-smooth muscle actin. Furthermore, the response of cells to 60 mM KCl was tested, confirming the presence of functional L-type voltage-dependent Ca 2+ channels that are characteristic of smooth muscle cells. In conclusion, we have established a simple and reliable technique to isolate and culture PVSMCs from rat distal pulmonary veins. These PVSMCs exhibit features consistent with vascular smooth muscle cells, and they could subsequently be used to study pathophysiological mechanisms involving the pulmonary vein. Keywords: primary cell culture; pulmonary veins; pulmonary venous smooth muscle cells; rat INTRODUCTIONChronic hypoxia causes remodeling and alters contractile responses in both pulmonary arteries and pulmonary veins. 1-5 Primary cultures of pulmonary arterial smooth muscle cells (PASMCs) isolated from pulmonary arteries have been widely used to study the molecular mechanisms by which pulmonary arteries respond to hypoxia. These hypoxic responses greatly contribute to the pathogenesis and development of chronic hypoxic pulmonary hypertension (CHPH). [6][7][8] Although pulmonary veins also contain smooth muscle that is likely to be important in CHPH, the absence of reliable methods to culture pulmonary venous smooth muscle cells (PVSMCs) has greatly delayed the related research. Thus, there is a need for an easy, reliable and widely accepted method to obtain these cells.The purpose of this study was to develop a simple and efficient technique to isolate pulmonary veins, obtain primary cultures of PVSMCs and further characterize the phenotype and physiological functions of these cells. A method for primary cell culture of PVSMCs would be of great value for in vitro experiments to explore the mechanisms of CHPH and other pulmonary vein dysfunctions.

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Endothelial and Smooth Muscle Cell Ion Channels in Pulmonary Vasoconstriction and Vascular Remodeling

Makino

Firth

Yuan

2011

Comprehensive Physiology

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The pulmonary circulation is a low resistance and low pressure system. Sustained pulmonary vasoconstriction and excessive vascular remodeling often occur under pathophysiological conditions such as in patients with pulmonary hypertension. Pulmonary vasoconstriction is a consequence of smooth muscle contraction. Many factors released from the endothelium contribute to regulating pulmonary vascular tone, while the extracellular matrix in the adventitia is the major determinant of vascular wall compliance. Pulmonary vascular remodeling is characterized by adventitial and medial hypertrophy due to fibroblast and smooth muscle cell proliferation, neointimal proliferation, intimal, and plexiform lesions that obliterate the lumen, muscularization of precapillary arterioles, and in situ thrombosis. A rise in cytosolic free Ca2+ concentration ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction, while increased release of mitogenic factors, upregulation (or downregulation) of ion channels and transporters, and abnormalities in intracellular signaling cascades are key to the remodeling of the pulmonary vasculature. Changes in the expression, function, and regulation of ion channels in PASMC and pulmonary arterial endothelial cells play an important role in the regulation of vascular tone and development of vascular remodeling. This article will focus on describing the ion channels and transporters that are involved in the regulation of pulmonary vascular function and structure and illustrating the potential pathogenic role of ion channels and transporters in the development of pulmonary vascular disease.

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Chronic hypoxia inhibits K_v channel gene expression in rat distal pulmonary artery

Cited by 83 publications

References 39 publications

Dichloroacetate Inhibits Vascular Remodeling and Increases Voltage-gate K+ Expression in a High-altitude-induced Pulmonary Artery Hypertension Rat Model

Dichloroacetate Inhibits Vascular Remodeling and Increases Voltage-gate K+ Expression in a High-altitude-induced Pulmonary Artery Hypertension Rat Model

Isolation and primary culture of rat distal pulmonary venous smooth muscle cells

Endothelial and Smooth Muscle Cell Ion Channels in Pulmonary Vasoconstriction and Vascular Remodeling

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Chronic hypoxia inhibits Kv channel gene expression in rat distal pulmonary artery

Cited by 83 publications

References 39 publications

Dichloroacetate Inhibits Vascular Remodeling and Increases Voltage-gate K+ Expression in a High-altitude-induced Pulmonary Artery Hypertension Rat Model

Dichloroacetate Inhibits Vascular Remodeling and Increases Voltage-gate K+ Expression in a High-altitude-induced Pulmonary Artery Hypertension Rat Model

Isolation and primary culture of rat distal pulmonary venous smooth muscle cells

Endothelial and Smooth Muscle Cell Ion Channels in Pulmonary Vasoconstriction and Vascular Remodeling

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Chronic hypoxia inhibits K_v channel gene expression in rat distal pulmonary artery