Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

Zhang, Shen; Dong, Hui; Rubin, Lewis J.; Yuan, Jason X.‐J.

doi:10.1152/ajpcell.00383.2006

Cited by 80 publications

(59 citation statements)

References 63 publications

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“…Zhang et al [161] demonstrated an upregulation of NCX and enhanced Ca 2+ entry via NCX reverse mode in pulmonary artery SMC from patients with idiopathic arterial hypertension. These authors previously showed that cultured human pulmonary artery SMC express high levels of NCX and that enhanced NCX activity in its reverse mode produced an increase in cytoplasmic Ca 2+ and promoted proliferation [163].…”

Section: Other Changes Involving Various Ion Channelsmentioning

confidence: 99%

The non-excitable smooth muscle: Calcium signaling and phenotypic switching during vascular disease

House

Potier

Bisaillon

et al. 2008

Pflugers Arch - Eur J Physiol

221

207

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Calcium (Ca 2+ ) is a highly versatile second messenger that controls vascular smooth muscle cell (VSMC) contraction, proliferation, and migration. By means of Ca 2+ permeable channels, Ca 2+ pumps and channels conducting other ions such as potassium and chloride, VSMC keep intracellular Ca 2+ levels under tight control. In healthy quiescent contractile VSMC, two important components of the Ca 2+ signaling pathways that regulate VSMC contraction are the plasma membrane voltageoperated Ca 2+ channel of the high voltage-activated type (L-type) and the sarcoplasmic reticulum Ca 2+ release channel, Ryanodine Receptor (RyR). Injury to the vessel wall is accompanied by VSMC phenotype switch from a contractile quiescent to a proliferative motile phenotype (synthetic phenotype) and by alteration of many components of VSMC Ca 2+ signaling pathways. Specifically, this switch that culminates in a VSMC phenotype reminiscent of a non-excitable cell is characterized by loss of L-type channels expression and increased expression of the low voltage-activated (T-type) Ca 2+ channels and the canonical transient receptor potential (TRPC) channels. The expression levels of intracellular Ca 2+ release channels, pumps and Ca 2+ -activated proteins are also altered: the proliferative VSMC lose the RyR3 and the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase isoform 2a pump and reciprocally regulate isoforms of the ca 2+ /calmodulin-dependent protein kinase II. This review focuses on the changes in expression of Ca 2+ signaling proteins associated with VSMC proliferation both in vitro and in vivo. The physiological implications of the altered expression of these Ca 2+ signaling molecules, their contribution to VSMC dysfunction during vascular disease and their potential as targets for drug therapy will be discussed.

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Section: Other Changes Involving Various Ion Channelsmentioning

confidence: 99%

The non-excitable smooth muscle: Calcium signaling and phenotypic switching during vascular disease

House

Potier

Bisaillon

et al. 2008

Pflugers Arch - Eur J Physiol

221

207

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“…However, treatment aimed at inhibiting both L-type calcium channels and the reverse-mode of the sodium-calcium exchanger in airway smooth muscle may prove effective at reversing the increased contractile tone associated with airway obstruction. Interestingly, inhibition of the sodium-calcium exchanger is currently touted as a potential clinical strategy for treating hypertensive conditions associated with increased calcium ion influx through the reverse-mode of the sodium-calcium exchanger [37,38,42,46,47]. It is apparent that further in vivo study is required in order to determine whether or not the sodium-calcium exchanger plays a role in obstructive airway disease.…”

Section: Store-refilling In Asm S Hirota and Lj Janssenmentioning

confidence: 99%

Store-refilling involves both L-type calcium channels and reverse-mode sodium–calcium exchange in airway smooth muscle

Hirota¹,

Janssen²

2007

Eur Respir J

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The aim of the present study was to examine the relative contributions to storerefilling of the two following voltage-regulated calcium ion influx pathways: 1) L-type-Ca 2+ channels; and 2) the reverse-mode of the sodium-calcium exchanger (NCX).Successive acetylcholine-induced contractions, triggered in bovine tracheal smooth muscle strips, were measured to determine the effect of intervention on contractions as an indication of the extent of store-refilling.Pre-treating the tissues with cromakalim significantly reduced the magnitude of successive contractions. Zero-Ca 2+ bathing media abolished the contractions, an effect that was completely reversed upon reintroduction of Ca 2+. Inhibition of L-type Ca 2+ channels, with nifedipine, significantly reduced the magnitude of the contractions. Similarly, inhibition of the reverse-mode of the NCX, with KB-R7943, significantly reduced the magnitude of the contractions. However, neither nifedipine nor KB-R7943 alone reduced contractions to the same extent as observed under zero-Ca 2+ conditions. Concurrent treatment with nifedipine and KB-R7943 almost abolished successive contractions. Furthermore, concurrent treatment with nifedipine and zero-Na + bathing media displayed a significantly greater effect than nifedipine alone. Probing the expression of NCX1 isoforms by Western blotting revealed the presence of three bands of 160, 120 and 110 kDa. The 120-and 110-kDa bands were identified as variably spliced NCX isoforms, NCX1.1 and NCX1.3, respectively. Taken together, these data suggest that influx of calcium ions through both L-type calcium channels and the reverse-mode of the sodium-calcium exchanger is necessary for complete store-refilling in airway smooth muscle.

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“…23 The effective reduction in 5-HT-elicited contraction by ten millimoles per liter Ni 2þ , extracellular Ca 2þ removal, KB-R7943, the combination of SKF-96365 and nifedipine, or verapamil, compared to the modest reduction in contraction due to nifedipine and diltiazem, suggest that voltage-independent Ca 2þ entry is predominantly responsible for 5-HT contraction before birth. 19,20,69,70 The pharmacological profiling we performed indicates that TRP channels, but not reverse-mode NCX activity, are critical to Ca 2þ -dependent 5-HT-elicited PA contraction in fetal sheep. 49,53 A prominent role for TRP channels was not surprising, since they contribute significantly to contraction and Ca 2þ signaling in vascular myocytes of other species.…”

mentioning

confidence: 94%

“…23 Long-term hypoxia also augments NSCC activity in PA smooth muscle cells of adult rat. 24,25 Reports also show that NCX 20 and transient receptor potential (TRP) channels, which encode for NSCCs, contribute to the development of PA hypertension in humans. [26][27][28][29][30][31] Long-term hypoxia also increases platelet-activated factorinduced Ca 2þ responses in pulmonary venous smooth muscle cells of fetal sheep, 32 which may be a consequence of increased platelet-activated factor receptor expression and resultant inositol 1,4,5-triphosphate generation.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Maternal Hypoxia

et al. 2011

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Antenatal maternal long-term hypoxia (LTH) can alter serotonin (5-HT) and calcium (Ca 2þ ) signaling in fetal pulmonary arteries (PAs) and is associated with persistent pulmonary hypertension of the newborn (PPHN). In humans, the antenatal maternal hypoxia can be secondary to smoking, anemia, and chronic obstructive pulmonary disorders. However, the mechanisms of antenatal maternal hypoxia-related PPHN are unresolved. Because both LTH and 5-HT are associated with PPHN, we tested the hypothesis that antenatal maternal LTH can increase 5-HT-mediated PA contraction and associated extracellular Ca 2þ influx through L-type Ca 2þ channels (Ca L ), nonselective cation channels (NSCCs), and reverse-mode sodium-calcium exchanger (NCX) in the near-term fetus. We performed wire myography and confocal-Ca 2þ imaging approaches on fetal lamb PA (*140 days of gestation) from normoxic ewes or those acclimatized to high-altitude LTH (3801 m) for *110 days. Long-term hypoxia reduced the potency but not the efficacy of 5-HT-induced PA contraction. Ketanserin (100 nmol/L), a 5-HT 2A antagonist, shifted 5-HT potency irrespective of LTH, while GR-55562 (1 mmol/L), a 5-HT 1B/D inhibitor, antagonized 5-HT-induced contraction in normoxic fetuses only. Various inhibitors for Ca L , NSCC, and reverse-mode NCX were used in contraction studies. Contraction was reliant on extracellular Ca 2þ regardless of maternal hypoxia, NSCC was more important to contraction than Ca L , and reverse-mode NCX had little or no role in contraction. Long-term hypoxia also attenuated the effects of 2-APB and flufenamic acid and reduced Ca 2þ responses observed by imaging studies. Overall, LTH reduced 5HT 1B/D function and increased NSCC-related Ca 2þ -dependent contraction in ovine fetuses, which may compromise pulmonary vascular function in the newborn.

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Upregulation of Na⁺/Ca²⁺ exchanger contributes to the enhanced Ca²⁺ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

Cited by 80 publications

References 63 publications

The non-excitable smooth muscle: Calcium signaling and phenotypic switching during vascular disease

The non-excitable smooth muscle: Calcium signaling and phenotypic switching during vascular disease

Store-refilling involves both L-type calcium channels and reverse-mode sodium–calcium exchange in airway smooth muscle

Long-Term Maternal Hypoxia

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