L-type Ca2+channels, resting [Ca2+]i, and ET-1-induced responses in chronically hypoxic pulmonary myocytes

Shimoda, Larissa A.; Sham, James S.K.; Shimoda, Tenille H.; Sylvester, J. J.

doi:10.1152/ajplung.2000.279.5.l884

Cited by 131 publications

(180 citation statements)

References 47 publications

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“…Therefore, we cannot discard the possibility that other mechanisms besides Ca 2ϩ mediate the CH-induced activation of calcineurin/NFAT. In addition, other humoral factors that are upregulated by hypoxia could contribute to the increased NFAT activity demonstrated in this study, such as ET-1 and Ang II (4,36,37,(63)(64)(65)(66)(67)(68)(69)(70).…”

Section: Ch Induces Nfatc3 Activation In Pulmonarymentioning

confidence: 81%

NFATc3 Mediates Chronic Hypoxia-induced Pulmonary Arterial Remodeling with α-Actin Up-regulation

Garcı́a

Spangler

Alò

et al. 2007

Journal of Biological Chemistry

130

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Physiological responses to chronic hypoxia include polycythemia, pulmonary arterial remodeling, and vasoconstriction. Chronic hypoxia causes pulmonary arterial hypertension leading to right ventricular hypertrophy and heart failure. During pulmonary hypertension, pulmonary arteries exhibit increased expression of smooth muscle-␣-actin and -myosin heavy chain. NFATc3 (nuclear factor of activated T cells isoform c3), which is a Ca 2؉ -dependent transcription factor, has been recently linked to smooth muscle phenotypic maintenance through the regulation of the expression of ␣-actin. The aim of this study was to determine if: (a) NFATc3 is expressed in murine pulmonary arteries, (b) hypoxia induces NFAT activation, (c) NFATc3 mediates the up-regulation of ␣-actin during chronic hypoxia, and (d) NFATc3 is involved in chronic hypoxia-induced pulmonary vascular remodeling. NFATc3 transcript and protein were found in pulmonary arteries. NFAT-luciferase reporter mice were exposed to normoxia (630 torr) or hypoxia (380 torr) for 2, 7, or 21 days. Exposure to hypoxia elicited a significant increase in luciferase activity and pulmonary arterial smooth muscle nuclear NFATc3 localization, demonstrating NFAT activation. Hypoxia induced up-regulation of ␣-actin and was prevented by the calcineurin/NFAT inhibitor, cyclosporin A (25 mg/kg/day s.c.). In addition, NFATc3 knock-out mice did not showed increased ␣-actin levels and arterial wall thickness after hypoxia. These results strongly suggest that NFATc3 plays a role in the chronic hypoxia-induced vascular changes that underlie pulmonary hypertension.As altitude increases, the barometric pressure and atmospheric oxygen partial pressure decrease. This decrease in barometric pressure is the basic cause of all hypoxia-related problems in high altitude pathophysiology. Similar levels of hypoxia are present in patients with chronic bronchitis, emphysema, cystic fibrosis, asthma, and severe restrictive lung diseases (1). Chronic hypoxia (CH) 2 causes pulmonary hypertension due to pulmonary vasoconstriction, arterial remodeling, and polycythemia, which ultimately results in right ventricular (RV) hypertrophy and often heart failure (2). Pulmonary vasoconstriction is thought to be caused by elevated vascular tone through increased pulmonary arterial smooth muscle cell (PASMC) intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (3-8) and increased sensitivity of the contractile apparatus to Ca 2ϩ (9 -12).Regardless of the cause of pulmonary hypertension, the structural change that is thought to underlie the increased vascular resistance is remodeling of small pulmonary arteries. A prominent feature of this vascular remodeling is medial thickening. In proximal pulmonary vessels, medial enlargement is caused by hypertrophy and hyperplasia of the pre-existing smooth muscle cells (reviewed in Ref.

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Section: Ch Induces Nfatc3 Activation In Pulmonarymentioning

confidence: 81%

NFATc3 Mediates Chronic Hypoxia-induced Pulmonary Arterial Remodeling with α-Actin Up-regulation

Garcı́a

Spangler

Alò

et al. 2007

Journal of Biological Chemistry

130

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“…In PASMCs during CHPH, the increases in basal [Ca 21 ] i and the maintenance of cell contraction appear attributable to the activation of Ca 21 influx through pathways other than voltage-dependent Ca 21 channels (VDCCs), because the removal of extracellular Ca 21 , but not of VDCC blockers, decreased [Ca 21 ] i in PASMCs during chronic hypoxia, and relaxed arteries in chronically hypoxic rats (5). Store-operated calcium channels (SOCCs) are believed to be composed of members of transient receptor potential canonical (TRPC) family, which assemble as either homotetramer or heterotetramer channels and mediate store-operated calcium entry (SOCE) (6).…”

mentioning

confidence: 99%

BMP4 Increases Canonical Transient Receptor Potential Protein Expression by Activating p38 MAPK and ERK1/2 Signaling Pathways in Pulmonary Arterial Smooth Muscle Cells

et al. 2013

Am J Respir Cell Mol Biol

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Abnormal bone morphogenetic protein (BMP) signaling has been implicated in the pathogenesis of pulmonary hypertension. We previously found that BMP4 elevated basal intracellular Ca 21 ([Ca 21 ] i ) concentrations in distal pulmonary arterial smooth muscle cells (PASMCs), attributable in large part to enhanced store-operated Ca 21 entry through store-operated Ca 21 channels (SOCCs). Moreover, BMP4 up-regulated the expression of canonical transient receptor potential (TRPC) proteins thought to compose SOCCs. The present study investigated the signaling pathways through which BMP4 regulates TRPC expression and basal [Ca 21 ] i in distal PASMCs. Real-time quantitative PCR was used for the measurement of mRNA, Western blotting was used for the measurement of protein, and fluorescent microscopic for [Ca 21 ] i was used to determine the involvement of p38 and extracellular regulated kinase (ERK)-1/2 mitogen-activated protein kinase (MAPK) signaling in BMP4-induced TRPC expression and the elevation of [Ca 21 ] i in PASMCs. We found that the treatment of BMP4 led to the activation of both p38 MAPK and ERK1/2 in rat distal PASMCs. The induction of TRPC1, TRPC4, and TRPC6 expression, and the increases of [Ca 21 ] i caused by BMP4 in distal PASMCs, were inhibited by treatment with either SB203580 (10 mM), the selective inhibitor for p38 activation, or the specific p38 small interfering RNA (siRNA). Similarly, those responses induced by BMP4 were also abolished by treatment with PD98059 (5 mM), the selective inhibitor of ERK1/2, or by the knockdown of ERK1/2 using its specific siRNA. These results indicate that BMP4 participates in the regulation of Ca 21 signaling in PASMCs by modulating TRPC channel expression via activating p38 and ERK1/2 MAPK pathways. [Ca 21 ] i in PASMCs during chronic hypoxia, and relaxed arteries in chronically hypoxic rats (5). Store-operated calcium channels (SOCCs) are believed to be composed of members of transient receptor potential canonical (TRPC) family, which assemble as either homotetramer or heterotetramer channels and mediate store-operated calcium entry (SOCE) (6). We recently demonstrated the predominant expression of TRPC1, TRPC4, and TRPC6, and the presence of SOCE in PASMCs (7). Exposure to chronic hypoxia enhanced the expressions of TRPC1, TRPC6, and SOCE in rat distal PASMCs (1, 2). Using a specific small interfering (si)RNA individually targeted to TRPC1 and TRPC6, we found they both contributed to the hypoxic enhancement of SOCE and the maintenance of elevated basal [Ca 21 ] i in PASMCs (8). These studies provided fundamental information indicating that the elevation of basal [Ca 21 ] i in PASMCs during chronic hypoxia are in large part caused by enhanced SOCE via the up-regulation of TRPC proteins.Bone morphogenetic protein (BMP) family members comprise multifunctional cytokines that play crucial roles during embryonic development, organogenesis, and adult tissue remodeling by regulating cell proliferation, growth, differentiation, and apoptosis (9). BMP4,...

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“…pulmonary hypertension MANY CHRONIC LUNG DISEASES cause prolonged alveolar hypoxia, resulting in the development of pulmonary hypertension. The elevation in pulmonary arterial pressure is due to both active contraction of vascular smooth muscle and structural remodeling (21,24,36,38). Pulmonary vascular remodeling in response to chronic hypoxia has been well characterized and includes pulmonary arterial smooth muscle cell (PASMC) hypertrophy and hyperplasia, intimal thickening, and extension of smooth muscle into previously nonmuscular arterioles (21, 36).…”

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confidence: 99%

Chronic hypoxia elevates intracellular pH and activates Na⁺/H⁺exchange in pulmonary arterial smooth muscle cells

Rios¹,

Fallon²,

Wang³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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116

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(CH), caused by many lung diseases, results in pulmonary hypertension due, in part, to increased muscularity of small pulmonary vessels. Pulmonary arterial smooth muscle cell (PASMC) proliferation in response to growth factors requires increased intracellular pH (pH i) mediated by activation of Na ϩ /H ϩ exchange (NHE); however, the effect of CH on PASMC pH i homeostasis is unknown. Thus we measured basal pH i and NHE activity and expression in PASMCs isolated from mice exposed to normoxia or CH (3 wk/10% O 2). pHi was measured using the pH-sensitive fluorescent dye BCECF-AM. NHE activity was determined from Na ϩ -dependent recovery from NH 4-induced acidosis, and NHE expression was determined by RT-PCR and immunoblot. PASMCs from chronically hypoxic mice exhibited elevated basal pH i and increased NHE activity. NHE1 was the predominate isoform present in mouse PASMCs, and both gene and protein expression of NHE1 was increased following exposure to CH. Our findings indicate that exposure to CH caused increased pH i, NHE activity, and NHE1 expression, changes that may contribute to the development of pulmonary hypertension, in part, via pH-dependent induction of PASMC proliferation. pulmonary hypertension MANY CHRONIC LUNG DISEASES cause prolonged alveolar hypoxia, resulting in the development of pulmonary hypertension. The elevation in pulmonary arterial pressure is due to both active contraction of vascular smooth muscle and structural remodeling (21,24,36,38). Pulmonary vascular remodeling in response to chronic hypoxia has been well characterized and includes pulmonary arterial smooth muscle cell (PASMC) hypertrophy and hyperplasia, intimal thickening, and extension of smooth muscle into previously nonmuscular arterioles (21, 36). The exact cellular mechanisms governing hypoxia-induced PASMC growth are not completely known; however, changes in intracellular pH (pH i ) have been demonstrated to be required for cell growth and/or proliferation in pulmonary (33) and systemic tissue (6,17,22), suggesting a possible pivotal role for H ϩ homeostasis in mediating this response.

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L-type Ca²⁺channels, resting [Ca²⁺]_i, and ET-1-induced responses in chronically hypoxic pulmonary myocytes

Cited by 131 publications

References 47 publications

NFATc3 Mediates Chronic Hypoxia-induced Pulmonary Arterial Remodeling with α-Actin Up-regulation

NFATc3 Mediates Chronic Hypoxia-induced Pulmonary Arterial Remodeling with α-Actin Up-regulation

BMP4 Increases Canonical Transient Receptor Potential Protein Expression by Activating p38 MAPK and ERK1/2 Signaling Pathways in Pulmonary Arterial Smooth Muscle Cells

Chronic hypoxia elevates intracellular pH and activates Na⁺/H⁺exchange in pulmonary arterial smooth muscle cells

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L-type Ca2+channels, resting [Ca2+]i, and ET-1-induced responses in chronically hypoxic pulmonary myocytes

Cited by 131 publications

References 47 publications

NFATc3 Mediates Chronic Hypoxia-induced Pulmonary Arterial Remodeling with α-Actin Up-regulation

NFATc3 Mediates Chronic Hypoxia-induced Pulmonary Arterial Remodeling with α-Actin Up-regulation

BMP4 Increases Canonical Transient Receptor Potential Protein Expression by Activating p38 MAPK and ERK1/2 Signaling Pathways in Pulmonary Arterial Smooth Muscle Cells

Chronic hypoxia elevates intracellular pH and activates Na+/H+exchange in pulmonary arterial smooth muscle cells

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L-type Ca²⁺channels, resting [Ca²⁺]_i, and ET-1-induced responses in chronically hypoxic pulmonary myocytes

Chronic hypoxia elevates intracellular pH and activates Na⁺/H⁺exchange in pulmonary arterial smooth muscle cells