Low-Voltage-Activated (T-Type) Calcium Channels Control Proliferation of Human Pulmonary Artery Myocytes

Rodman, David M.; Reese, K.A.; Harral, Julie W.; Fouty, Brian; Wu, Songwei; West, James; Hoedt-Miller, Marloes; Tada, Yuji; Li, Kai-Xun; Cool, Carlyne D.; Fagan, Karen A.; Cribbs, Leanne L.

doi:10.1161/01.res.0000163066.07472.ff

Cited by 117 publications

(102 citation statements)

References 24 publications

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“…Interestingly, this study also demonstrated that expression of cystathionine -lyase (CSE), the major vascular enzyme producing H2S, was inhibited by balloon injury, a finding in agreement with its down-regulation in hypertension [37]. Since (a) the expression of T-type Ca 2+ channels increases in VSMC proliferation [25; 26], (b) they are a prerequisite for VSMC proliferation and neointima formation following vascular injury [26][27][28][29][30] and (c) we have recently demonstrated that H2S regulates the activity of the T-type Ca 2+ channel Cav3.2 [33], the present study was conducted in order to investigate whether the inhibitory effects of H2S on proliferation might be mediated via T-type Ca 2+ channel inhibition. Our investigation was prompted not only by the importance of H2S and T-type Ca 2+ channels in VSMC proliferation, but also by the fact that CO, another gasotransmitter known to inhibit VSMC proliferation, appears to act in this way via inhibition of Ttype Ca 2+ channels [5].…”

Section: Resultssupporting

confidence: 68%

“…The relative importance of different Ca 2+ influx pathways contributing to proliferation are currently under investigation but there is compelling evidence for the involvement of voltage-gated T-type Ca 2+ channels: in VSMCs, T-type Ca 2+ channel expression increases during proliferation [25; 26], and they are required for VSMC proliferation both in vitro and in neointima formation observed following vascular injury [26][27][28][29][30]. In numerous forms of cancer high expression of T-type Ca 2+ channels has been observed and, as in VSMCs, their expression supports proliferation [31].…”

Section: Introductionmentioning

confidence: 99%

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H2S does not regulate proliferation via T-type Ca2+ channels

Elíes

Johnson

Boyle

et al. 2015

Biochemical and Biophysical Research Communications

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T-type Ca 2+ channels (Cav3.1, 3.2 and 3.3) strongly influence proliferation of various cell types, including vascular smooth muscle cells (VSMCs) and certain cancers. We have recently shown that the gasotransmitter carbon monoxide (CO) inhibits T-type Ca 2+ channels and, in so doing, attenuates proliferation of VSMC. We have also shown that the T-type Ca 2+ channel Cav3.2 is selectively inhibited by hydrogen sulfide (H2S) whilst the other channel isoforms (Cav3.1 and Cav3.3) are unaffected. Here, we explored whether inhibition of Cav3.2 by H2S could account for the anti-proliferative effects of this gasotransmitter. H2S suppressed proliferation in HEK293 cells expressing Cav3.2, as predicted by our previous observations. However, H2S was similarly effective in suppressing proliferation in wild type (non-transfected) HEK293 cells and those expressing the H2S insensitive channel, Cav3.1. Further studies demonstrated that T-type Ca 2+ channels in the smooth muscle cell line A7r5 and in human coronary VSMCs strongly influenced proliferation. In both cell types, H2S caused a concentration-dependent inhibition of proliferation, yet by far the dominant T-type Ca 2+ channel isoform was the H2S-insensitive channel, Cav3.1.Our data indicate that inhibition of T-type Ca 2+ channel-mediated proliferation by H2S is independent of the channels' sensitivity to H2S.

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Section: Resultssupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

H2S does not regulate proliferation via T-type Ca2+ channels

Elíes

Johnson

Boyle

et al. 2015

Biochemical and Biophysical Research Communications

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“…59 Increased [Ca 2+ ] i is required for PASMC growth 60,61 and migration 55 and has been documented in cells from hypoxic animals. 42 VGCCs contribute to stimulated proliferation 62 63 ). In particular, Ca 2+ activates nuclear factor of activated T cells (NFAT), which reduces K + channel expression, 64 providing a link between alterations in [Ca 2+ ] i , dysregulated K + channel expression/activity, and PASMC growth.…”

Section: Mechanisms Of Hph: Lessons From Animal Modelsmentioning

confidence: 99%

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

2016

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Pulmonary blood vessel structure and tone are maintained by a complex interplay between endogenous vasoactive factors and oxygen-sensing intermediaries. Under physiological conditions, these signaling networks function as an adaptive interface between the pulmonary circulation and environmental or acquired perturbations to preserve oxygenation and maintain systemic delivery of oxygen-rich hemoglobin. Chronic exposure to hypoxia, however, triggers a range of pathogenetic mechanisms that include hypoxia-inducible factor 1α (HIF-1α)-dependent upregulation of the vasoconstrictor peptide endothelin 1 in pulmonary endothelial cells. In pulmonary arterial smooth muscle cells, chronic hypoxia induces HIF-1α-mediated upregulation of canonical transient receptor potential proteins, as well as increased Rho kinase-Ca 2+ signaling and pulmonary arteriole synthesis of the profibrotic hormone aldosterone. Collectively, these mechanisms contribute to a contractile or hypertrophic pulmonary vascular phenotype. Genetically inherited disorders in hemoglobin structure are also an important etiology of abnormal pulmonary vasoreactivity. In sickle cell anemia, for example, consumption of the vasodilator and antimitogenic molecule nitric oxide by cell-free hemoglobin is an important mechanism underpinning pulmonary hypertension. Contemporary genomic and transcriptomic analytic methods have also allowed for the discovery of novel risk factors relevant to sickle cell disease, including GALNT13 gene variants. In this report, we review cutting-edge observations characterizing these and other pathobiological mechanisms that contribute to pulmonary vascular and right ventricular vulnerability.Keywords: hypoxia, pulmonary hypertension, genetics. In the autumn of 2015 at the Lost Valley Ranch in Sedalia, Colorado, the 34th Grover Conference, on pulmonary circulation in the "omics" era, convened for a 4-day symposium to discuss contemporary scientific concepts in the genetics, genomics, proteomics, and epigenetics of pulmonary vascular diseases. This biannual meeting, sponsored by the American Thoracic Society and co-led this year by Drs. C. Gregory Elliot, Wendy K. Chung, D. Hunter Best, and Eric D. Austin, commemorates the perpetual and transformative scientific contributions of Dr. Robert Grover 1 to the fields of high-altitude medicine and pulmonary vascular disease. This review is part of an ongoing Pulmonary Circulation thematic series that aims to provide a synopsis of key concepts presented at this year's Grover Conference.Here, we summarize the discussions that constituted a section of the conference emphasizing novel genetic and molecular mechanisms underpinning "pulmonary vascular and ventricular dysfunction in the susceptible patient." To accomplish this, three concepts are reviewed in detail: the functional relevance of chronic hypoxia (CH), discovered through genomic analyses; novel molecular mechanisms and phenotypic signatures of pulmonary vascular disease in sickle cell disease; and hormonal regulation of vascular f...

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“…The pathways controlling the activation of these differentiation markers are dependent on the RhoA-Rho kinase (ROK) cascade [146], providing a novel signaling cascade in which physiological signals that couple excitation to contraction also contribute to transcriptional regulation of VSMC differentiation marker genes. The function of the T-type Ca 2+ channel (named for their transient currents) has not been fully established, though several studies suggested their involvement in potentiating smooth muscle cell proliferation [34,118,119].…”

Section: Loss Of L-type and Gain Of T-type Voltage Gated Ca 2+ 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

215

202

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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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Low-Voltage-Activated (T-Type) Calcium Channels Control Proliferation of Human Pulmonary Artery Myocytes

Abstract: Abstract-While Ca 2ϩ influx is essential for activation of the cell cycle machinery, the processes that regulate Ca 2ϩ influx in this context have not been fully elucidated. Electrophysiological and molecular studies have identified multiple Ca 2ϩ

Cited by 117 publications

References 24 publications

H2S does not regulate proliferation via T-type Ca2+ channels

H2S does not regulate proliferation via T-type Ca2+ channels

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

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

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