Diversity of voltage-dependent K+ channels in human pulmonary artery smooth muscle cells

Electrical excitability, which plays an important role in excitation-contraction coupling in the pulmonary vasculature, is regulated by transmembrane ion flux in pulmonary artery smooth muscle cells (PASMC). This study examined the heterogeneous nature of native voltage-dependent K+ channels in human PASMC. Both voltage-gated K+ (KV) currents and Ca2+-activated K+ (KCa) currents were observed and characterized. In cell-attached patches of PASMC bathed in Ca2+-containing solutions, depolarization elicited a wide range of K+ unitary conductances (6–290 pS). When cells were dialyzed with Ca2+-free and K+-containing solutions, depolarization elicited four components of KV currents in PASMC based on the kinetics of current activation and inactivation. Using RT-PCR, we detected transcripts of 1) 22 KV channel α-subunits (KV1.1–1.7, KV1.10, KV2.1, KV3.1, KV3.3–3.4, KV4.1–4.2, KV5.1, KV 6.1–6.3, KV9.1, KV9.3, KV10.1, and KV11.1), 2) three KV channel β-subunits (KVβ1–3), 3) four KCa channel α-subunits ( Slo-α1 and SK2–SK4), and 4) four KCa channel β-subunits (KCaβ1–4). Our results show that human PASMC exhibit a variety of voltage-dependent K+ currents with variable kinetics and conductances, which may result from various unique combinations of α- and β-subunits forming the native channels. Functional expression of these channels plays a critical role in the regulation of membrane potential, cytoplasmic Ca2+, and pulmonary vasomotor tone.

Download Full-text

Functional Ion Channels in Human Pulmonary Artery Smooth Muscle Cells: Voltage-Dependent Cation Channels

Pulmonary Circulation ◽

10.4103/2045-8932.78103 ◽

2011 ◽

Vol 1 (1) ◽

pp. 48-71 ◽

Cited By ~ 53

Author(s):

Amy L. Firth ◽

Carmelle V. Remillard ◽

Oleksandr Platoshyn ◽

Ivana Fantozzi ◽

Eun A. Ko ◽

...

Keyword(s):

Smooth Muscle ◽

Ion Channels ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Cation Channels ◽

Voltage Dependent ◽

Pulmonary Artery Smooth Muscle ◽

Human Pulmonary Artery

Download Full-text

Differential effects of TGF-β1 and BMP-4 on the hypoxic induction of cyclooxygenase-2 in human pulmonary artery smooth muscle cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00012.2004 ◽

2004 ◽

Vol 287 (5) ◽

pp. L919-L927 ◽

Cited By ~ 28

Author(s):

Karen K. K. Sheares ◽

Trina K. Jeffery ◽

Lu Long ◽

Xudong Yang ◽

Nicholas W. Morrell

Keyword(s):

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Critical Role ◽

Muscle Cells ◽

Cyclooxygenase 2 ◽

Hypoxic Induction ◽

Pulmonary Artery Smooth Muscle ◽

Cox 2 ◽

Tgf Β1

Chronic hypoxia-induced pulmonary hypertension results partly from proliferation of smooth muscle cells in small peripheral pulmonary arteries. Previously, we demonstrated that hypoxia modulates the proliferation of human peripheral pulmonary artery smooth muscle cells (PASMCs) by induction of cyclooxygenase-2 (COX-2) and production of antiproliferative prostaglandins ( 55 ). The transforming growth factor (TGF)-β superfamily plays a critical role in the regulation of pulmonary vascular remodeling, although to date an interaction with hypoxia has not been examined. We therefore investigated the pathways involved in the hypoxic induction of COX-2 in peripheral PASMCs and the contribution of TGF-β1 and bone morphogenetic protein (BMP)-4 in this response. In the present study, we demonstrate that hypoxia induces activation of p38MAPK, ERK1/2, and Akt in PASMCs and that these pathways are involved in the hypoxic regulation of COX-2. Whereas inhibition of p38MAPK or ERK1/2 activity suppressed hypoxic induction of COX-2, inhibition of the phosphoinositide 3-kinase pathway enhanced hypoxic induction of COX-2. Furthermore, exogenous TGF-β1 induced COX-2 mRNA and protein expression, and our findings demonstrate that release of TGF-β1 by PASMCs during hypoxia contributes to the hypoxic induction of COX-2 via the p38MAPK pathway. In contrast, BMP-4 inhibited the hypoxic induction of COX-2 by an MAPK-independent pathway. Together, these findings suggest that the TGF-β superfamily is part of an autocrine/paracrine system involved in the regulation of COX-2 expression in the distal pulmonary circulation, and this modulates hypoxia-induced pulmonary vascular cell proliferation.

Download Full-text

Regulation and function of Cav3.1 T-type calcium channels in IGF-I-stimulated pulmonary artery smooth muscle cells

AJP Cell Physiology ◽

10.1152/ajpcell.00107.2010 ◽

2011 ◽

Vol 300 (3) ◽

pp. C517-C525 ◽

Cited By ~ 21

Author(s):

Florentina Pluteanu ◽

Leanne L. Cribbs

Keyword(s):

Cell Cycle ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Low Voltage ◽

Muscle Cells ◽

Pulmonary Vasculature ◽

Igf I ◽

Intracellular Ca ◽

Pulmonary Artery Smooth Muscle

Arterial smooth muscle cells enter the cell cycle and proliferate in conditions of disease and injury, leading to adverse vessel remodeling. In the pulmonary vasculature, diverse stimuli cause proliferation of pulmonary artery smooth muscle cells (PASMCs), pulmonary artery remodeling, and the clinical condition of pulmonary hypertension associated with significant health consequences. PASMC proliferation requires extracellular Ca2+ influx that is intimately linked with intracellular Ca2+ homeostasis. Among the primary sources of Ca2+ influx in PASMCs is the low-voltage-activated family of T-type Ca2+ channels; however, up to now, mechanisms for the action of T-type channels in vascular smooth muscle cell proliferation have not been addressed. The Cav3.1 T-type Ca2+ channel mRNA is upregulated in cultured PASMCs stimulated to proliferate with insulin-like growth factor-I (IGF-I), and this upregulation depends on phosphatidylinositol 3-kinase/Akt signaling. Multiple stimuli that trigger an acute rise in intracellular Ca2+ in PASMCs, including IGF-I, also require the expression of Cav3.1 Ca2+ channels for their action. IGF-I also led to cell cycle initiation and proliferation of PASMCs, and, when expression of the Cav3.1 Ca2+ channel was knocked down by RNA interference, so were the expression and activation of cyclin D, which are necessary steps for cell cycle progression. These results confirm the importance of T-type Ca2+ channels in proper progression of the cell cycle in PASMCs stimulated to proliferate by IGF-I and suggest that Ca2+ entry through Cav3.1 T-type channels in particular interacts with Ca2+-dependent steps of the mitogenic signaling cascade as a central component of vascular remodeling in disease.

Download Full-text