Pathogenic role of ion channels in pulmonary arterial hypertension

Experimental Physiology is a leading promoter of international research into fundamental homeostatic and adaptive responses in health and pathophysiological mechanisms in diseases. As such, Experimental Physiology sponsored a symposium, entitled Role of Ion Channels in Pulmonary Arterial Hypertension, at the 2016 International Conference of Physiological Sciences, 25–28 September 2016, in Beijing. The goals of the symposium were as follows: (i) to increase awareness of evidence-based recommendations for pulmonary hypertension treatment; (ii) to identify strategies and targets of treatment pathways; and (iii) to promote collaboration between national and international consortia, vascular disease-related organizations and pulmonary vascular disease professionals, physicians and pathophysiologists, in order to study the underlying pathogenic roles of ion channels in pulmonary arterial hypertension (PAH). Pulmonary arterial hypertension is a progressive and fatal disease, with an estimated median survival rate of only 2.8 years, with 1, 3 and 5 year survival rates of 68, 48 and 34%, respectively. Without treatment, the elevated pulmonary vascular resistance and pulmonary arterial pressure in PAH increase the afterload to the right ventricle, which can progress to right heart failure and death (Tang et al. 2016a). The primary causes of elevated pulmonary vascular resistance in patients with PAH are fourfold, namely sustained pulmonary vasoconstriction, pulmonary vascular remodelling, in situ thrombosis and increased pulmonary vascular wall stiffness. Important signalling mechanisms of bone morphogenic proteins in the development of vascular remodelling and PAH have recently been reviewed by Lu and colleagues and include advances and therapeutic implications (Yang et al. 2017). Despite significant progress in research, the exact pathogenic mechanisms responsible for PAH remain uncertain. Ion channels are macromolecular pore-forming proteins in the plasma membrane. By allowing passive movement of ions across the membranes between intracellular compartments, ion channels drive crucial physiological functions of healthy vasculature. Clear correlations have been identified between ion channel dysfunctions and elevated pulmonary vascular resistance and pulmonary arterial pressure in PAH patients. Pulmonary artery smooth muscle cells (PASMCs) from patients with PAH exhibit attenuated K+ channel function. An increased concentration of cytosolic free Ca2+ ([Ca2+]i) in PASMCs is a major trigger for pulmonary vasoconstriction and a crucial stimulus for PASMC proliferation and migration. Pulmonary artery smooth muscle cells isolated from animal models of pulmonary hypertension and from patients with PAH display an abnormal depolarized resting membrane potential and elevated [Ca2+]i, caused by attenuated expression of K+ channels. Decreased expression and function of these K+ channels, including Kv1.2, Kv1.5 and Kv2.1 channels, lead to increased cytosolic Ca2+ influx, which is instrumental in pulmonary vasoconstriction and stimulates PASMC proliferation and migration (Wang et al. 2006). Tang et al. (2016b) presented a systematic review of evidence documenting that the calcium-sensing receptor (CaSR) plays crucial roles in the development and progression of pulmonary hypertension. As a member of the class C family of G-protein-coupled receptors, CaSR mediates activation of downstream signalling, which increases the intracellular Ca2+ concentration, Ca2+ sensitivity and cell contraction and promotes cell proliferation. Elevated [Ca2+]i in PASMCs is a primary trigger for pulmonary vasoconstriction and a key stimulus for PASMC proliferation. Application of extracellular Ca2+ increased [Ca2+]i in PASMCs isolated from idiopathic pulmonary arterial hypertension (IPAH) patients compared with PASMCs from control patients as a result of increased expression of CaSR in PASMCs and lung tissues. The increased [Ca2+]i results from Ca2+ release from intracellular stores and Ca2+ influx through receptor-operated Ca2+ channels and store-operated Ca2+ channels. Given that transient receptor potential canonical (TRPC) channels have been shown to function as both receptor-operated Ca2+ channels and store-operated Ca2+ channels in PASMCs, the elevated CaSR expression might functionally couple with TRPC6 channels in PASMCs in IPAH patients to play an important role in the development and progression of pulmonary vascular remodelling and pulmonary hypertension. Zeng et al. (2017) first demonstrated that mitochondrial H2O2-sensitized CaSRs, activated by extracellular Ca2+, mediate an increase of hypoxia-induced Ca2+ entry and initiates hypoxic pulmonary vasoconstriction. Monocrotaline enhanced the assembly of CaSRs, triggered the mobilization of calcium signalling, damaged pulmonary artery endothelial cells and induced pulmonary hypertension (in rat studies). Recent research demonstrated that hypoxia-induced mitogenic factor contributes to the development of pulmonary hypertension by binding with the intracellular domain of the CaSR. Pharmacological blockade or targeted deletion of the CaSR has been shown to inhibit the CaSR-mediated increase [Ca2+]i and significantly attenuate the development of pulmonary hypertension (in experimental animal models). Thus, pharmacological targets of CaSR might reveal new therapeutic strategies to control the aberrant Ca2+ signalling observed in PAH patients. Huetsch and Shimoda (2015) reported that sodium–hydrogen exchange is an important contributor to pHi control in PASMCs. Sodium–hydrogen exchange activity was increased in PASMCs isolated from hypoxia/Sugen 5416 (Hyp+Su) rats and in cultured PASMCs derived from human subjects with IPAH, compared with controls. This increased sodium–hydrogen exchange activity might contribute to pathological PASMC function in PAH and might be involved in the development of PAH, although its effect does not appear to be mediated by global changes in pHi homeostasis. Ward reported that reactive oxygen species (ROS), as physiological second messengers, play a potentially important physiological role in regulating Ca2+ entry into vascular smooth muscle, facilitated by a serendipitous finding concerning the sphingolipid sphingosylphosphorylcholine (Ward, 2017). It is not surprising that ROS signalling, like that for Ca2+, should be compartmentalized in physiological conditions. However, ROS signalling may be compromised by pathological increases in oxidant production in pulmonary hypertension, leading to promiscuous actions that contribute to the aetiology (Ward, 2017). These studies suggest that an unconstrained elevation in ROS would strongly affect ion channel function and potentiate G-protein-coupled receptor- and depolarization-induced Ca2+ entry, contributing to the enhanced pulmonary vasoconstriction and pulmonary vascular remodelling. In conclusion, dysregulated expression and dysfunctional activity of ion channels initiate pathogenic triggers, including sustained pulmonary vasoconstriction and excessive pulmonary vascular remodelling, and increased cellular proliferation and decreased cellular apoptosis, both key contributors to the development and progression of PAH. Therefore, the roles of ion channels in PAH strongly merit continued research, both in the effort to determine precisely the physiological pathogenesis of pulmonary vascular remodelling and to develop ion channel targets as potential pathways for treatment of PAH. None declared. The views expressed here do not necessarily reflect the views of the presenters in the symposium. We would like to acknowledge our colleagues across all of the partnering organizations for their many contributions to the conference and for helping to produce and disseminate the symposium findings.