Ion channels as convergence points in the pathology of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a fatal disease of the cardiopulmonary system that lacks curative treatments. The main pathological event in PAH is elevated vascular resistance in the pulmonary circulation, caused by abnormal vasoconstriction and vascular remodelling. Ion channels are key determinants of vascular smooth muscle tone and homeostasis, and four PAH channelopathies (KCNK3, ABCC8, KCNA5, TRPC6) have been identified so far. However, the contribution of ion channels in other forms of PAH, which account for the majority of PAH patients, has been less well characterised. Here we reason that a variety of triggers of PAH (e.g. BMPR2 mutations, hypoxia, anorectic drugs) that impact channel function may contribute to the onset of the disease. We review the molecular mechanisms by which these ‘extrinsic’ factors converge on ion channels and provoke their dysregulation to promote the development of PAH. Ion channels of the pulmonary vasculature are therefore promising therapeutic targets because of the modulation they provide to both vasomotor tone and proliferation of arterial smooth muscle cells.

Metabolic Deregulation in Pulmonary Hypertension

“…Several recent reports (e.g., [ 45 , 46 , 47 , 48 ]) discuss the roles played by ionic channels and mitochondrial membrane potential controllers in vascular muscle tone and homeostasis. Figure 8 presents the regulations and the WIR contributions to the lung transcriptomic alteration of nine key genes.…”

“…Several recent reports (e.g., [45][46][47][48]) discuss the roles played by ionic channels and mitochondrial membrane potential controllers in vascular muscle tone and homeostasis. Note that hypoxia, either with or without monocrotaline treatment, significantly decoupled the expression coordination of these genes.…”

Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension

“…PAH pathophysiology is complex with multiple genetic and environmental factors being related to the disease. It is interesting to note that many of these triggers converge in ion channels, including Kv1.5 (6,7,46). For instance, Kv1.5 channel expression, trafficking, or activity can be modulated by several proteins encoded by genes already associated with PAH such as BMPR2 (31), CAV1 (9, 47), and NOTCH3 (48).…”

Role of Ion Channel Remodeling in Endothelial Dysfunction Induced by Pulmonary Arterial Hypertension

“…A passive flux of ions across the plasma membrane along the electrochemical gradient is controlled by the activity of ion channels. They are classified into two major classes: the cation channels, which comprise Na + , Ca 2+ , and K + channels, and the anion channels, which contain Cl − and bicarbonate channels [4,5].…”

“…Despite availability of effective current therapies, no cure exists for PAH, and lung transplantation remains the last therapy possibility for suitable PAH patients, with a 29% survival rate at 10 years post-transplantation [2]. Consequently, it is essential to clarify the distribution and mechanism of ions and their corresponding ion channels in PAH to potentially develop more effective drugs for the treatment of PAH [5]. Indeed, the identification of heterozygous loss-of-function mutations in the KCNK3 (potassium two pore domain channel subfamily K member 3) gene that encodes the tandem of P domains in weak inward rectifier K + channels (TWIK)-related acid-sensitive potassium channel 1 (TASK1) and loss-of-function mutation in the ABCC8 (coding for adenosine triphosphate (ATP)sensitive potassium channel subunit) as a cause for PAH, has revived interest in the concept of channelopathy [6].…”