Our systematic analysis of anion channels and transporters in idiopathic pulmonary arterial hypertension (IPAH) showed marked upregulation of the Cl⁻channel TMEM16A gene. We hypothesised that TMEM16A overexpression might represent a novel vicious circle in the molecular pathways causing pulmonary arterial hypertension (PAH).We investigated healthy donor lungs (n=40) and recipient lungs with IPAH (n=38) for the expression of anion channel and transporter genes in small pulmonary arteries and pulmonary artery smooth muscle cells (PASMCs).In IPAH, TMEM16A was strongly upregulated and patch-clamp recordings confirmed an increased Cl⁻current in PASMCs (n=9–10). These cells were depolarised and could be repolarised by TMEM16A inhibitors or knock-down experiments (n=6–10). Inhibition/knock-down of TMEM16A reduced the proliferation of IPAH-PASMCs (n=6). Conversely, overexpression of TMEM16A in healthy donor PASMCs produced an IPAH-like phenotype. Chronic application of benzbromarone in two independent animal models significantly decreased right ventricular pressure and reversed remodelling of established pulmonary hypertension.Our findings suggest that increased TMEM16A expression and activity comprise an important pathologic mechanism underlying the vasoconstriction and remodelling of pulmonary arteries in PAH. Inhibition of TMEM16A represents a novel therapeutic approach to reverse remodelling in PAH.

TWIK-related acid-sensitive potassium channel 1 (TASK-1 encoded by KCNK3) belongs to the family of two-pore domain potassium channels. This gene subfamily is constitutively active at physiological resting membrane potentials in excitable cells, including smooth muscle cells, and has been particularly linked to the human pulmonary circulation. TASK-1 channels are sensitive to a wide array of physiological and pharmacological mediators that affect their activity such as unsaturated fatty acids, extracellular pH, hypoxia, anaesthetics and intracellular signalling pathways. Recent studies show that modulation of TASK-1 channels, either directly or indirectly by targeting their regulatory mechanisms, has the potential to control pulmonary arterial tone in humans. Furthermore, mutations in KCNK3 have been identified as a rare cause of both familial and idiopathic pulmonary arterial hypertension. This review summarises our current state of knowledge of the functional role of TASK-1 channels in the pulmonary circulation in health and disease, with special emphasis on current advancements in the field.

The tryptophan metabolite kynurenine is significantly increased in pulmonary arterial hypertension (PAH) patients, and it is a potent vasodilator of systemic arteries. Our aim was to investigate the role of kynurenine in the pulmonary circulation. Serum tryptophan, kynurenine, and kynurenic acid levels were measured in 20 idiopathic PAH (IPAH) patients, 20 healthy controls, and 20 patients with chronic lung disease or metabolic syndrome without PH. Laser-dissected pulmonary arteries from IPAH and control lungs were tested for the expression of indoleamine-2, 3-dioxygenase (IDO), the rate-limiting enzyme for the conversion from tryptophan to kynurenine. Acute effects of kynurenine were tested in pulmonary vascular preparations, two different models of chronic pulmonary hypertension (PH), and in human pulmonary arterial smooth muscle cells (hPASMCs). In IPAH vs. control serum, kynurenine was significantly elevated (3.6 ± 0.2 vs. 2.6 ± 0.1 µM, P < 0.0001), and strongly associated with PH (area under the curve = 0.86), but kynurenine levels were not elevated in lung disease and metabolic syndrome. Among all investigated tryptophan metabolites, kynurenine displayed the strongest correlation with mean pulmonary arterial pressure (mPAP) (ρ: 0.770, P < 0.0001). Tryptophan was significantly decreased in IPAH lungs; however, IDO expression was not changed. In hPASMCs, kynurenine increased both cAMP and cGMP; in intrapulmonary arteries, it relaxed the preconstriction via NO/cGMP and cAMP pathways, and in two models of established PH, it acutely decreased the mPAP. Our data suggest that kynurenine elevation might be specifically associated with mPAP; kynurenine acts on hPASMCs in synergy with NO and exerts acute pulmonary vasodilatation in chronic PH models. Kynurenine might provide both a new biomarker and a new therapeutic option for PH.

The bleomycin mouse model is the extensively used model to study pulmonary fibrosis; however, the inflammatory cell kinetics and their compartmentalization is still incompletely understood. Here we assembled historical flow cytometry data, totaling 303 samples and 16 inflammatory-cell populations, and applied advanced data modeling and machine learning methods to conclusively detail these kinetics.

Cardioprotective benefits of ω-3 fatty acids such as docosahexaenoic acid (DHA) are well established, but the regulatory effect of DHA on vascular tone and pressure in pulmonary hypertension is largely unknown.As DHA is a potent regulator of K⁺channels, we hypothesised that DHA modulates the membrane potential of pulmonary artery smooth muscle cells (PASMCs) through K⁺channels and thus exerts its effects on pulmonary vascular tone and pressure.We show that DHA caused dose-dependent activation of the calcium-activated K⁺(KCa) current in primary human PASMCs and endothelium-dependent relaxation of pulmonary arteries. This vasodilation was significantly diminished in KCa^–/–(Kcnma1^–/–) mice.In vivo, acute DHA returned the right ventricular systolic pressure in the chronic hypoxia-induced pulmonary hypertension animal model to the level of normoxic animals. Interestingly, in idiopathic pulmonary arterial hypertension the KCa channels and their subunits were upregulated. DHA activated KCa channels in these human PASMCs and hyperpolarised the membrane potential of the idiopathic pulmonary arterial hypertension PASMCs to that of the PASMCs from healthy donors.Our findings indicate that DHA activates PASMC KCa channels leading to vasorelaxation in pulmonary hypertension. This effect might provide a molecular explanation for the previously undescribed role of DHA as an acute vasodilator in pulmonary hypertension.

Rationale: Remodeling and fibrosis of the right ventricle (RV) may cause RV dysfunction and poor survival in patients with pulmonary hypertension. Objectives: To investigate the consequences of RV fibrosis modulation and the accompanying cellular changes on RV function. Methods: Expression of fibrotic markers was assessed in the RV of patients with pulmonary hypertension, the murine pulmonary artery banding, and rat monocrotaline and Sugen5416/hypoxia models. Invasive hemodynamic and echocardiographic assessment was performed on galectin-3 knockout or inhibitor-treated mice. Measurements and Main Results: Established fibrosis was characterized by marked expression of galectin-3 and an enhanced number of proliferating RV fibroblasts. Galectin-3 genetic and pharmacologic inhibition or antifibrotic treatment with pirfenidone significantly diminished RV fibrosis progression in the pulmonary artery banding model, without improving RV functional parameters. RV fibrotic regions were populated with mesenchymal cells coexpressing vimentin and PDGFRα (platelet-derived growth factor receptor-α), but generally lacked αSMA (α-smooth muscle actin) positivity. Serum levels of galectin-3 were increased in patients with idiopathic pulmonary arterial hypertension but did not correlate with cardiac function. No changes of galectin-3 expression were observed in the lungs. Conclusions: We identified extrapulmonary galectin-3 as an important mediator that drives RV fibrosis in pulmonary hypertension through the expansion of PDGFRα/vimentin-expressing cardiac fibroblasts. However, interventions effectively targeting fibrosis lack significant beneficial effects on RV function.