An Overview of miRNAs Involved in PASMC Phenotypic Switching in Pulmonary Hypertension

Pulmonary hypertension (PH) is occult, with no distinctive clinical manifestations and a poor prognosis. Pulmonary vascular remodelling is an important pathological feature in which pulmonary artery smooth muscle cells (PASMCs) phenotypic switching plays a crucial role. MicroRNAs (miRNAs) are a class of evolutionarily highly conserved single-stranded small noncoding RNAs. An increasing number of studies have shown that miRNAs play an important role in the occurrence and development of PH by regulating PASMCs phenotypic switching, which is expected to be a potential target for the prevention and treatment of PH. miRNAs such as miR-221, miR-15b, miR-96, miR-24, miR-23a, miR-9, miR-214, and miR-20a can promote PASMCs phenotypic switching, while such as miR-21, miR-132, miR-449, miR-206, miR-124, miR-30c, miR-140, and the miR-17~92 cluster can inhibit it. The article reviews the research progress on growth factor-related miRNAs and hypoxia-related miRNAs that mediate PASMCs phenotypic switching in PH.

Myeloid cell-specific deletion of inducible nitric oxide synthase protects against smoke-induced pulmonary hypertension in mice

Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), associated with increased mortality and morbidity. Intriguingly, pulmonary vascular alterations have been suggested to drive emphysema development. We previously identified inducible nitric oxide synthase (iNOS) as an essential enzyme for development and reversal of smoke-induced PH and emphysema, and showed that iNOS expression in bone-marrow-derived cells drives pulmonary vascular remodelling, but not parenchymal destruction. In this study, we aimed to identify the iNOS-expressing cell type driving smoke-induced PH and to decipher pro-proliferative pathways involved.To address this question we used 1) myeloid cell-specific iNOS knockout mice in chronic smoke exposure, 2) co-cultures of macrophages and pulmonary artery smooth muscle cells (PASMC) to decipher underlying signalling pathways.Myeloid cell-specific iNOS knockout prevented smoke-induced PH but not emphysema in mice. Moreover, iNOS deletion in myeloid cells ameliorated the increase in expression of CD206, a marker of M2 polarisation, on interstitial macrophages. Importantly, the observed effects on lung macrophages were hypoxia-independent, as these mice developed hypoxia-induced PH. In vitro, smoke-induced PASMC proliferation in co-cultures with M2-polarised macrophages could be abolished by iNOS deletion in phagocytic cells, as well as by ERK inhibition in PASMC. Crucially, CD206-positive and iNOS-positive macrophages accumulated in proximity of remodelled vessels in the lungs of COPD patients, as shown by immunohistochemistry.In summary, our results demonstrate that iNOS deletion in myeloid cells confers protection against PH in smoke-exposed mice and provide evidence for an iNOS-dependent communication between M2-like macrophages and PASMC in underlying pulmonary vascular remodelling.

Pulmonary Hypertension - A Distinct Perspective

In this review, we have discussed pulmonary hypertension including definition, classification, pathophysiology, epidemiology, diagnosis and treatment of each class of PH as per latest available data and guidelines. Pulmonary hypertension is defined as an increase in mean pulmonary arterial pressure of ≥ 20 mmHg at rest. The clinical classification of pulmonary hypertension (as per world health organization) includes five different classes constructed on the basis of clinical causes of pulmonary hypertension. The main pathophysiology involved in the development of pulmonary hypertension of all types is prolonged pulmonary vasoconstriction caused by multiple factors which ultimately leads to pulmonary vascular remodelling (structural as well as functional). The primary treatment of pulmonary hypertension comprises of correction/control of underlying cause of pulmonary hypertension. The prevalence of pulmonary hypertension is increasing in developed as well as developing countries and thus its awareness is important for timely diagnosis and management of this chronic condition. The main aim of our review is to provide all the necessary information regarding pulmonary hypertension in one document. KEYWORDS Pulmonary Hypertension, Chronic Thromboembolism, Left Heart Disease, Lung Disease, Pulmonary Arterial Hypertension

Endothelial Cell-Derived SO2 Controls Endothelial Cell Inflammation, Smooth Muscle Cell Proliferation, and Collagen Synthesis to Inhibit Hypoxic Pulmonary Vascular Remodelling

Hypoxic pulmonary vascular remodelling (PVR) is the major pathological basis of aging-related chronic obstructive pulmonary disease and obstructive sleep apnea syndrome. The pulmonary artery endothelial cell (PAEC) inflammation, and pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy and collagen remodelling are the important pathophysiological components of PVR. Endogenous sulfur dioxide (SO2) was found to be a novel gasotransmitter in the cardiovascular system with its unique biological properties. The study was aimed to investigate the role of endothelial cell- (EC-) derived SO2 in the progression of PAEC inflammation, PASMC proliferation, hypertrophy and collagen remodelling in PVR and the possible mechanisms. EC-specific aspartic aminotransferase 1 transgenic (EC-AAT1-Tg) mice were constructed in vivo. Pulmonary hypertension was induced by hypoxia. Right heart catheterization and echocardiography were used to detect mouse hemodynamic changes. Pathologic analysis was performed in the pulmonary arteries. High-performance liquid chromatography was employed to detect the SO2 content. Human PAECs (HPAECs) with lentiviruses containing AAT1 cDNA or shRNA and cocultured human PASMCs (HPASMCs) were applied in vitro. SO2 probe and enzyme-linked immunosorbent assay were used to detect the SO2 content and determine p50 activity, respectively. Hypoxia caused a significant reduction in SO2 content in the mouse lung and HPAECs and increases in right ventricular systolic pressure, pulmonary artery wall thickness, muscularization, and the expression of PAEC ICAM-1 and MCP-1 and of PASMC Ki-67, collagen I, and α-SMA ( p < 0.05 ). However, EC-AAT1-Tg with sufficient SO2 content prevented the above increases induced by hypoxia ( p < 0.05 ). Mechanistically, EC-derived SO2 deficiency promoted HPAEC ICAM-1 and MCP-1 and the cocultured HPASMC Ki-67 and collagen I expression, which was abolished by andrographolide, an inhibitor of p50 ( p < 0.05 ). Meanwhile, EC-derived SO2 deficiency increased the expression of cocultured HPASMC α-SMA ( p < 0.05 ). Taken together, these findings revealed that EC-derived SO2 inhibited p50 activation to control PAEC inflammation in an autocrine manner and PASMC proliferation, hypertrophy, and collagen synthesis in a paracrine manner, thereby inhibiting hypoxic PVR.

Serum and Pulmonary Uric Acid in Pulmonary Arterial Hypertension

RationaleEarlier studies have suggested an association between uric acid (UA) and pulmonary arterial hypertension (PAH) severity, but it remains unknown whether UA contributes to the disease pathogenesis.ObjectivesTo study the prognostic values of circulating UA at era of current management of PAH and investigate the role of UA in the pulmonary vascular remodelling.MethodsSerum UA levels were determined in idiopathic, heritable, or anorexigen PAH at baseline and first re-evaluation in the French PAH registry. We studied protein levels of xanthine oxidase (XO) and the URATv1 transporter in lungs of control and PAH patients and of monocrotaline (MCT) and sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH).ResultsHigh serum UA levels are associated with a poor prognosis at first follow-up, but not at baseline. Both the generating enzyme XO and URATv1 are upregulated in the wall of remodelled pulmonary arteries in iPAH patients and MCT and SuHx rats. High UA concentrations promote a mild increase in cell growth in iPAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, we demonstrate that oxonic acid-induced hyperuricemia did not aggravate MCT-induced PH in rats. Finally, we show that chronic treatments of MCT and SuHx rats with benzbromarone mildly attenuate pulmonary vascular remodelling.ConclusionsUA levels in iPAH patients is associated with impaired clinical and hemodynamic profile and might be used as a noninvasive indicator of clinical prognostic during follow-up. Our findings also indicate that metabolism of UA is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH.

Spermine promotes pulmonary vascular remodelling and its synthase is a therapeutic target for pulmonary arterial hypertension

Pathological mechanisms of pulmonary arterial hypertension (PAH) remain largely unexplored. Effective treatment of PAH remains a challenge. The aim of this study was to discover the underlying mechanism of PAH through functional metabolomics and to help develop new strategies for prevention and treatment of PAH.Metabolomic profiling of plasma in patients with idiopathic PAH was evaluated through high-performance liquid chromatography mass spectrometry, with spermine identified to be the most significant and validated in another independent cohort. The roles of spermine and spermine synthase were examined in pulmonary arterial smooth muscle cells (PASMCs) and rodent models of pulmonary hypertension.Using targeted metabolomics, plasma spermine levels were found to be higher in patients with idiopathic PAH compared to healthy controls. Spermine administration promoted proliferation and migration of PASMCs and exacerbated vascular remodelling in rodent models of pulmonary hypertension. The spermine-mediated deteriorative effect can be attributed to a corresponding upregulation of its synthase in the pathological process. Inhibition of spermine synthase in vitro suppressed platelet-derived growth factor-BB-mediated proliferation of PASMCs, and in vivo attenuated monocrotaline-mediated pulmonary hypertension in rats.Plasma spermine promotes pulmonary vascular remodelling. Inhibiting spermine synthesis could be a therapeutic strategy for PAH.

A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.