Is the fibroblast growth factor signaling pathway a victim of receptor tyrosine kinase inhibition in pulmonary parenchymal and vascular remodeling?
El Agha Elie,Schwind Felix,Ruppert Clemens,Günther Andreas,Bellusci Saverio,Schermuly Ralph T,Kosanovic Djuro
American journal of physiology. Lung cellular and molecular physiology
Idiopathic pulmonary arterial hypertension (IPAH), pulmonary hypertension (PH) due to lung disease and/or hypoxia and idiopathic pulmonary fibrosis (IPF) are increasingly recognized as important contributors to mortality and morbidity worldwide. Among others, the current treatment paradigm considers broad inhibition of receptor tyrosine kinases, a strategy that likely leads to collateral inhibition of signaling pathways that are critical for lung repair and regeneration. Fibroblast growth factor 7 (FGF7) and FGF10 signaling in the lung through FGF receptor 2 (FGFR2) are involved in epithelial cell protection and renewal, and mutations in their corresponding genes in humans are linked to increased susceptibility to lung pathologies, such as chronic obstructive pulmonary disease and bronchopulmonary dysplasia. In this report, we present data demonstrating significant upregulation of FGF7, FGF10, and FGFR2 in IPF and IPAH lungs compared with donor lungs. These ligands and their cognate receptor converged on the remodeled parenchyma and vasculature of IPF and IPAH lungs. Interestingly, the expression levels of FGFR1, which has been previously shown to play a pathological role in PH development, were not significantly changed in either disease state. Intriguingly, the expression levels of FGF7, FGF10, and FGFR2 were lower in IPF lung regions undergoing active remodeling, and inversely correlated with IPAH severity, indicating that increased expression might reflect lung repair rather than lung pathology, and warranting further research on the precise role of FGF signaling in pulmonary parenchymal and vascular remodeling.
Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling.
Zhang Shanshan,Liu Xiaoli,Ge Li Li,Li Kailin,Sun Yongchao,Wang Fang,Han Ying,Sun Chao,Wang Jue,Jiang Wen,Xin Qian,Xu Chaoyue,Chen Yuan,Chen Ou,Zhang Zhaohua,Luan Yun
BACKGROUND:Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling, right ventricular hypertrophy and failure. So far no effective treatment exists for this disease; hence, novel approaches are urgently needed. The aim of the present research was to observe the treatment effect of mesenchymal stromal cell derived exosomes and reveal the mechanism. METHODS:Monocrotaline (MCT)-induced PH in rats and hypoxia-induced cell damage model were established, respectively. Exosomes derived from the supernatant of human umbilical cord mesenchymal stem cells (MSC-exo) were injected into MCT-PH model rat or added into the cells cultured medium. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot methods were used in vivo and vitro. RESULTS:The results showed that MSC-exo could significantly attenuate right ventricular (RV) hypertrophy and pulmonary vascular remodelling in MCT-PH rats. In the cell culture experiments, we found that MSC-exo could significantly inhibit hypoxia-induced pulmonary arterial endothelial cell (PAEC) apoptosis and pulmonary arterial smooth muscle cells (PASMC) proliferation. Furthermore, the pulmonary arterioles endothelial-to-mesenchymal transition (EndMT) was obviously suppressed. Moreover, the present study suggest that MSC-exo can significantly upregulate the expression of Wnt5a in MCT-PH rats and hypoxic pulmonary vascular cells. Furthermore, with Wnt5a gene silencing, the therapeutic effect of MSC-exo against hypoxia injury was restrained. CONCLUSIONS:Synthetically, our data provide a strong evidence for the therapeutic of MSC-exo on PH, more importantly, we confirmed that the mechanism was associated with up-regulation of the expression of Wnt5a. These results offer a theoretical basis for clinical prevention and treatment of PH.
TWIK-2 channel deficiency leads to pulmonary hypertension through a rho-kinase-mediated process.
Pandit Lavannya M,Lloyd Eric E,Reynolds Julia O,Lawrence William S,Reynolds Corey,Wehrens Xander H T,Bryan Robert M
Hypertension (Dallas, Tex. : 1979)
TWIK-2 (KCNK6) is a member of the 2-pore domain (K2P) family of potassium channels, which are highly expressed in the vascular system. We tested the hypothesis that TWIK-2 deficiency leads to pulmonary hypertension. TWIK-2 knockout mice and their wildtype littermates at 8 weeks of age had similar mean right ventricular systolic pressures (24±3 and 21±3 mm Hg, respectively.) Significantly, by 20 weeks of age, the mean right ventricular systolic pressures in TWIK-2 knockout mice increased to 35±3 mm Hg (P≤0.036), whereas mean right ventricular systolic pressures in wildtype littermates remained at 22±3 mm Hg. Elevated mean right ventricular systolic pressures in the TWIK-2 knockout mice was accompanied by pulmonary vascular remodeling as determined by a 25% increase in the cross-sectional area of the vessels occupied by the vessel wall. Additionally, secondary branches of the pulmonary artery from 20-week-old TWIK-2 knockout mice showed an enhanced contractile response to U46619 (10(-6) moles/L), a thromboxane A2 mimetic, which was completely abolished with the Rho-kinase inhibitor, Y27632 (10(-6) and 10(-5) moles/L). Treatment of TWIK-2 knockout mice with the Rho-kinase inhibitor, fasudil, in the drinking water for 12 weeks, abolished the development of pulmonary hypertension and attenuated the vessel remodeling. We concluded that mice deficient in the TWIK-2 channel develop pulmonary hypertension between 8 and 20 weeks of age through a mechanism involving Rho-kinase. Our results suggest that downregulation of TWIK-2 in the pulmonary vasculature may be an underlying mechanism in the development of pulmonary hypertension.
Increased levels of platelet-derived microparticles in pulmonary hypertension.
Ogawa Aiko,Matsubara Hiromi
INTRODUCTION:Thrombosis and coagulation abnormalities are thought to be involved in disease progression of pulmonary hypertension. Platelet-derived microparticles (PDMP) are released from platelets following stimulation and have recently been demonstrated to play an important role in pathogenesis of various diseases. This study aimed to evaluate PDMP levels in patients with pulmonary hypertension. MATERIALS AND METHODS:Our cross-sectional study enrolled a total of 113 participants including 73 patients with pulmonary hypertension and 40 participants to serve as a control group. PDMP levels were measured using a PDMP ELISA kit, which detects glycoproteins CD42a and CD42b. Clinical parameters, including exercise capacity and hemodynamic parameters, were collected, and the relationship to PDMP levels were evaluated. RESULTS:PDMP levels were significantly higher in patients than in participants in the control group (23.2 ± 39.4 U/mL and 7.8 ± 3.6 U/mL, respectively, P < 0.05). PDMP levels in patients with chronic thromboembolic pulmonary hypertension were correlated with right atrial pressure and cardiac index. PDMP levels were higher in male patients with idiopathic pulmonary arterial hypertension. Furthermore, patients administered a higher dose of epoprostenol had a tendency for lower PDMP levels. CONCLUSIONS:The data suggest that PDMP levels are increased in patients with pulmonary hypertension. Further study is needed to understand the mechanism and impact of PDMP on disease progression.
Role of integrin-linked kinase in the hypoxia-induced phenotypic transition of pulmonary artery smooth muscle cells: Implications for hypoxic pulmonary hypertension.
Hou Jiantong,Liu Bo,Zhu Boqian,Wang Dong,Qiao Yong,Luo Erfei,Nawabi Abdul Qadir,Yan Gaoliang,Tang Chengchun
Experimental cell research
The phenotypic transition of pulmonary artery smooth muscle cells (PASMCs) from a contractile/differentiated to synthetic/de-differentiated phenotype is an important mechanism for the occurrence and development of hypoxic pulmonary hypertension (HPH). Integrin-linked kinase (ILK) is an early hypoxic response factor whose kinase activity is significantly affected during early hypoxia. Myocardin and ETS-like protein 1 (Elk-1) are co-activators of serum response factor (SRF) and can bind to SRF to mediate the phenotypic transition of PASMCs. However, little is known about the role of ILK on the phenotypic transition of these PASMCs. Thus, in our study, we explored the role of ILK in this process. We found that the expression of ILK and myocardin decreased gradually with the increase in hypoxia exposure time in the pulmonary arteries of rats. We observed that hypoxia exposure for 1 h caused an increase in the phosphorylation of Elk-1 but did not affect the expression of ILK, myocardin, or SRF. Exposure to hypoxic treatment for 1 h decreased ILK kinase activity and caused Elk-1 to suppress myocardin binding to SRF and the smooth muscle (SM) α-actin gene promoters. In addition, hypoxia exposure for 24 h decreased the expression of ILK, myocardin, SM α-actin, and calponin but increased the expression of osteopontin. Silencing of the myocardin gene significantly decreased the expression of SM α-actin and calponin but increased the expression of osteopontin. Silencing of the ILK gene significantly decreased the expression of myocardin, SM α-actin, and calponin but increased the expression of osteopontin. ILK overexpression reversed the effects of 24 h of hypoxia on the expression of myocardin, SM α-actin, calponin, and osteopontin and reversed the decrease in binding of myocardin to the SM α-actin promoter caused by 24 h of hypoxia exposure. Thus, our results suggest that ILK initiates the phenotypic transition of PASMCs. The underlying mechanism may involve hypoxia downregulating ILK kinase activity and protein expression, causing Elk-1 to compete with myocardin for binding to the SM α-actin promoter, which downregulates the expression of the downstream target myocardin and results in the phenotypic transition of PASMCs from a contractile to a synthetic phenotype. This may be an important mechanism in the development of HPH.
Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension.
Rudyk Olena,Rowan Alice,Prysyazhna Oleksandra,Krasemann Susanne,Hartmann Kristin,Zhang Min,Shah Ajay M,Ruppert Clemens,Weiss Astrid,Schermuly Ralph T,Ida Tomoaki,Akaike Takaaki,Zhao Lan,Eaton Philip
Proceedings of the National Academy of Sciences of the United States of America
Chronic hypoxia causes pulmonary hypertension (PH), vascular remodeling, right ventricular (RV) hypertrophy, and cardiac failure. Protein kinase G Iα (PKGIα) is susceptible to oxidation, forming an interprotein disulfide homodimer associated with kinase targeting involved in vasodilation. Here we report increased disulfide PKGIα in pulmonary arteries from mice with hypoxic PH or lungs from patients with pulmonary arterial hypertension. This oxidation is likely caused by oxidants derived from NADPH oxidase-4, superoxide dismutase 3, and cystathionine γ-lyase, enzymes that were concomitantly increased in these samples. Indeed, products that may arise from these enzymes, including hydrogen peroxide, glutathione disulfide, and protein-bound persulfides, were increased in the plasma of hypoxic mice. Furthermore, low-molecular-weight hydropersulfides, which can serve as "superreductants" were attenuated in hypoxic tissues, consistent with systemic oxidative stress and the oxidation of PKGIα observed. Inhibiting cystathionine γ-lyase resulted in decreased hypoxia-induced disulfide PKGIα and more severe PH phenotype in wild-type mice, but not in Cys42Ser PKGIα knock-in (KI) mice that are resistant to oxidation. In addition, KI mice also developed potentiated PH during hypoxia alone. Thus, oxidation of PKGIα is an adaptive mechanism that limits PH, a concept further supported by polysulfide treatment abrogating hypoxia-induced RV hypertrophy in wild-type, but not in the KI, mice. Unbiased transcriptomic analysis of hypoxic lungs before structural remodeling identified up-regulation of endothelial-to-mesenchymal transition pathways in the KI compared with wild-type mice. Thus, disulfide PKGIα is an intrinsic adaptive mechanism that attenuates PH progression not only by promoting vasodilation but also by limiting maladaptive growth and fibrosis signaling.
Cell Death in the Lung: The Apoptosis-Necroptosis Axis.
Sauler Maor,Bazan Isabel S,Lee Patty J
Annual review of physiology
Regulated cell death is a major mechanism to eliminate damaged, infected, or superfluous cells. Previously, apoptosis was thought to be the only regulated cell death mechanism; however, new modalities of caspase-independent regulated cell death have been identified, including necroptosis, pyroptosis, and autophagic cell death. As an understanding of the cellular mechanisms that mediate regulated cell death continues to grow, there is increasing evidence that these pathways are implicated in the pathogenesis of many pulmonary disorders. This review summarizes our understanding of regulated cell death as it pertains to the pathogenesis of chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and pulmonary arterial hypertension.
Long noncoding RNAs: emerging roles in pulmonary hypertension.
Jin Qi,Zhao Zhihui,Zhao Qing,Yu Xue,Yan Lu,Zhang Yi,Luo Qin,Liu Zhihong
Heart failure reviews
Pulmonary hypertension (PH) is a complex and progressive disease characterized by increased pulmonary vascular resistance and pulmonary artery pressure, leading to pulmonary vascular remodeling, right heart failure, and ultimately death. Although several molecular pathways related to vascular remodeling have been reported, the mechanism behind this fatal disease with poor prognosis remains largely unclear. Long noncoding RNAs (lncRNAs) have been proven to be playing crucial roles in various biological processes, and emerging studies demonstrated lncRNAs as essential epigenetic modifiers involved in the onset and development of PH. The present review summarizes the types and biogenesis of lncRNAs, focuses on the biological function of lncRNAs in vascular diseases, and highlights all proven lncRNAs as well as highly potential lncRNA candidates involved in PH. Moreover, the interaction between lncRNA and corresponding miRNA in PH is also emphasized. Finally, we discuss current challenges and future prospects of lncRNAs as potential biomarkers and therapeutic targets for PH. Current data indicate lncRNAs are vital regulators of PH and may act as promising diagnostic and therapeutic targets for PH.
Noncanonical Wnt planar cell polarity signaling in lung development and disease.
Vladar Eszter K,Königshoff Melanie
Biochemical Society transactions
The planar cell polarity (PCP) signaling pathway is a potent developmental regulator of directional cell behaviors such as migration, asymmetric division and morphological polarization that are critical for shaping the body axis and the complex three-dimensional architecture of tissues and organs. PCP is considered a noncanonical Wnt pathway due to the involvement of Wnt ligands and Frizzled family receptors in the absence of the beta-catenin driven gene expression observed in the canonical Wnt cascade. At the heart of the PCP mechanism are protein complexes capable of generating molecular asymmetries within cells along a tissue-wide axis that are translated into polarized actin and microtubule cytoskeletal dynamics. PCP has emerged as an important regulator of developmental, homeostatic and disease processes in the respiratory system. It acts along other signaling pathways to create the elaborately branched structure of the lung by controlling the directional protrusive movements of cells during branching morphogenesis. PCP operates in the airway epithelium to establish and maintain the orientation of respiratory cilia along the airway axis for anatomically directed mucociliary clearance. It also regulates the establishment of the pulmonary vasculature. In adult tissues, PCP dysfunction has been linked to a variety of chronic lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, and idiopathic pulmonary arterial hypertension, stemming chiefly from the breakdown of proper tissue structure and function and aberrant cell migration during regenerative wound healing. A better understanding of these (impaired) PCP mechanisms is needed to fully harness the therapeutic opportunities of targeting PCP in chronic lung diseases.
Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease.
Neubert Lavinia,Borchert Paul,Stark Helge,Hoefer Anne,Vogel-Claussen Jens,Warnecke Gregor,Eubel Holger,Kuenzler Patrick,Kreipe Hans-Heinrich,Hoeper Marius M,Kuehnel Mark,Jonigk Danny
The American journal of pathology
Pulmonary hypertension and pulmonary vascular remodeling (PVR) are common in many lung diseases leading to right ventricular dysfunction and death. Differences in PVR result in significant prognostic divergences in both the pulmonary arterial and venous compartments, as in pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD), respectively. Our goal was to identify compartment-specific molecular hallmarks of PVR, considering the risk of life-threatening pulmonary edema in PVOD, if treated by conventional pulmonary hypertension therapy. Formalin-fixed and paraffin-embedded tissues from fresh explanted human lungs of patients with PVOD (n = 19), PAH (n = 20), idiopathic pulmonary fibrosis (n = 13), and chronic obstructive pulmonary disease (n = 15), were analyzed for inflammation and kinome-related gene regulation. The generated neuronal network differentiated PVOD from PAH samples with a sensitivity of 100% and a specificity of 92% in a randomly chosen validation set, a level far superior to established diagnostic algorithms. Further, various alterations were identified regarding the gene expression of explanted lungs with PVR, compared with controls. Specifically, the dysregulation of microtubule-associated serine/threonine kinase 2 and protein-o-mannose kinase SGK196 in all disease groups suggests a key role in pulmonary vasculopathy for the first time. Our findings promise to help develop novel target-specific interventions and innovative approaches to facilitate clinical diagnostics in an elusive group of diseases.
Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition.
Rinastiti Pranindya,Ikeda Koji,Rahardini Elda Putri,Miyagawa Kazuya,Tamada Naoki,Kuribayashi Yuko,Hirata Ken-Ichi,Emoto Noriaki
Pulmonary hypertension is a progressive lung disease with poor prognosis due to the consequent right heart ventricular failure. Pulmonary artery remodeling and dysfunction are culprits for pathologically increased pulmonary arterial pressure, but their underlying molecular mechanisms remain to be elucidated. Previous genome-wide association studies revealed a significant correlation between the genetic locus of family with sequence similarity 13, member A (FAM13A) and various lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis; however whether FAM13A is also involved in the pathogenesis of pulmonary hypertension remained unknown. Here, we identified a significant role of FAM13A in the development of pulmonary hypertension. FAM13A expression was reduced in the lungs of mice with hypoxia-induced pulmonary hypertension. We identified that FAM13A was expressed in lung vasculatures, especially in endothelial cells. Genetic loss of FAM13A exacerbated pulmonary hypertension in mice exposed to chronic hypoxia in association with deteriorated pulmonary artery remodeling. Mechanistically, FAM13A decelerated endothelial-to-mesenchymal transition potentially by inhibiting β-catenin signaling in pulmonary artery endothelial cells. Our data revealed a protective role of FAM13A in the development of pulmonary hypertension, and therefore increasing and/or preserving FAM13A expression in pulmonary artery endothelial cells is an attractive therapeutic strategy for the treatment of pulmonary hypertension.