25 years of lipid-lowering therapy: secular trends in therapy of coronary patients.

BACKGROUND AND AIM: Guidelines on dyslipidemia and lipid-lowering therapy (LLT) over the years recommend lower low-density lipoprotein cholesterol (LDL-C) goals by more intense therapy. Nevertheless, LDL­C has increased in the general population. Real-world trends of LLT medication as well as of LDL­C levels in cardiovascular high-risk patients are unclear. METHODS: From 2158 patients who were referred for elective coronary angiography, lipid medication was analyzed at admission in three cardiovascular observational studies (OS) over the last 25 years: OS1: 1999-2000, OS2: 2005-2008 and OS3: 2022-2023. The three studies were performed at the same cardiology unit of a tertiary care hospital in Austria. RESULTS: The proportion of patients without LLT significantly decreased from OS1 through OS2 to OS3 (49.4%, 45.6%, and 18.5%, respectively, ptrend < 0.001). Moreover, the percentage of patients under high-intensity statin treatment significantly increased from 0% to 5.1%, and 56.5% (ptrend < 0.001). Significantly more patients became treated by more than one compound (OS1: 1.8%, OS2: 1.6%, OS3: 31.2%; ptrend < 0.001). In the latest OS3, a trend to fixed-dose combination of statins with ezetimibe was observed. Mean LDL­C levels decreased from 129 mg/dL over 127 mg/dL to 83 mg/dL, respectively (ptrend < 0.001). Of the patients on high-intensity therapy 34% met the recent ESC/EAS goals (LDL-C < 55 mg/dL), but only 3% on non-intense therapy. CONCLUSION: We conclude that during the observational period of a quarter of a century, treatment intensity increased and LDL­C levels improved considerably. Guidelines apparently matter in this high-risk population and are considered by primary care physicians.

'How to adapt forests?'-Exploring the role of leaf trait diversity for long-term forest biomass under new climate normals.

Forests, critical components of global ecosystems, face unprecedented challenges due to climate change. This study investigates the influence of functional diversity-as a component of biodiversity-to enhance long-term biomass of European forests in the context of changing climatic conditions. Using the next-generation flexible trait-based vegetation model, LPJmL-FIT, we explored the impact of functional diversity on long-term forest biomass under three different climate change scenarios (video abstract: https://www.pik-potsdam.de/~billing/video/2023/video_abstract_billing_et_al_LPJmLFIT.mp4). Four model set-ups were tested with varying degrees of functional diversity and best-suited functional traits. Our results show that functional diversity positively influences long-term forest biomass, particularly when climate warming is low (RCP2.6). Under these conditions, high-diversity simulations led to an approximately 18.2% increase in biomass compared to low-diversity experiments. However, as climate change intensity increased, the benefits of functional diversity diminished (RCP8.5). A Bayesian multilevel analysis revealed that both full leaf trait diversity and diversity of plant functional types contributed significantly to biomass enhancement under low warming scenarios in our model simulations. Under strong climate change, the presence of a mixture of different functional groups (e.g. summergreen and evergreen broad-leaved trees) was found more beneficial than the diversity of leaf traits within a functional group (e.g. broad-leaved summergreen trees). Ultimately, this research challenges the notion that planting only the most productive and climate-suited trees guarantees the highest future biomass and carbon sequestration. We underscore the importance of high functional diversity and the potential benefits of fostering a mixture of tree functional types to enhance long-term forest biomass in the face of climate change.

Microbial fingerprints reveal interaction between museum objects, curators, and visitors.

Microbial communities reside at the interface between humans and their environment. Whether the microbiome can be leveraged to gain information on human interaction with museum objects is unclear. To investigate this, we selected objects from the Museum für Naturkunde and the Pergamonmuseum in Berlin, Germany, varying in material and size. Using swabs, we collected 126 samples from natural and cultural heritage objects, which were analyzed through 16S rRNA sequencing. By comparing the microbial composition of touched and untouched objects, we identified a microbial signature associated with human skin microbes. Applying this signature to cultural heritage objects, we identified areas with varying degrees of exposure to human contact on the Ishtar gate and Sam'al gate lions. Furthermore, we differentiated objects touched by two different individuals. Our findings demonstrate that the microbiome of museum objects provides insights into the level of human contact, crucial for conservation, heritage science, and potentially provenance research.

Expression of hypoxia-inducible genes is suppressed in altered gravity due to impaired nuclear HIF1α accumulation.

Extravehicular activities, the backbone of manned space exploration programs, set astronauts into mild hypoxia. Unfortunately, microgravity aggravates threatening symptoms of hypoxia such as vision impairment and brain edema. Hypoxia-inducible factors (HIFs) sense cellular hypoxia and, subsequently, change the cells' expression profile instantaneously by rapidly translocating-most likely cytoskeleton-dependently-into the nucleus and subsequently forming transcription complexes with other proteins. We tested the hypothesis that this fundamental process could be altered by sudden changes in gravitational forces in parabolic flights using a newly developed pocket-size cell culture lab that deoxygenizes cells within 15 min. Sudden gravity changes (SGCs 1g-1.8g-0g-1.8g-1g) during hypoxic exposure suppressed expression of the HIF1α-dependent genes investigated as compared with hypoxia at constant 1g. Normoxic cells subjected to SGCs showed reduced nuclear but not cytoplasmatic HIF1α signal and appeared to have disturbed cytoskeleton architecture. Inhibition of the actin-dependent intracellular transport using a combination of myosin V and VI inhibitors during hypoxia mimicked the suppression of the HIF1α-dependent genes observed during hypoxic exposure during SGCs. Thus, SGCs seem to disrupt the cellular response to hypoxia by impairing the actin-dependent translocation of HIF1α into the nucleus.

Cervical vertebral body replacement using a modern in situ expandable and angulable corpectomy cage system: early clinical and radiological outcome.

PURPOSE: Vertebral body replacement (VBR) cages are commonly implanted to reconstruct the cervical vertebrae in cases of tumour, trauma, spondylodiscitis, and degeneration. Expandable cages have been widely used for this purpose; however, the lacking congruence at the implant-bone interface and consequent implant displacement were considered as a serious drawback of such systems. Aim of this study is to evaluate the early clinical and radiological outcome of a modern in situ not only expandable but also angulable cervical corpectomy cage system. METHODS: A total of 42 patients who underwent a single or multilevel cervical VBR procedure were included and retrospectively evaluated in this single-centre case series. The neurological status was assessed using American Spinal Injury Association (ASIA) score. Complications were categorized into surgical (including implant-associated) and general medical. Radiographic parameters included regional angulation, segmental height, and coronal alignment. RESULTS: Mean age was 59.5 ± 20.6 years. The recorded ASIA score improved postoperatively by 10 points (p  0.0001). Surgical including implant-associated complication rates were 19.05%. Radiographic evaluation showed a height gain of 11.2 mm (p < 0.0001), lordotic correction of 7° (p < 0.0001), and coronal alignment of 3° (p < 0.0001). At the last follow-up, loss of angulation correction of 1.9° (p  0.0002), subsidence of 1.92 mm (p  0.0006), and fusion rates of 68.42% were observed. CONCLUSIONS: The use of an in situ angulable and expandable cage system in cervical VBR seems to offer better results compared to conventional static or expandable cages regarding segmental height gain, lordotic correction, and clinical improvement as well as low complication and revision rates. Significant height gain in multilevel surgeries is associated with higher rates of implant-associated complications.

Drivers of phenological changes in southern Europe.

The life cycle of plants is largely determined by climate, which renders phenological responses to climate change a highly suitable bioindicator of climate change. Yet, it remains unclear, which are the key drivers of phenological patterns at certain life stages. Furthermore, the varying responses of species belonging to different plant functional types are not fully understood. In this study, the role of temperature and precipitation as environmental drivers of phenological changes in southern Europe is assessed. The trends of the phenophases leaf unfolding, flowering, fruiting, and senescence are quantified, and the corresponding main environmental drivers are identified. A clear trend towards an earlier onset of leaf unfolding, flowering, and fruiting is detected, while there is no clear pattern for senescence. In general, the advancement of leaf unfolding, flowering and fruiting is smaller for deciduous broadleaf trees in comparison to deciduous shrubs and crops. Many broadleaf trees are photoperiod-sensitive; therefore, their comparatively small phenological advancements are likely the effect of photoperiod counterbalancing the impact of increasing temperatures. While temperature is identified as the main driver of phenological changes, precipitation also plays a crucial role in determining the onset of leaf unfolding and flowering. Phenological phases advance under dry conditions, which can be linked to the lack of transpirational cooling leading to rising temperatures, which subsequently accelerate plant growth.

Improved method for surgical induction of chronic hypertension in mice.

Chronic hypertension can be induced in mice by one-kidney one-clip (1K1C) or two-kidney one-clip surgery, transgenic overexpression of angiotensinogen and renin, administration of deoxycorticosterone acetate-salt, supplying Nitro-L-arginine methyl-ester in the drinking water and Angiotensin-II infusion. Although each model has its own pros and cons, selection of a model that mimics human hypertensive disease accurately is essential to ensure rigor and reproducibility in hypertension research. 1K1C mice represent an efficient, budget-friendly, and translationally capable model; however, their use in preclinical research has remained largely hindered due to concerns about potential technical complexity and lack of reported information regarding procedure-related mortality rates. Here, we describe in detail an improved version of the 1K1C surgery in mice that has zero intraoperative mortality and excellent survival rates in a long-term setting and permits the development of stable chronic hypertension and its target organ complications. Key to this outcome is unilateral nephrectomy 1 week after renal artery clipping to decelerate the blood pressure (BP) increase, which allows the organism to adapt better to the BP rise. The technical and animal welfare improvements presented here may promote the acceptance of the 1K1C model.

Examining Sentiment in Complex Texts. A Comparison of Different Computational Approaches.

Can we rely on computational methods to accurately analyze complex texts? To answer this question, we compared different dictionary and scaling methods used in predicting the sentiment of German literature reviews to the "gold standard" of human-coded sentiments. Literature reviews constitute a challenging text corpus for computational analysis as they not only contain different text levels-for example, a summary of the work and the reviewer's appraisal-but are also characterized by subtle and ambiguous language elements. To take the nuanced sentiments of literature reviews into account, we worked with a metric rather than a dichotomous scale for sentiment analysis. The results of our analyses show that the predicted sentiments of prefabricated dictionaries, which are computationally efficient and require minimal adaption, have a low to medium correlation with the human-coded sentiments (r between 0.32 and 0.39). The accuracy of self-created dictionaries using word embeddings (both pre-trained and self-trained) was considerably lower (r between 0.10 and 0.28). Given the high coding intensity and contingency on seed selection as well as the degree of data pre-processing of word embeddings that we found with our data, we would not recommend them for complex texts without further adaptation. While fully automated approaches appear not to work in accurately predicting text sentiments with complex texts such as ours, we found relatively high correlations with a semiautomated approach (r of around 0.6)-which, however, requires intensive human coding efforts for the training dataset. In addition to illustrating the benefits and limits of computational approaches in analyzing complex text corpora and the potential of metric rather than binary scales of text sentiment, we also provide a practical guide for researchers to select an appropriate method and degree of pre-processing when working with complex texts.

The Neuropeptide α-Calcitonin Gene-Related Peptide as the Mediator of Beneficial Effects of Exercise in the Cardiovascular System.

Regular physical activity exerts cardiovascular protective effects in healthy individuals and those with chronic cardiovascular diseases. Exercise is accompanied by an increased plasma concentration of α-calcitonin gene-related peptide (αCGRP), a 37-amino acid peptide with vasodilatory effects and causative roles in migraine. Moreover, mouse models revealed that loss of αCGRP disrupts physiological adaptation of the cardiovascular system to exercise in normotension and aggravates cardiovascular impairment in primary chronic hypertension, both can be reversed by αCGRP administration. This suggests that αCGRP agonists could be a therapeutic option to mediate the cardiovascular protective effects of exercise in clinical setting where exercise is not possible or contraindicated. Of note, FDA has recently approved αCGRP antagonists for migraine prophylaxis therapy, however, the cardiovascular safety of long-term anti-CGRP therapy in individuals with cardiovascular diseases has yet to be established. Current evidence from preclinical models suggests that chronic αCGRP antagonism may abolish the cardiovascular protective effects of exercise in both normotension and chronic hypertension.

Pericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivo.

BACKGROUND: Ways to prevent disease-induced vascular modifications that accelerate brain damage remain largely elusive. Improved understanding of perivascular cell signalling could provide unparalleled insight as these cells impact vascular stability and functionality of the neurovascular unit as a whole. Identifying key drivers of astrocyte and pericyte responses that modify cell-cell interactions and crosstalk during injury is key. At the cellular level, injury-induced outcomes are closely entwined with activation of the hypoxia-inducible factor-1 (HIF-1) pathway. Studies clearly suggest that endothelial HIF-1 signalling increases blood-brain barrier permeability but the influence of perivascular HIF-1 induction on outcome is unknown. Using novel mouse lines with astrocyte and pericyte targeted HIF-1 loss of function, we herein show that vascular stability in vivo is differentially impacted by perivascular hypoxia-induced HIF-1 stabilization. METHODS: To facilitate HIF-1 deletion in adult mice without developmental complications, novel Cre-inducible astrocyte-targeted (GFAP-CreERT2; HIF-1αfl/fl and GLAST-CreERT2; HIF-1αfl/fl) and pericyte-targeted (SMMHC-CreERT2; HIF-1αfl/fl) transgenic animals were generated. Mice in their home cages were exposed to either normoxia (21% O2) or hypoxia (8% O2) for 96 h in an oxygen-controlled humidified glove box. All lines were similarly responsive to hypoxic challenge and post-Cre activation showed significantly reduced HIF-1 target gene levels in the individual cells as predicted. RESULTS: Unexpectedly, hypoxia-induced vascular remodelling was unaffected by HIF-1 loss of function in the two astrocyte lines but effectively blocked in the pericyte line. In correlation, hypoxia-induced barrier permeability and water accumulation were abrogated only in pericyte targeted HIF-1 loss of function mice. In contrast to expectation, brain and serum levels of hypoxia-induced VEGF, TGF-ß and MMPs (genes known to mediate vascular remodelling) were unaffected by HIF-1 deletion in all lines. However, in agreement with the permeability data, immunofluorescence and electron microscopy showed clear prevention of hypoxia-induced tight junction disruption in the pericyte loss of function line. CONCLUSION: This study shows that pericyte but not astrocyte HIF-1 stabilization modulates endothelial tight junction functionality and thereby plays a pivotal role in hypoxia-induced vascular dysfunction. Whether the cells respond similarly or differentially to other injury stimuli will be of significant relevance.

Hierarchical imaging and computational analysis of three-dimensional vascular network architecture in the entire postnatal and adult mouse brain.

The formation of new blood vessels and the establishment of vascular networks are crucial during brain development, in the adult healthy brain, as well as in various diseases of the central nervous system. Here, we describe a step-by-step protocol for our recently developed method that enables hierarchical imaging and computational analysis of vascular networks in postnatal and adult mouse brains. The different stages of the procedure include resin-based vascular corrosion casting, scanning electron microscopy, synchrotron radiation and desktop microcomputed tomography imaging, and computational network analysis. Combining these methods enables detailed visualization and quantification of the 3D brain vasculature. Network features such as vascular volume fraction, branch point density, vessel diameter, length, tortuosity and directionality as well as extravascular distance can be obtained at any developmental stage from the early postnatal to the adult brain. This approach can be used to provide a detailed morphological atlas of the entire mouse brain vasculature at both the postnatal and the adult stage of development. Our protocol allows the characterization of brain vascular networks separately for capillaries and noncapillaries. The entire protocol, from mouse perfusion to vessel network analysis, takes ~10 d.

Targeting neovascularization and respiration of tumor grafts grown on chick embryo chorioallantoic membranes.

Since growing tumors stimulate angiogenesis, via vascular endothelial growth factor (VEGF), angiogenesis inhibitors (AIs, blockers of the VEGF signaling pathway) have been introduced to cancer therapy. However, AIs often yielded only modest and short-lived gains in cancer patients and more invasive tumor phenotypes in animal models. Combining anti-VEGF strategies with lactate uptake blockers may boost both efficacy and safety of AIs. We assessed this hypothesis by using the ex ovo chorioallantoic membrane (CAM) assay. We show that AI-based monotherapy (Avastin®, AVA) increases tumor hypoxia in human CAM cancer cell xenografts and cell spread in human as well as canine CAM cancer cell xenografts. In contrast, combining AVA treatment with lactate importer MCT1 inhibitors (α-cyano-4-hydroxycinnamic acid (CHC) or AZD3965 (AZD)) reduced both tumor growth and cell dissemination of human and canine explants. Moreover, combining AVA+AZD diminished blood perfusion and tumor hypoxia in human explants. Thus, the ex ovo CAM assay as an easy, fast and cheap experimental setup is useful for pre-clinical cancer research. Moreover, as an animal-free experimental setup the CAM assay can reduce the high number of laboratory animals used in pre-clinical cancer research.

CGRP Receptor Antagonism in COVID-19: Potential Cardiopulmonary Adverse Effects.

Recently, the US FDA has authorized a drug repurposing trial with calcitonin gene-related peptide (CGRP) receptor antagonists to reduce lung inflammation in coronavirus 2019 (COVID-19). However, the well-established cardiopulmonary protective effects of CGRP raise concerns about the safety of antagonizing CGRP in COVID-19. Awareness regarding potential cardiopulmonary adverse effects may enable their early detection and prevent illness from worsening.

Blood Pressure Normalization-Independent Cardioprotective Effects of Endogenous, Physical Activity-Induced αCGRP (α Calcitonin Gene-Related Peptide) in Chronically Hypertensive Mice.

RATIONALE: αCGRP (α calcitonin gene-related peptide), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure. OBJECTIVE: However, we hypothesize that endogenous, physical activity-induced αCGRP has blood pressure-independent cardioprotective effects in chronic hypertension. METHODS AND RESULTS: Chronically hypertensive (one-kidney-one-clip surgery) wild-type and αCGRP-/- sedentary or voluntary wheel running mice were treated with vehicle, αCGRP, or the αCGRP receptor antagonist CGRP8-37. Cardiac function and myocardial phenotype were evaluated echocardiographically and by molecular, cellular, and histological analysis, respectively. Blood pressure was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological remodeling and heart failure in sedentary, chronically hypertensive wild-type mice. In these mice, voluntary wheel running significantly improved myocardial phenotype and function, which was abolished by CGRP8-37 treatment. In αCGRP-/- mice, αCGRP treatment, in contrast to voluntary wheel running, improved myocardial phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary, murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-dependent blunting of pathological cardiac remodeling. CONCLUSIONS: Endogenous, physical activity-induced αCGRP has blood pressure-independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger patients with hypertension.

Expression of Hypoxia-Inducible Factor 1α (HIF-1α) and Genes of Related Pathways in Altered Gravity.

Immune system deterioration in space represents a major risk, which has to be mitigated for exploration-class missions into the solar system. Altered gravitational forces have been shown to regulate adaptation processes in cells of the immune system, which are important for appropriate risk management, monitoring and development of countermeasures. T lymphocytes and cells of the monocyte-macrophage system are highly migratory cell types that frequently encounter a wide range of oxygen tensions in human tissues and in hypoxic areas, even under homeostatic conditions. Hypoxia-inducible factor 1 and 2 (HIF's) might have an important role in activation of T cells and cells of the monocyte-macrophages system. Thus, we investigated the regulation of HIF-dependent and, therefore, hypoxia-signaling systems in both cell types in altered gravity and performed transcript and protein analysis from parabolic flight and suborbital ballistic rocket experiments. We found that HIF-1α and HIF-1-dependent transcripts were differently regulated in altered gravity, whereas HIF-1α-dependent gene expression adapted after 5 min microgravity. Inter-platform comparisons identified PDK1 as highly responsive to gravitational changes in human U937 myelomonocytic cells and in Jurkat T cells. We suggest HIF-1 as a potential pharmacological target for counteracting immune system deterioration during space flight.

Neuronal erythropoietin overexpression is protective against kanamycin-induced hearing loss in mice.

Aminoglycosides have detrimental effects on the hair cells of the inner ear, yet these agents indisputably are one of the cornerstones in antibiotic therapy. Hence, there is a demand for strategies to prevent aminoglycoside-induced ototoxicity, which are not available today. In vitro data suggests that the pleiotropic growth factor erythropoietin (EPO) is neuroprotective against aminoglycoside-induced hair cell loss. Here, we use a mouse model with EPO-overexpression in neuronal tissue to evaluate whether EPO could also in vivo protect from aminoglycoside-induced hearing loss. Auditory brainstem response (ABR) thresholds were measured in 12-weeks-old mice before and after treatment with kanamycin for 15 days, which resulted in both C57BL/6 and EPO-transgenic animals in a high-frequency hearing loss. However, ABR threshold shifts in EPO-transgenic mice were significantly lower than in C57BL/6 mice (mean difference in ABR threshold shift 13.6 dB at 32 kHz, 95% CI 3.8-23.4 dB, p = 0.003). Correspondingly, quantification of hair cells and spiral ganglion neurons by immunofluorescence revealed that EPO-transgenic mice had a significantly lower hair cell and spiral ganglion neuron loss than C57BL/6 mice. In conclusion, neuronal overexpression of EPO is protective against aminoglycoside-induce hearing loss, which is in accordance with its known neuroprotective effects in other organs, such as the eye or the brain.

New Generation of Resistant Sugar Beet Varieties for Advanced Integrated Management of Cercospora Leaf Spot in Central Europe.

Cercospora leaf spot (CLS) epidemics in sugar beet have been increasing in recent years causing higher use of fungicides. Concomitantly, the availability of effective fungicides is at risk because of resistance development in the fungus, the lack of new active ingredients as well as restrictive approval practices. A key option for an integrated management of CLS is cultivation of resistant varieties. Because of the yield penalty in resistant varieties, acceptance in commercial practice so far has been low. The aim of our study was to characterize recent sugar beet varieties registered in Germany in terms of resistance and tolerance to CLS and their value for integrated pest management. The genetic basis of CLS resistance in varieties is protected by intellectual property rights even after variety registration and not open to the public due to economic competition. To gain reliable data for cultivation, varieties have to be tested for their resistance traits under field conditions at varying levels of infection with Cercospora beticola. In collaboration with variety related stakeholders, 15 sugar beet varieties were tested in 49 field trials in Germany from 2014 to 2016 for their yield response to CLS. The trials were set up in a split-plot design with and without infection (i.e., with and without fungicide). The classification of varietal reaction to CLS is based on symptomatic leaf area (susceptibility) and the resulting relative yield loss (tolerance). Since the relation between both parameters varied among varieties, it was used as an additional parameter to describe tolerance. On this basis, three groups of varieties were identified. They can be characterized as a susceptible, a resistant and a presumably tolerant cluster. A comparison of the data with an older dataset originating from 2009 to 2011 revealed that yield performance of recent varieties with resistance to C. beticola caught up with susceptible varieties due to breeding progress. They showed no yield penalty in the absence of the disease and better economic performance than susceptible varieties. It is assumed that these varieties will allow a substantial reduction of fungicide use for an advanced integrated pest management under central European conditions.

Aquaporin 1 controls the functional phenotype of pulmonary smooth muscle cells in hypoxia-induced pulmonary hypertension.

Vascular remodelling in hypoxia-induced pulmonary hypertension (PH) is driven by excessive proliferation and migration of endothelial and smooth muscle cells. The expression of aquaporin 1 (AQP1), an integral membrane water channel protein involved in the control of these processes, is tightly regulated by oxygen levels. The role of AQP1 in the pathogenesis of PH, however, has not been directly addressed so far. This study was designed to characterize expression and function of AQP1 in pulmonary vascular cells from human arteries and in the mouse model of hypoxia-induced PH. Exposure of human pulmonary vascular cells to hypoxia significantly induced the expression of AQP1. Similarly, levels of AQP1 were found to be upregulated in lungs of mice with hypoxia-induced PH. The functional role of AQP1 was further tested in human pulmonary artery smooth muscle cells demonstrating that depletion of AQP1 reduced proliferation, the migratory potential, and, conversely, increased apoptosis of these cells. This effect was associated with higher expression of the tumour suppressor gene p53. Using the mouse model of hypoxia-induced PH, application of GapmeR inhibitors targeting AQP1 abated the hypoxia-induced upregulation of AQP1 and, of note, reversed PH by decreasing both right ventricular pressure and hypertrophy back to the levels of control mice. Our data suggest an important functional role of AQP1 in the pathobiology of hypoxia-induced PH. These results offer novel insights in our pathogenetic understanding of the disease and propose AQP1 as potential therapeutic in vivo target.

Analysis of hypoxia-induced noncoding RNAs reveals metastasis-associated lung adenocarcinoma transcript 1 as an important regulator of vascular smooth muscle cell proliferation.

Vascular remodeling, a pathogenic hallmark in pulmonary hypertension, is mainly driven by a dysbalance between proliferation and apoptosis of human pulmonary artery smooth muscle cells. It has previously been shown that microRNAs are involved in the pathogenesis of pulmonary hypertension. However, the role of long noncoding RNAs has not been evaluated. long noncoding RNA expression was quantified in human pulmonary artery smooth muscle cells using PCR arrays and quantitative PCR. Knockdown of genes was performed by transfection of siRNA or GapmeR. Proliferation and migration were measured using BrdU incorporation and wound healing assays. The mouse model of hypoxia-induced PH was used to determine the physiological meaning of identified long noncoding RNAs. The expression of 84 selected long noncoding RNAs was assessed in hypoxic human pulmonary artery smooth muscle cells and the levels of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were significantly increased. Depletion of hypoxia-inducible factor 1α abolished the hypoxia-induced upregulation of metastasis-associated lung adenocarcinoma transcript 1 expression. Silencing of MALAT1 significantly decreased proliferation and migration of human pulmonary artery smooth muscle cells. In vivo, MALAT1 expression was significantly increased in lungs of hypoxic mice. Of note, targeting of MALAT1 by GapmeR ameliorated heart hypertrophy in mice with pulmonary hypertension. This is the first report on functional characterization of MALAT1 in the pulmonary vasculature. Our data provide evidence that MALAT1 expression is significantly increased by hypoxia, probably by hypoxia-inducible factor 1α. Intervention experiments confirmed that MALAT1 regulates the proliferative phenotype of smooth muscle cells and silencing of MALAT1 reduced heart hypertrophy in mice with pulmonary hypertension. These data indicate a potential role of MALAT1 in the pathogenesis of pulmonary hypertension. Impact statement Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA that mediates several biological processes. In the context of vascular biology, MALAT1 has been shown to be inducible by hypoxia and to control cell proliferation. These processes are of major importance for the pathophysiology of hypoxia-induced pulmonary hypertension (PH). Until now, the physiological role of MALAT1 in PH remains unclear. By using smooth muscle cells and by employing an established PH mouse model, we provide evidence that hypoxia induces MALAT1 expression. Moreover, depletion of MALAT1 inhibited migration and proliferation of smooth muscle cells, probably by the induction of cyclin-dependent kinase inhibitors. Of note, MALAT1 was significantly increased in mice exposed to hypoxia and silencing of MALAT1 ameliorated heart hypertrophy in mice with hypoxia-induced PH. Since vascular remodeling and right heart failure as a consequence of pulmonary pressure overload is a major problem in PH, these data have implications for our pathogenetic understanding.