miR-22-3p in the rostral ventrolateral medulla promotes hypertension through inhibiting ß-arrestin-1.

It has been documented that increased sympathetic activity contributes to the development of cardiovascular diseases, such as hypertension. We previously reported that ß-arrestin-1, a multifunctional cytoskeletal protein, was downregulated in the rostral ventrolateral medulla (RVLM) of the spontaneously hypertensive rat (SHR), and its overexpression elicited an inhibitory effect on sympathetic activity in hypertension. microRNA (miR)-22-3p has been reported to be associated with the pathological progress of hypertension. The purpose of this study was to determine the role of miR-22-3p in ß-arrestin-1-mediated central cardiovascular regulation in hypertension. It was observed that miR-22-3p was upregulated in the RVLM of SHRs compared with normotensive Wistar-Kyoto (WKY) rats, and it was subsequently confirmed to target the ß-arrestin-1 gene using a dual-luciferase reporter assay. miR-22-3p was downregulated in the RVLM using adeno-associated virus with 'tough decoys', which caused a significant increase of ß-arrestin-1 expression and decrease of noradrenaline and blood pressure (BP) in SHRs. However, upregulation of miR-22-3p using lentivirus in the RVLM of WKY rats significantly increased BP. In in vitro PC12 cells, enhanced oxidative stress activity induced by angiotensin II was counteracted by pretreatment with miR-22-3p inhibitor, and this effect could be abolished by ß-arrestin-1 gene knockdown. Furthermore, microglia exhaustion significantly diminished miR-22-3p expression, and enhanced ß-arrestin-1 expression in the RVLM of SHRs. Activation of BV2 cells in vitro evoked a significant increase of miR-22-3p expression, and this BV2 cell culture medium was also able to facilitate miR-22-3p expression in PC12 cells. Collectively, our findings support a critical role for microglia-derived miR-22-3p in inhibiting ß-arrestin-1 in the RVLM, which is involved in central cardiovascular regulation in hypertension. KEY POINTS: Impairment of ß-arrestin-1 function in the rostral ventrolateral medulla (RVLM) has been reported to be associated with the development of sympathetic overactivity in hypertension. However, little is known about the potential mechanisms of ß-arrestin-1 dysfunction in hypertension. miR-22-3p is implicated in multiple biological processes, but the role of miR-22-3p in central regulation of cardiovascular activity in hypertension remains unknown. We predicted that miR-22-3p could directly bind to the ß-arrestin-1 gene (Arrb1), and this hypothesis was confirmed by using a dual-luciferase reporter assay. Inhibition of ß-arrestin-1 by miR-22-3p was further verified in both in vivo and in vitro experiments. Furthermore, our results suggested miR-22-3p as a risk factor for oxidative stress in the RVLM, thus contributing to sympatho-excitation and hypertension. Our present study provides evidence that microglia-derived miR-22-3p may underlie the pathogenesis and progression of neuronal hypertension by inhibiting ß-arrestin-1 in the RVLM.

Bioinspired Heterogeneous Construction of Lignocellulose-Reinforced COF Membranes for Efficient Proton Conduction.

The exponential interest in covalent organic frameworks (COFs) arises from the direct correlation between their diverse and intriguing properties and the modular design principle. However, the insufficient interlamellar interaction among COF nanosheets greatly hinders the formation of defect-free membranes. Therefore, developing a methodology for the facile fabrication of these materials remains an enticing and highly desirable objective. Herein, ultrahigh proton conductivity and superior stability are achieved by taking advantage of COF composite membranes where 2D TB-COF nanosheets are linked by 1D lignocellulosic nanofibrils (LCNFs) through π-π and electrostatic interactions to form a robust and ordered structure. Notably, the high concentration of -SO3 H groups within the COF pores and the abundant proton transport paths at COFs-LCNFs interfaces impart composite membranes ultrahigh proton conductivity (0.348 S cm-1 at 80 °C and 100% RH). Moreover, the directional migration of protons along the stacked nanochannels of COFs is facilitated by oxygen atoms on the keto groups, as demonstrated by density functional theory (DFT) calculations. The simple design concept and reliable operation of the demonstrated mixed-dimensional composite membrane are expected to provide an ideal platform for next-generation conductive materials.

Identification of a cinnamoyl-CoA reductase from Cinnamomum cassia involved in trans-cinnamaldehyde biosynthesis.

MAIN CONCLUSION: The identification of a functional cinnamoyl-CoA reductase enzyme from Cinnamomum cassia involved in trans-cinnamaldehyde biosynthesis offers the potential for enhancing trans-cinnamaldehyde production through genetic engineering. A significant accumulation of trans-cinnamaldehyde has been found in the bark tissues of C. cassia, used in traditional Chinese medicine. trans-Cinnamaldehyde exhibits various pharmacological properties such as anti-inflammatory, analgesic, and protection of the stomach and the digestive tract. However, further elucidation and characterization of the biosynthetic pathway for trans-cinnamaldehyde is required. In this study, we conducted an integrated analysis of trans-cinnamaldehyde accumulation profiles and transcriptomic data from five different C. cassia tissues to identify the genes involved in its biosynthesis. The transcriptome data we obtained included nearly all genes associated with the trans-cinnamaldehyde pathway, with the majority demonstrating high abundance in branch barks and trunk barks. We successfully cloned four C. cassia cinnamoyl-CoA reductases (CcCCRs), a key gene in trans-cinnamaldehyde biosynthesis. We found that the recombinant CcCCR1 protein was the only one that more efficiently converted cinnamoyl-CoA into trans-cinnamaldehyde. CcCCR1 exhibited approximately 14.7-fold higher catalytic efficiency (kcat/Km) compared to the Arabidopsis thaliana cinnamoyl-CoA reductase 1 (AtCCR1); therefore, it can be utilized for engineering higher trans-cinnamaldehyde production as previously reported. Molecular docking studies and mutagenesis experiments also validated the superior catalytic activity of CcCCR1 compared to AtCCR1. These findings provide valuable insights for the functional characterization of enzyme-coding genes and hold potential for future engineering of trans-cinnamaldehyde biosynthetic pathways.

Single-center experience with self-expanding transcatheter aortic valve system for symptomatic high-risk patients with severe aortic regurgitation: One-year outcomes.

AIMS: To evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) for the treatment of aortic regurgitation (AR). METHODS: From September 2019 to February 2022, 62 patients who underwent transfemoral TAVI procedure for pure, symptomatic severe AR with the VitaFlow system were enrolled in the current study. The outcomes were assessed according to the Valve Academic Research Consortium 3 criteria. Procedural results and clinical outcomes for 1 year were analyzed. RESULTS: The mean age was 71.56 ± 7.34 years and 58.1% were male. The mean Society of Thoracic Surgeons score was 5.44 ± 3.22%. The device success rate was 79.0%. Only one patient was converted to open surgery. The in-hospital mortality rate was 1.6%. The 1-year all-cause mortality rate was 6.5%. The new permanent pacemaker implantation rate was 29.0% in-hospital and 30.7% at 1-year follow-up. The second valve implantation rate was 14.5%. No patient developed more than moderate paravalvular leakage during follow-up. The mean ejection fraction improved from 54.05 ± 10.83% at baseline to 59.32 ± 8.70% (p < 0.001 compared with baseline) at 12 months. Left ventricular end-diastolic diameter decreased from 61.62 ± 5.58 mm at baseline to 55.20 ± 4.51 mm (p < 0.001 compared with the baseline) at 12 months. CONCLUSIONS: Transfemoral TAVI procedure shows efficacy in treating patients with severe pure native AR. The safety is improved with the development of the VitaFlow system.

Correlated Hybrid DNA Structures Explored by the oxDNA Model.

Thermodynamically, perfect DNA hybridization can be formed between probes and their corresponding targets due to the favorable energy. However, this is not the case dynamically. Here, we use molecular dynamics (MD) simulations based on the oxDNA model to investigate the process of DNA microarray hybridization. In general, correlated hybrid DNA structures are formed, including one probe associated with several targets as well as one target hybrid with multiple probes leading to the target-mediated hybridization. The formation of these two types of correlated structures largely depends on the surface coverage of the DNA microarray. Moreover, DNA sequence, DNA length, and spacer length have an impact on the structural formation. Our findings shed light on the dynamics of DNA hybridization, which is important for the application of DNA microarray.

Comparison of total percutaneous in situ microneedle puncture and chimney technique for left subclavian artery fenestration in thoracic endovascular aortic repair for type B aortic dissection.

OBJECTIVE: To compare the outcomes of totally percutaneous in situ microneedle puncture for left subclavian artery (LSA) fenestration (ISMF) and chimney technique in type B aortic dissection (TBAD) during thoracic endovascular aortic repair (TEVAR). MATERIALS AND METHODS: Data on patients who underwent either chimney-TEVAR (n = 89) or ISMF-TEVAR (n = 113) from October 2018 to April 2022 were analyzed retrospectively. The primary outcomes were mortality and major complications at 30 days and during follow-up. RESULTS: The technical success rate was 84.3% in the chimney group and 93.8% in the ISMF group (p = 0.027). The incidence of immediate endoleakage was significantly higher in the chimney than ISMF group (15.7% vs 6.2%, respectively; p = 0.027). The 1- and 3-year survival rates in the chimney and ISMF groups were 98.9% ± 1.1% vs 98.1% ± 0.9% and 86.5% ± 6.3% vs 92.6% ± 4.1%, respectively (log-rank p = 0.715). The 3-year rate of cumulative freedom from branch occlusion in the chimney and ISMF group was 95.4% ± 2.3% vs 100%, respectively (log-rank p = 0.023). CONCLUSION: Both ISMF-TEVAR and chimney-TEVAR achieved satisfactory short- and mid-term outcomes for the preservation of the LSA in patients with TBAD. ISMF-TEVAR appears to offer better clinical outcomes with higher patency and lower reintervention rates. However, ISMF-TEVAR had longer operation times with higher procedure expenses. CLINICAL RELEVANCE STATEMENT: When LSA revascularization is required during TEVAR, in situ, fenestration, and chimney techniques are all safe and effective methods; in situ, fenestration-TEVAR appears to offer better clinical outcomes, but takes longer and is more complicated. KEY POINTS: LSA revascularization during TEVAR reduces post-operative complication rates. Both in situ ISMF-TEVAR and chimney-TEVAR are safe and effective techniques for the preservation of the LSA during TEVAR. The chimney technique is associated with a higher incidence of endoleakage and branch occlusion, but ISMF-TEVAR is a more complicated and expensive technique.

Testing latent classes in gut microbiome data using generalized Poisson regression models.

Human microbiome research has gained increasing importance due to its critical roles in comprehending human health and disease. Within the realm of microbiome research, the data generated often involves operational taxonomic unit counts, which can frequently present challenges such as over-dispersion and zero-inflation. To address dispersion-related concerns, the generalized Poisson model offers a flexible solution, effectively handling data characterized by over-dispersion, equi-dispersion, and under-dispersion. Furthermore, the realm of zero-inflated generalized Poisson models provides a strategic avenue to simultaneously tackle both over-dispersion and zero-inflation. The phenomenon of zero-inflation frequently stems from the heterogeneous nature of study populations. It emerges when specific microbial taxa fail to thrive in the microbial community of certain subjects, consequently resulting in a consistent count of zeros for these individuals. This subset of subjects represents a latent class, where their zeros originate from the genuine absence of the microbial taxa. In this paper, we introduce a novel testing methodology designed to uncover such latent classes within generalized Poisson regression models. We establish a closed-form test statistic and deduce its asymptotic distribution based on estimating equations. To assess its efficacy, we conduct an extensive array of simulation studies, and further apply the test to detect latent classes in human gut microbiome data from the Bogalusa Heart Study.

Joint modeling approaches for censored predictors due to detection limits with applications to metabolites data.

Measures of substance concentration in urine, serum or other biological matrices often have an assay limit of detection. When concentration levels fall below the limit, exact measures cannot be obtained, and thus are left censored. The problem becomes more challenging when the censored data come from heterogeneous populations consisting of exposed and non-exposed subjects. If the censored data come from non-exposed subjects, their measures are always zero and hence censored, forming a latent class governed by a distinct censoring mechanism compared with the exposed subjects. The exposed group's censored measurements are always greater than zero, but less than the detection limit. It is very often that the exposed and non-exposed subjects may have different disease traits or different relationships with outcomes of interest, so we need to disentangle the two different populations for valid inference. In this article, we aim to fill the methodological gaps in the literature by developing a novel joint modeling approach to not only address the censoring issue in predictors, but also untangle different relationships of exposed and non-exposed subjects with the outcome. Simulation studies are performed to assess the numerical performance of our proposed approach when the sample size is small to moderate. The joint modeling approach is also applied to examine associations between plasma metabolites and blood pressure in Bogalusa Heart Study, and identify new metabolites that are highly associated with blood pressure.

Tandem Catalysis for Simultaneous Removal of NOx and C3H8 with Inhibition of N2O.

Tandem catalysis is widely adopted for multipollutant control in mobile sources but has rarely been reported in stationary source emission elimination. This work proposed a tandem arrangement way with up-streamed V2O5/TiO2 + down-streamed Cr2O3/TiO2 catalysts, which could achieve the efficient synergistic control of NOx and C3H8 in industrial flue gas. Moreover, this arrangement successfully alleviated the unwanted N2O formation during the NH3 -SCR process. Compared to the conventional impregnation method of the Cr2O3-V2O5/TiO2 catalyst, the tandem catalysts of V2O5/TiO2 + Cr2O3/TiO2 could enhance the NOx and C3H8 conversion by 4.2% and 39.5%, respectively, at 350 °C. It might be attributed to the fact that Cr species was the active site for C3H8 oxidation, and the tandem arrangement of catalysts was beneficial to even dispersion of active components on supports. Furthermore, due to the preferential NOx removal over the up-streamed V2O5/TiO2 catalyst, the tandem catalysts obviously alleviated the N2O formation caused by Cr species during the NH3-SCR process. Herein, it significantly decreased N2O formation by 240.5% at 350 °C compared to the Cr2O3-V2O5/TiO2 catalyst, achieving multipollutant emission control from industrial flue gas with the performance of "one stone three birds".

Angiotensin II type-2 receptor signaling facilitates liver injury repair and regeneration via inactivation of Hippo pathway.

The angiotensin II type 2 receptor (AT2R) is a well-established component of the renin-angiotensin system and is known to counteract classical activation of this system and protect against organ damage. Pharmacological activation of the AT2R has significant therapeutic benefits, including vasodilation, natriuresis, anti-inflammatory activity, and improved insulin sensitivity. However, the precise biological functions of the AT2R in maintaining homeostasis in liver tissue remain largely unexplored. In this study, we found that the AT2R facilitates liver repair and regeneration following acute injury by deactivating Hippo signaling and that interleukin-6 transcriptionally upregulates expression of the AT2R in hepatocytes through STAT3 acting as a transcription activator binding to promoter regions of the AT2R. Subsequently, elevated AT2R levels activate downstream signaling via heterotrimeric G protein Gα12/13-coupled signals to induce Yap activity, thereby contributing to repair and regeneration processes in the liver. Conversely, a deficiency in the AT2R attenuates regeneration of the liver while increasing susceptibility to acetaminophen-induced liver injury. Administration of an AT2R agonist significantly enhances the repair and regeneration capacity of injured liver tissue. Our findings suggest that the AT2R acts as an upstream regulator in the Hippo pathway and is a potential target in the treatment of liver damage.

The relationship between air pollution and the occurrence of hypertensive disorders of pregnancy: Evidence from a study in Wuhan, China.

Ambient air pollution has been reported to be a risk factor for hypertensive disorders of pregnancy (HDP). Past studies have reported supportive evidence, but evidence from China is scarce and does not integrate the different periods of the pregnancy course. In this study, 1945 pregnant women with HDP and healthy pregnancies between 2016 and 2022 from the Renmin Hospital of Wuhan University registry network database were analysed. The geographic information, biological information and demographic information of the case were fused in the analysis. Machine learning methods were used to obtain the weight of the variable. Then, we used the generalized linear mixed model to evaluate the relationship between increased exposure to each pollutant at different periods of HDP and examined it in different groups. The results showed that SO2 had the predominate impact (12.65 %) on HDP compared with other air pollutants. SO2 exposure was associated with an increased risk of HDP. Increased unit SO2 concentrations were accompanied by an increased risk of HDP (OR = 1.33, 95 % CI: 1.13, 1.566), and the susceptible window for this effect was mainly in the first trimester (OR = 1.242, 95 % CI: 1.092, 1.412). In addition, SO2 exposure was associated with an increased risk of HDP in urban maternity (OR = 1.356, 95 % CI: 1.112, 1.653), obese maternity (OR = 3.58, 95 % CI: 1.608, 7.971), no higher education maternity (OR = 1.348, 95 % CI: 1.065, 1.706), nonzero delivery maternity (OR = 1.981, 95 % CI: 1.439, 2.725), maternal with first time maternity (OR = 1.247, 95 % CI: 1.007, 1.544) and other groups. In summary, SO2 exposure in early pregnancy is one of the risk factors for HDP, and the increased risk of HDP due to increased SO2 exposure may be more pronounced in obese, urban, low-education, and nonzero delivery populations.

Effect of Local Zoledronic Acid Application in Alveolar Bone Healing: An Experimental Study.

BACKGROUND: This experimental study aimed to assess the three-dimensional and histological changes of the alveolar socket with local application of ZA. METHODS: Nine male New Zealand white rabbits were randomly allocated into 4-, 8-, and 12-week groups after the extraction of 4 incisor teeth. The upper and lower right sockets were filled with ZA + collagen sponge (ZA-CS group), while the left sockets were filled with collagen sponge alone (CS group) postoperatively. At 4, 8, and 12 weeks (T1, T2, and T3) after the extraction, radiographic and histomorphometric evaluations were conducted for both groups. RESULTS: The increase in alveolar bone density of the ZA-CS group at T2 and T3 was significantly higher than the CS group (P＜0.01). Three-dimensional evaluations demonstrated no statistically significant differences in ridge height and width between the 2 groups at T2 and T3. On histological evaluation, the ZA-CS group included significantly fewer TRAP-positive cells than the CS group at T1 (P＜0.05). In ALP staining, all cases in both groups were classified as positive at each time point. Masson trichrome staining showed significantly higher mean red collagen volume fraction in the ZA-CS group (76.09%, 79.64%) than in the CS group (66.17%, 69.22%) at T2 and T3, respectively (P＜0.05 and ＜0.01). CONCLUSIONS: Although local ZA application with collagen sponge did not reduce alveolar ridge contraction, it improved the bone density and maturity of newly formed bone after tooth extraction.

Security in Transformer Visual Trackers: A Case Study on the Adversarial Robustness of Two Models.

Visual object tracking is an important technology in camera-based sensor networks, which has a wide range of practicability in auto-drive systems. A transformer is a deep learning model that adopts the mechanism of self-attention, and it differentially weights the significance of each part of the input data. It has been widely applied in the field of visual tracking. Unfortunately, the security of the transformer model is unclear. It causes such transformer-based applications to be exposed to security threats. In this work, the security of the transformer model was investigated with an important component of autonomous driving, i.e., visual tracking. Such deep-learning-based visual tracking is vulnerable to adversarial attacks, and thus, adversarial attacks were implemented as the security threats to conduct the investigation. First, adversarial examples were generated on top of video sequences to degrade the tracking performance, and the frame-by-frame temporal motion was taken into consideration when generating perturbations over the depicted tracking results. Then, the influence of perturbations on performance was sequentially investigated and analyzed. Finally, numerous experiments on OTB100, VOT2018, and GOT-10k data sets demonstrated that the executed adversarial examples were effective on the performance drops of the transformer-based visual tracking. White-box attacks showed the highest effectiveness, where the attack success rates exceeded 90% against transformer-based trackers.

All-fiber sensor for simultaneous measurement of refractive index and temperature based on hole-assisted three-core fiber.

A hole-assisted three-core fiber (HATCF) has been proposed as a sensor for simultaneous measurement of refractive index (RI) and temperature. An 8 mm long HATCF is fused between two single mode fibers (SMFs). One air hole of the HATCF is opened by femtosecond laser ablation technique to expose a suspended core to the external environment. Due to the same diameters of the two suspended cores, the resonance couplings between the center core and the two suspended cores occur at the same wavelength, which leads to a strong resonance dip. When the solution is filled into the open air hole, the resonance dip is split in two dips because the phase matching wavelength between center core and the suspended core in the open air hole is changed. Simultaneous measurement of RI and temperature can be achieved by monitoring the wavelengths of the two dips. The measured RI and temperature sensitivities are 1369 nm/RIU in the range of 1.333-1.388 and 83.48 pm/°C in the range of 25-70 °C. The proposed sensor has outstanding advantages such as simple structure, high integration and dual parameter measurement, making it a potential application in the field of biological detection.

Simultaneous measurement of temperature and salinity based on a hole-assisted dual-core fiber.

An optical fiber sensor based on a hole-assisted dual-core fiber (HADCF) has been proposed and experimentally demonstrated for dual-parameter measurements. The dual-mode interferometer created uses the LP01 mode and LP11 mode in the suspended core of a specialist optical fiber, combined with a directional coupler formed by using the suspended core and the center core in a 16 mm long HADCF. Using this, the simultaneous measurement of salinity (due to the presence of NaCl) and temperature has been achieved through monitoring the interference dip and resonance dip. The sensitivities of the measurement of salinity and temperature are 190.7 pm/‰ and -188.2 pm/°C, respectively. The sensor developed has the advantages of simplicity of fabrication, a high level of integration and the potential for measurement of dual parameters, supporting its potential applications in marine environment measurements.

High-resolution compact spectrometer based on periodic tapered coreless fiber.

This Letter proposes a method that balances miniaturization and high performance of fiber optic speckle spectrometers. The periodically tapered coreless fiber is used as the scattering element to excite more higher-order modes in the coreless fiber. As a result, a remarkable spectral resolution of 0.03 nm in the near-infrared spectrum can be achieved with a 5-cm-long fiber. Narrow linewidth and broadband spectra in the wavelength of 1540-1560 nm are reconstructed separately, demonstrating the excellent performance of the designed all-fiber spectrometer. The spectral resolution of our proposed spectrometer is comparable to that of a 2-m multimode fiber spectrometer and has a significant improvement in miniaturization.

Topological Fracton Quantum Phase Transitions by Tuning Exact Tensor Network States.

Gapped fracton phases of matter generalize the concept of topological order and broaden our fundamental understanding of entanglement in quantum many-body systems. However, their analytical or numerical description beyond exactly solvable models remains a formidable challenge. Here we employ an exact 3D quantum tensor-network approach that allows us to study a Z_{N} generalization of the prototypical X cube fracton model and its quantum phase transitions between distinct topological states via fully tractable wave function deformations. We map the (deformed) quantum states exactly to a combination of a classical lattice gauge theory and a plaquette clock model, and employ numerical techniques to calculate various entanglement order parameters. For the Z_{N} model we find a family of (weakly) first-order fracton confinement transitions that in the limit of N→∞ converge to a continuous phase transition beyond the Landau-Ginzburg-Wilson paradigm. We also discover a line of 3D conformal quantum critical points (with critical magnetic flux loop fluctuations) which, in the N→∞ limit, appears to coexist with a gapless deconfined fracton state.

Iridium-catalysed thioether-directed regioselective cycloaddition of internal alkynes with azides.

We report herein a cationic iridium-catalysed thioether-directed alkyne-azide cycloaddition reaction. Diverse 2-alkynyl phenyl sulfides can undergo cycloaddition with different azides in a regioselective fashion. The reaction features high efficiency, a short reaction time, and a broad substrate scope, providing modular access to complex S-containing triazoles.

Z-Selective access to α-trifluoromethyl arylenes through Pd-catalysed fluoroarylation of 1,1-difluoroallenes.

The synthesis of stereo-defined α-trifluoromethyl arylenes is of great importance in medical chemistry, organic chemistry, and materials science. However, despite the recent advances, the Z-selective formation of α-trifluoromethyl arylenes has remained underdeveloped. Here, we describe a facile approach towards Z-α-trifluoromethyl arylenes through Pd-catalysed stereoselective fluoroarylation of 1,1-difluoroallenes in the presence of a bulky monophosphine ligand.

Inhibition of PCSK9 Improves the Development of Pulmonary Arterial Hypertension Via Down-Regulating Notch3 Expression.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by continuous constriction and occlusion of small pulmonary arteries, leading to the development of right ventricular failure and death. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a kind of serine protease enzyme that increases low-density lipoprotein cholesterol (LDLC) levels through degrading low-density lipoprotein cholesterol receptors (LDLr). However, whether inhibition of PCSK9 can alleviate PAH has not been reported. METHODS AND RESULTS: We reported that PCSK9 expression was up-regulated in lung tissues of PAH patients. In addition, we used PCSK9 monoclonal antibody subcutaneously to inhibit PCSK9 expression in mice exposed to chronic hypoxia (10%) in combination with SU5416, a VEGF receptor inhibitor. Hypoxia plus SU5416-induced PAH was attenuated in PCSK9 monoclonal antibody-treated mice compared with wild-type mice. PCSK9 inhibited pulmonary vascular remodeling in mice. Moreover, PCSK9 knockdown significantly altered the proliferation and migration of hypoxia-induced PASMCs. We also found that PCSK9 monoclonal antibody inhibited Notch3 expression in vivo and in vitro. CONCLUSION: Our results suggest that the PCSK9-Notch3 signaling pathway is critical for the proliferation and migration of PASMCs and provides a potential drug target for the treatment of PAH.