Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension

Respiratory Research, Journal Year: 2022, Volume and Issue: 23(1)

Published: Jan. 11, 2022

Hypoxic pulmonary hypertension (HPH) is a chronic progressive advanced disorder pathologically characterized by vascular remodeling. Notch4 as cell surface receptor critical for development. However, little known about the role and mechanism of in development hypoxic remodeling.Lung tissue samples were collected to detect expression from patients with HPH matched controls. Human artery smooth muscle cells (HPASMCs) cultured normoxic conditions. Real-time quantitative PCR western blotting used examine mRNA protein levels Notch4. HPASMCs transfected small interference RNA (siRNA) against or overexpression plasmid, respectively. Cell viability, proliferation, apoptosis, migration assessed using Counting Kit-8, Edu, Annexin-V/PI, Transwell assay. The interaction between ERK, JNK, P38 MAPK analyzed co-immunoprecipitation. Adeno-associated virus 1-mediated siRNA (AAV1-si-Notch4) was injected into airways rats. Right ventricular systolic pressure (RVSP), right hypertrophy remodeling evaluated.In this study, we demonstrate that highly expressed media upregulated lung tissues rats compared control groups. In vitro, hypoxia induces high Delta-4 HPASMCs. increased promotes proliferation inhibits apoptosis via signaling pathways. Furthermore, co-immunoprecipitation result elucidates ERK/JNK/P38. vivo, silencing partly abolished increase RVSP caused rats.These findings reveal an important Notch4-ERK/JNK/P38 axis provide potential therapeutic target HPH.

Language: Английский

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SOX17 is a Critical Factor in Maintaining Endothelial Function in Pulmonary Hypertension by an Exosome‐Mediated Autocrine Manner

Advanced Science, Journal Year: 2023, Volume and Issue: 10(14)

Published: March 15, 2023

Endothelial dysfunction is considered a predominant driver for pulmonary vascular remodeling in hypertension (PH). SOX17, key regulator of homoeostasis, has been found to harbor mutations PH patients, which are associated with susceptibility. Here, this study explores whether SOX17 mediates the autocrine activity artery ECs maintain endothelial function and homeostasis its underlying mechanism. It that expression downregulated endothelium remodeled arteries IPH patients SU5416/hypoxia (Su/hypo)-induced mice as well dysfunctional HPAECs. knockdown accelerates progression Su/hypo-induced mice. overexpression attenuates PH. SOX17-associated exosomes block proliferation, apoptosis, inflammation HPAECs, preventing arterial Mechanistic analyses demonstrates overexpressing promotes exosome-mediated release miR-224-5p miR-361-3p, internalized by injured HPAECs an manner, ultimately repressing upregulation NR4A3 PCSK9 genes improving function. These results suggest gene maintaining through regulating exosomal miRNAs manner.

Language: Английский

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Single cell transcriptomic analyses reveal diverse and dynamic changes of distinct populations of lung interstitial macrophages in hypoxia-induced pulmonary hypertension

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: April 15, 2024

Introduction Hypoxia is a common pathological driver contributing to various forms of pulmonary vascular diseases leading hypertension (PH). Pulmonary interstitial macrophages (IMs) play pivotal roles in immune and dysfunction, inflammation, abnormal remodeling, fibrosis PH. However, IMs’ response hypoxia their role PH progression remain largely unknown. We utilized murine model hypoxia-induced investigate the repertoire functional profiles IMs acute prolonged hypoxia, aiming elucidate contributions development. Methods conducted single-cell transcriptomic analyses characterize following exposure hypobaric for varying durations (0, 1, 3, 7, 21 days). Hallmark pathways from mouse Molecular Signatures Database were molecular function IM subpopulation hypoxia. Results Our analysis revealed an early inflammatory phase during (Days 1-3), which was resolved by Day followed pro-remodeling 7-21). These phases marked distinct subpopulations IMs: MHCII hi CCR2 + EAR2 cells characterized phase, while TLF VCAM1 dominated phase. The exhibited enrichment interferon-gamma, IL-2, IL-6 pathways, showed dysregulated chemokine production, hemoglobin clearance, tissue repair profiles, along with activation complement pathways. Discussion findings demonstrate existence populations corresponding exposure, regulating remodeling pathogenesis. This understanding offers potential avenues targeted interventions, tailored specific disease. Moreover, further identification triggers holds promise unveiling novel therapeutic strategies hypertension.

Language: Английский

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Elucidating VSMC phenotypic transition mechanisms to bridge insights into cardiovascular disease implications

Frontiers in Cardiovascular Medicine, Journal Year: 2024, Volume and Issue: 11

Published: May 13, 2024

Cardiovascular diseases (CVD) are the leading cause of death worldwide, despite advances in understanding cardiovascular health. Significant barriers still exist effectively preventing and managing these diseases. Vascular smooth muscle cells (VSMCs) crucial for maintaining vascular integrity can switch between contractile synthetic functions response to stimuli such as hypoxia inflammation. These transformations play a pivotal role progression diseases, facilitating modifications disease advancement. This article synthesizes current mechanisms signaling pathways regulating VSMC phenotypic transitions, highlighting their potential therapeutic targets interventions.

Language: Английский

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New Insight in HDACs: Potential Therapeutic Targets for the Treatment of Atherosclerosis

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: April 21, 2022

Atherosclerosis (AS) features include progressive hardening and reduced elasticity of arteries. AS is the leading cause morbidity mortality. An increasing amount evidence showed that epigenetic modifications on genes serve are a main several diseases, including AS. Histone deacetylases (HDACs) promote deacetylation at lysine residues, thereby condensing chromatin structures further inhibiting transcription downstream genes. HDACs widely affect various physiological pathological processes through transcriptional regulation or other non-histone proteins. In recent years, role in vascular systems has been revealed, their effects atherosclerosis have reported. this review, we discuss members systems, determine diverse roles AS, reveal HDAC inhibitors progression. We provide new insights into potential as drugs for treatment.

Language: Английский

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Elucidating the relationship between migraine risk and brain structure using genetic data

Brain, Journal Year: 2022, Volume and Issue: 145(9), P. 3214 - 3224

Published: March 20, 2022

Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants brain morphometry differences associated with migraine risk. However, the relationship between has not been examined on level, causal nature association structure risk determined. Using largest available genome-wide to date, we overlap intracranial volume, as well regional volumes nine subcortical structures. We further focused identification biological annotation each specific regions genome shared structure. Finally, whether size any causally increased using Mendelian randomization approach. observed significant negative correlation volume (rG = -0.11, P 1 × 10-3) but region. jointly genomic every Gene enrichment these pointed possible links neuronal signalling vascular regulation. provide evidence smaller total brain, hippocampal ventral diencephalon risk, larger amygdala. leveraged power large show pathways influence several structures, suggesting altered high may be genetically mediated. Further interrogation results showed support for neurovascular hypothesis aetiology shed light potentially viable therapeutic targets.

Language: Английский

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Neferine ameliorates hypertensive vascular remodeling modulating multiple signaling pathways in spontaneously hypertensive rats

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 158, P. 114203 - 114203

Published: Jan. 5, 2023

Neferine exhibits therapeutic effects on anti-hypertension. However, the effect of neferine hypertensive vascular remodeling remains unexplored. Therefore, current study was to investigate and its underlying mechanisms.Total 30 male spontaneously rats (SHRs) were divided randomly into five groups, including SHR, Neferine-L (2.5 mg/kg/day), Neferine-M (5 Neferine-H (10 Valsartan mg/kg/day) groups (n = 6 for each group). Wistar Kyoto (WKY) set as control group 6). Noninvasive blood pressure system, ultrasound, hematoxylin eosin staining, masson trichrome staining used detect pressure, pulse wave velocity (PWV), pathological changes collagen content in abdominal aortas SHRs. RNA-sequencing immunohistochemistry(IHC) analyses identify verify differentially expressed transcripts activation associated signaling pathways SHRs.Various concentrations or valsartan treatment substantially reduced elevation PWV, aortic thickening KEGG recognized 441 several enriched (including PI3K/AKT TGF-β/Smad2/3 pathways) after treatment. Masson trichromatic IHC analysis demonstrated that decreased down-regulated protein expression PCNA, I & III, fibronectin, well p-PI3K, p-AKT, TGF-β1 p-Smad2/3 tissues SHRs.Neferine anti-hypertension reduces remodeling, suppresses abnormal multiple pathways, TGF-β1/Smad2/3 pathways.

Language: Английский

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Notch3/Hes5 Induces Vascular Dysfunction in Hypoxia-Induced Pulmonary Hypertension Through ER Stress and Redox-Sensitive Pathways

Hypertension, Journal Year: 2023, Volume and Issue: 80(8), P. 1683 - 1696

Published: May 31, 2023

BACKGROUND: Notch3 (neurogenic locus notch homolog protein 3) is implicated in vascular diseases, including pulmonary hypertension (PH)/pulmonary arterial hypertension. However, molecular mechanisms remain elusive. We hypothesized increased activation induces oxidative and endoplasmic reticulum (ER) stress downstream redox signaling, associated with procontractile artery state, dysfunction, PH development. METHODS: Studies were performed TgNotch3 R169C mice (harboring gain-of-function [GOF] mutation) exposed to chronic hypoxia induce PH, examined by hemodynamics. Molecular cellular studies smooth muscle cells from patients mouse lung. Notch3-regulated genes/proteins, ER stress, ROCK (Rho-associated kinase) expression/activity, Ca 2+ transients generation of reactive oxygen species, nitric oxide measured. Pulmonary reactivity was assessed the presence fasudil (ROCK inhibitor) 4-phenylbutyric acid (ER inhibitor). RESULTS: Hypoxia induced a more severe phenotype versus controls. exhibited enhanced expression targets Hes Family BHLH Transcription Factor 5 (Hes5), contraction impaired vasorelaxation that improved fasudil/4-phenylbutyric acid. mutation vessel transients, activation, species generation, reduced NO blunted sGC (soluble guanylyl cyclase)/cGMP signaling. These effects ameliorated N-acetylcysteine. recapitulated Notch3/Hes5 changes observed mice. CONCLUSIONS: GOF amplifies dysfunction hypoxic PH. This involves ROCK. highlight novel role for Notch3/Hes5-redox signaling important interplay between

Language: Английский

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

Cardiovascular Drugs and Therapy, Journal Year: 2023, Volume and Issue: unknown

Published: May 31, 2023

Language: Английский

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Hemodynamic and Clinical Profiles of Pulmonary Arterial Hypertension Patients with GDF2 and BMPR2 Variants

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2734 - 2734

Published: Feb. 27, 2024

Asians have a higher carrier rate of pulmonary arterial hypertension (PAH)-related genetic variants than Caucasians do. This study aimed to identify PAH-related using whole exome sequencing (WES) in Asian idiopathic and heritable PAH cohorts. A WES library was constructed, candidate were further validated by polymerase chain reaction Sanger the cohort. In total 69 patients, highest incidence found BMPR2, ATP13A3, GDF2 genes. Regarding BMPR2 gene variants, there two nonsense (c.994C>T, p. Arg332*; c.1750C>T, Arg584*), one missense variant (c.1478C>T, Thr493Ile), novel in-frame deletion (c.877_888del, Leu293_Ser296del). likely pathogenic (c.259C>T, Gln87*) (c.1207G>A, Val403Ile; c.38T>C, Leu13Pro). The subgroups had worse hemodynamics. Moreover, patients younger significantly lower value (135.6 ± 36.2 pg/mL, p = 0.002) comparison non-BMPR2/non-GDF2 mutant group (267.8 185.8 pg/mL). carriers hemodynamics compared with group. control may be protective or corrected modifier certain backgrounds.

Language: Английский

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