Muscle Cells Research Articles

Enzymatic Hydrolysate of Low-Molecular-Weight Soybean Peptides Suppresses Hydrogen Peroxide-Induced Apoptosis of Murine Myoblast C2C12 Cells Possibly via AMPK Activation.

Skeletal muscle health is essential for metabolic homeostasis, and dysregulated apoptosis in muscle cells can lead to muscle wasting and degenerative diseases. Although soybean-derived peptides are known for their bioactive properties, including antioxidant and anti-apoptotic effects, their impact on apoptosis regulation in skeletal muscle cells remains underexplored. This study aims to investigate the effects of low-molecular-weight soy peptide hydrolysate (SPH) on apoptosis and related markers in C2C12 myoblasts. SPH was prepared by enzymatic hydrolysis, and its antioxidant and anti-apoptotic activities were analyzed through in vitro assays (i.e., ABTS, DPPH). Cellular studies were used to evaluate SPH effects on ROS scavenging and apoptosis. Results show that SPH enhanced antioxidant activity, reduced ROS levels, and promoted cell proliferation in a dose-dependent manner. SPH notably decreased apoptosis under oxidative stress by down-regulating p53, c-Caspase-3, and Cyto-c, while promoting HO-1 expression, likely via AMPK activation. Importantly, SPH had no significant impact on inflammation-related proteins or MAPK activation. These findings suggest that SPH may have therapeutic potential against oxidative stress and apoptosis in muscle cells through intrinsic pathways, contributing to muscle health maintenance.

Development of 3D Muscle Cell Culture-Based Screening System for Metabolic Syndrome Drug Research.

Developing effective drug screening methods for type 2 diabetes requires physiologically relevant models. Traditional 2D cell cultures have limitations in replicating invivo conditions, leading to challenges in assessing drug efficacy. To overcome these issues, we developed a 3D artificial muscle model that induces insulin resistance, a hallmark of type 2 diabetes. Using C2C12 myoblasts cultured in a scaffold of 1% alginate and 1 mg/mL collagen type 1, we optimized conditions for differentiation and structural stability. Insulin resistance was induced using palmitic acid (PA), and glucose uptake was assessed using the fluorescent glucose analog 2-NBDG. The 3D model demonstrated superior glucose uptake responses compared with 2D cultures, with a threefold increase in insulin-stimulated glucose uptake on days 4 and 8 of differentiation. Induced insulin resistance was observed with 0.1 mM PA, which maintained cell viability and differentiation capacity. The model was validated through comparative drug screening using rosiglitazone and metformin, as well as 165 candidate compounds provided by Korea Chemical Bank. Drug screening revealed that three out of five hit compounds identified in both 2D and 3D models exhibited greater efficacy in 3D cultures, with results consistent with ex vivo assays using mouse soleus muscle. This model closely mimics invivo conditions, offering a robust platform for type 2 diabetes drug discovery while supporting ethical research practices.

SMURF1-Induced Ubiquitination of FTH1 Disrupts Iron Homeostasis and Suppresses Myogenesis

Ferritin heavy chain 1 (FTH1) is pivotal in the storage, release, and utilization of iron, plays a crucial role in the ferroptosis pathway, and exerts significant impacts on various diseases. Iron influences skeletal muscle development and health by promoting cell growth, ensuring energy metabolism and ATP synthesis, maintaining oxygen supply, and facilitating protein synthesis. However, the precise molecular mechanisms underlying iron’s regulation of skeletal muscle growth and development remain elusive. In this study, we demonstrated that the conditional knockout (cKO) of FTH1 in skeletal muscle results in muscle atrophy and impaired exercise endurance. In vitro studies using FTH1 cKO myoblasts revealed notable decreases in GSH concentrations, elevated levels of lipid peroxidation, and the substantial accumulation of Fe2+, collectively implying the induction of ferroptosis. Mechanistically, E3 ubiquitin-protein ligase SMURF1 (SMURF1) acts as an E3 ubiquitin ligase for FTH1, thereby facilitating the ubiquitination and subsequent degradation of FTH1. Consequently, this activation of the ferroptosis pathway by SMURF1 impedes myoblast differentiation into myotubes. This study identifies FTH1 as a novel regulator of muscle cell differentiation and skeletal muscle development, implicating its potential significance in maintaining skeletal muscle health through the regulation of iron homeostasis.

Silencing drug transporters in human primary muscle cells modulates atorvastatin pharmacokinetics: A pilot study.

Non-adherence to atorvastatin treatment is relatively common and partly due to statin-related myotoxicities (SRMs). The risk of developing SRM is dose- and concentration-dependent, highlighting the importance of atorvastatin pharmacokinetics. This study explored the inter-individual variabilities in expression of the atorvastatin transporter gene contributing to modulation of atorvastatin within the muscle cell. mRNA levels of efflux and influx transporters were measured and modulated with siRNAs to evaluate effects on intracellular accumulation of atorvastatin in primary cultures of differentiated myotubes from 12 human volunteers. All genes assessed were expressed with a high inter-individual variability. In differentiated myotubes, efflux transporters were expressed at higher levels than the influx carriers. When considering efflux and influx transporters separately, ABCC1 and SLCO2B1 are the most highly expressed efflux and influx transporters. Suppression of ABCC1, ABCC4 and/or ABCG2 mRNA levels with siRNA significantly increased intracellular accumulation of atorvastatin in differentiated myotubes. Interestingly, the siRNA targeting ABCG2 had a moderate effect on intracellular accumulation of atorvastatin in a volunteer expressing the ABCG2 variant rs2231142 (c.421C>A, p.Gln141Lys). This hypothesis was further validated in a HEK recombinant model overexpressing ABCG2 either wild-type (421C) or variant (421A). Reduction of SLCO1B1 and SLCO2B1 mRNA levels significantly modified intracellular accumulation of atorvastatin in only some volunteers, depending on the expression levels of transporters. Silencing ABCC1, ABCC4 or ABCG2 expression alters accumulation of atorvastatin in myotubes, whereas the effect of silencing influx transporters depends on the expression of these transporters.

Production of cell culture-based micro-tissue from muscle and fin cell lines of Lates calcarifer using biocompatible scaffolds

Production of cell culture-based micro-tissue from muscle and fin cell lines of Lates calcarifer using biocompatible scaffolds

Inflammation induced PFKFB3-mediated glycolysis promoting myometrium contraction through the PI3K-Akt-mTOR pathway in preterm birth mice.

Inflammation is a significant risk factor for preterm birth. Inflammation enhances glycolytic processes in various cell types and contributes to the development of myometrial contractions. However, the potential of inflammation to activate glycolysis in pregnant murine uterine smooth muscle cells (mUSMCs) and its role in promoting inflammatory preterm birth remain unexplored. In this study, lipopolysaccharide was employed to establish both cell and animal inflammation models. We found that inflammation of mUSMCs during late pregnancy could initiate glycolysis and promoted cell contraction. Subsequently, the inhibition of glycolysis using the glycolysis inhibitor 2-deoxyglucose can reverse inflammation-induced cell contraction. The expression of 6-phosphofructokinase 2 kinase (PFKFB3) was significantly upregulated in mUSMCs following lipopolysaccharide stimulation. Additionally, lactate accumulation and enhanced contraction were observed. Inhibition of PFKFB3 reversed the lactate accumulation and enhanced contraction induced by inflammation. We also found that inflammation activated the phosphatidylinositol 3-kinase (PI3K) - protein kinase B (Akt) - mammalian target of rapamycin (mTOR) pathway, leading to the upregulation of PFKFB3 expression. The PI3K-Akt pathway inhibitor LY294002 and the mTOR pathway inhibitor Rapamycin effectively inhibited the upregulation of PFKFB3 protein expression, lactate production, and the enhancement of cell contraction induced by lipopolysaccharide. This study indicates that inflammation regulates PFKFB3 through the PI3K-Akt-mTOR pathway, which enhances the glycolytic process in pregnant mUSMCs, ultimately leading to myometrial contraction.

Vasorelaxant effects and its mechanisms of the rhizome of Acorus gramineus on isolated rat thoracic aorta

In conventional medicine, the rhizome of Acorus gramineus Solander (AGR) is used to treat cardiovascular and cerebrovascular diseases. Decoctions containing AGR exert vasorelaxant effects. Therefore, this research aimed to delve deeper into the vasorelaxant effects and underlying mechanisms of AGR and its constituents (α-asarone and β-asarone). We assessed the vasorelaxant effect of a 50% ethanol extract of AGR (AGRE) using aortic rings from Sprague–Dawley rats pre-constricted with phenylephrine (PE) and potassium chloride (KCl). The findings suggested that the mechanism of this effect was independent of endothelial cells and was associated with vascular smooth muscle cells (VSMC). Since vasodilatory mechanisms associated with VSMC are predominantly influenced by K+ and Ca2+ channels, we explored various channels, including calcium-activated K+, voltage-dependent (delayed rectifier) K+, ATP-sensitive K+, inwardly rectifying K+, receptor-operated Ca2+ (ROCC), and voltage-dependent Ca2+ channels (VDCC). Selective blockers were used to examine K+ channels, which inhibited vasorelaxant effect of AGRE. These findings suggest that AGRE-induced vasorelaxation is facilitated through K+ channels. In addition, the blockage of Ca2+ influx was observed in both groups treated with PE and KCl. Therefore, AGR appears to block Ca2+ influx through ROCC and VDCC. In conclusion, AGR demonstrates vasorelaxant effects by acting on VSMC.

Role of the calcium-sensing receptor in regulating vascular function.

Functional expression of the calcium-sensing receptor (CaSR) in calcitropic tissues, for example, parathyroid glands and kidneys, is important for maintaining Ca2+ homeostasis. It is also established that the CaSR is present in tissues previously thought to be noncalcitropic and this review discusses the role of the CaSR in vascular function, focusing mainly on contractility but also outlining its role in cell proliferation and calcification. Stimulation of the CaSR by extracellular Ca2+ concentration ([Ca2+]o) on perivascular sensory nerves and vascular endothelial cells is associated with vasodilatation through the release of vasoactive substances and stimulation of IKCa channels and nitric oxide synthesis, respectively, which mediate endothelium-derived hyperpolarizations and activation of BKCa channels and KATP channels in vascular smooth muscle cells (VSMCs). CaSR-induced vasoconstrictions are mediated by the CaSR expressed in VSMCs, which are coupled to the Gq/11 protein-coupled pathway. In addition, the CaSR expressed on VSMCs also regulates proliferation and calcification. Consequently, the CaSR has been implicated in regulating systemic and pulmonary blood pressure and calcimimetics and calcilytics are potential therapeutic targets for cardiovascular diseases, such as hypertension, pulmonary artery hypertension, and atherosclerosis.

Single intraluminal delivery of a nitric oxide-donor results in inhibition of intimal thickening in the rabbit femoral artery.

Vascular smooth muscle cell proliferation and vascular homeostasis is thought to be regulated by nitric oxide and prostaglandins. We examined the effect of exogenous linsidomine, a NO releasing compound, in a model of balloon injury iliac arteries of rabbits. On the cellular levels NO can exert effects like cellular survival, growth and proliferation inhibition. Smooth muscle cell (SMC) proliferation was quantified as change of intima-media-ratio. Linsidomine injection or its vehicle was performed with an infusion-balloon catheter directly into the vessel wall. Balloon angioplasty resulted in a significant increase of intima-media-ratio during three weeks. Linsidomine treatment decreased the intima media ratio significantly (0.65±0.05 vs 1,2±0.2 intima-media-ratio, p<0.05). However, control vessels had an intima media ratio of 0.15±0.02. This effect was similar to NOS-2 transfected vessels following angioplasty. In in vitro experiments linsidomine inhibited significantly and dose-dependently rabbit smooth muscle cell proliferation measured by BrdU incorporation. Further linsidomine increased rate of apoptotic SMC's, however this effect was p53 independent. Simultaneous angioplasty of the rabbit iliac artery and direct injection of linsidomine into the vessel wall seem to be an effective strategy to reduce neointima formation. Despite single administration, local application of linsidomine resulted in potent inhibition of intima proliferation.

RETRACTION: Decellularized Scaffolds with Double-Layer Aligned Microchannels Induce the Oriented Growth of Bladder Smooth Muscle Cells: Toward Urethral and Ureteral Reconstruction.

Q. Cheng, L. Zhang, J. Zhang, X. Zhou, B. Wu, D. Wang, T. Wei, M. Shafiq, S. Li, D. Zhi, Y. Guan, K. Wang, and D. Kong, "Decellularized Scaffolds with Double-Layer Aligned Microchannels Induce the Oriented Growth of Bladder Smooth Muscle Cells: Toward Urethral and Ureteral Reconstruction," Advanced Healthcare Materials 12, no. 26 (2023): 2300544, https://doi.org/10.1002/adhm.202300544. The above article, published online on 28 August 2023 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Uta Goebel; and Wiley-VCH GmbH. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed inappropriate duplication of image sections and/or formatting artefacts in Figures 2B, 5A, and 7C, as well as errors in Figure S8 and its quantifications. The authors have stated that these image alterations wereperformed to enhance the visual appearance of the images and do not impact the clinical and scientific findings outlined in the paper. Nevertheless, due to the number and the level of inconsistencies identified in the published figures, the editors considered the conclusions substantially compromised and decided to retract the article.

Super-Enhancer Target Gene CBP/p300-Interacting Transactivator With Glu/Asp-Rich C-Terminal Domain, 2 Cooperates With Transcription Factor Forkhead Box J3to Inhibit Pulmonary Vascular Remodeling.

The function of super-enhancers (SEs) in pulmonary hypertension (PH), especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs), is currently unknown. We identified SEs-targeted genes in PASMCs with chromatin immunoprecipitation (ChIP)-sequence by H3K27ac antibody and proved that CBP/p300-interacting transactivator with Glu/Asp-rich C-terminal domain, 2 (CITED2) is an SEs-targeted gene through bioinformatics prediction, ChIP-PCR, dual-luciferase reporter gene assays and other experimental methods. We also found that the expression of CITED2 and the transcription factor Forkhead Box J3 (FOXJ3) was reduced in hypoxic mouse PASMCs. In addition, the expression of CITED2 and FOXJ3 also decreased in both the patients with idiopathic pulmonary arterial hypertension (iPAH) and the human PASMCs exposed to hypoxia. The decreased expression of CITED2 was reversed by co-transfection of FOXJ3 and SEs plasmids. Overexpressing of CITED2 attenuated the PASMCs proliferation induced by hypoxia. Lentiviral overexpression of CITED2 also reversed hypoxia-induced pulmonary hypertension mice model. Mechanically, the expression of CITED2 by affecting by FOXJ3, which binding with three SEs located in the about 2000 bp of TSS. In conclusion, we first identified that CITED2 is a kind of SEs-targeted gene, modulated by FOXJ3. The FOXJ3/SEs/CITED2 axis may become a new therapeutic target of PH.

Fibrinopeptide a promotes the proliferation and migration of vascular smooth muscle cells by regulating the integrin αVβ3/PI3K/AKT signaling pathway.

Atherosclerosis is characterized by subintimal proliferation and migration of vascular smooth muscle cells (VSMCs) in response to stimuli such as coagulation and inflammatory factors. Fibrinopeptide A (FPA), a biomarker for coagulation system activation, is elevated in patients with ischemic heart disease. However, its role in the pathophysiology of cardiovascular disorders remains unclear. This study aimed to investigate the impact of FPA on VSMCs proliferation and migration and elucidate the underlying molecular mechanisms. Transcriptome sequencing and bioinformatics analysis were employed to elucidate molecular pathways. Scratch wound and Transwell assays were performed to evaluate cell migration capacity. Molecular expression patterns were assessed using immunofluorescence, real-time quantitative PCR, and Western blot assays. The differentially expressed genes (DEGs) in the FPA-treated VSMCs were enriched in the cell cycle and PI3K/AKT signaling pathway. FPA treatment enhanced VSMCs' migratory capacity and upregulated integrin αVβ3, PI3K, P-AKT, AKT, Cyclin D1, and PCNA expression. The integrin αVβ3 inhibitor Cyclo-RGDfk effectively suppressed VSMCs migration and reduced the expression levels of these genes in FPA-stimulated VSMCs. These results suggested that FPA promotes the proliferation and migration of VSMCs by regulating the PI3K/AKT signaling pathway through integrin αVβ3.

Ultrasonic characteristics of inserted central catheter related fibroblastic sleeve

This study was aimed to summarize the ultrasonic characteristics of inserted central catheter (ICC) related fibroblastic sleeve, providing theoretical basis for its early diagnosis. Clinical and ultrasonic data of patients with ICC confirmed by pathology to have fibroblastic sleeves in our hospital from June 4, 2020 to April 1, 2024 were collected. All ICCs were made of polyurethane. Patients required the ultrasound evaluation due to local swelling and pain, abnormal coagulation function, lack of response to flushing of saline and heparin, or before extubation. The ultrasonic characteristics of fibroblastic sleeve such as its starting point, shape, thickness, internal echo, number of layers, relationship to the catheter, and presence or absence of thrombosis were analyzed. After the removal of the ICC, there was a membrane-like structure adhesion on the surface of the catheter, which was composed of endothelial cells, smooth muscle cells, collagen and fibrous connective tissues. A total of 95 patients with pathologically confirmed fibroblastic sleeve were present, of which 44 patients had only fibroblastic sleeves (46.32%) and 51 patients had fibroblastic sleeves with thrombi (53.68%). The fibroblastic sleeve originated from the site where the catheter contacted the vein wall and extended in a distal direction, with a thickness ranged between 0.7 and 5.6 mm. With the pathological results as the gold standard, the optimal cut-off value for the diagnosis of fibroblastic sleeve with thrombosis was 2.58 mm, and the sensitivity and specificity of the diagnosis were 95.45% and 96.08%. Compared to echogenicity of the catheter wall, hyperechoic or isoechoic fibroblastic sleeves were observed in 89 patients, while hypoechoic fibroblastic sleeves were observed in 6 patients. There were significant differences in the location of catheterization and duration of catheterization between the single-layer group and the double-layer group (P < 0.05). Fibroblastic sleeves were tightly attached to the catheter walls in 78 patients and loosely attached to the catheter walls in 17 patients, with significant differences in the location of catheterization and duration of catheterization (P < 0.05). ICC-related fibroblastic sleeves have specific ultrasonic characteristics. Understanding these ultrasonic characteristics can provide a reliable basis for their early diagnosis and timely treatment.

Evaluation of metabolism-associated proteins in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) development is inversely associated with diabetes mellitus. Targeting glucose metabolism seems to be a beneficial strategy for preventing AAA growth. Several metabolism-related factors are associated with AAA development. This study aims to analyse the expression of the so far unstudied proteins irisin, follistatin, activin A and ghrelin (ligand and receptor) in human and murine aneurysmal tissue, to assess the involvement of these pathways in AAA. Gene and protein expression was evaluated in aneurysmal and control tissue samples, by qPCR and immunohistochemistry. Vascular smooth muscle cells (VSMC) were studied in vitro for expression. Circulating levels of the proteins of interest in human plasma samples were evaluated by ELISA. In human aneurysmal tissue, the proteins of interest are were predominantly expressed by VSMCs in neovessels. Expression by human VSMCs was confirmed in vitro. In human plasma, the concentration of Irisin was higher in AAA (+/- diabetes) compared to controls. Patients with AAA and type 2 diabetes treated with metformin had lower levels of follistatin and ghrelin. This study demonstrates irisin, follistatin and ghrelin as interesting proteins to be studied in the context of the observed negative association between AAA development and type 2 diabetes.

The interplay of ferroptosis and oxidative stress in the pathogenesis of aortic dissection

Aortic dissection (AD) is a life-threatening vascular condition marked by the separation or tearing of the aortic media. Ferroptosis, a form of iron-dependent programmed cell death, occurs alongside lipid peroxidation and the accumulation of reactive oxygen species (ROS). The relationship between ferroptosis and AD lies in its damaging effect on vascular cells. In AD, ferroptosis worsens the damage to vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), thereby weakening the vascular wall’s structural integrity and accelerating the onset and progression of the condition. However, the molecular mechanisms through which ferroptosis regulates the onset and progression of AD remain poorly understood. This article explores the relationship between ferroptosis and AD.

FRET-Based Sensor Zebrafish Reveal Muscle Cells Do Not Undergo Apoptosis in Starvation or Natural Aging-Induced Muscle Atrophy.

Muscle atrophy occurs during natural aging and under disease conditions. Muscle cell apoptosis is considered one of the main causes of muscle atrophy, while several recent studies argued that muscle cells do not die during muscle atrophy. Here, sensor zebrafish are generated to visualize muscle cell apoptosis and the engulfment of dead muscle cells by macrophages. Using these sensor zebrafish, starvation, and natural aging-induced muscle atrophy models are established. The data showed that the diameters of muscle cells decreased in both models; however, muscle cell apoptosis is not found in the process of muscle atrophy. In starvation-induced muscle atrophy, it also showed that the number of nuclei in muscle cells remained constant, and there is no increase in the number of macrophages in muscle tissues, both of which further confirmed that muscle cells do not die. In both models, transcriptional analysis showed that the apoptosis pathway is down-regulated, and autophagy and protein degradation pathways are up-regulated. All these data indicated that although there is a great reduction of muscle mass during starvation or aging-induced muscle atrophy, muscle cells do not die by apoptosis. These findings provide new insights into muscle atrophy and can benefit the treatments for muscle atrophy-related diseases.

BCL6 (B-cell lymphoma 6) expression in adenomyosis, leiomyomas and normal myometrium.

Adenomyosis and leiomyomas are common benign uterine disorders characterized by abnormal cellular proliferation. The BCL6 protein, a transcriptional repressor implicated in cell proliferation and oncogenesis, has been linked to the pathogenesis of endometriosis. This study investigates BCL6 expression in adenomyosis, leiomyomas, and normal myometrium using immunohistochemistry and deep learning neural networks. We analyzed paraffin blocks from total hysterectomies performed between 2009 and 2017, confirming diagnoses through pathological review. Immunohistochemistry was conducted using an automated system, and BCL6 expression was quantified using Fiji-ImageJ software. A supervised deep learning neural network was employed to classify samples based on DAB staining. Our results show that BCL6 expression is significantly higher in leiomyomas compared to adenomyosis and normal myometrium. No significant difference in BCL6 expression was observed between adenomyosis and controls. The deep learning neural network accurately classified samples with a high degree of precision, supporting the immunohistochemical findings. These findings suggest that BCL6 plays a role in the pathogenesis of leiomyomas, potentially contributing to abnormal smooth muscle cell proliferation. The study highlights the utility of automated immunohistochemistry and deep learning techniques in quantifying protein expression and classifying uterine pathologies. Future studies should investigate the expression of BCL6 in adenomyosis and endometriosis to further elucidate its role in uterine disorders.

Riding a Vascular Time Train to Spatiotemporally Attenuate Thrombosis and Restenosis by Double Presentation of Therapeutic Gas and Biomacromolecules

ABSTRACTEndothelial injury is a common occurrence following stent implantation, often leading to complications such as restenosis and thrombosis. To address this issue, we have developed a multi‐functional stent coating that combines a dopamine‐copper (DA‐Cu) base with therapeutic biomolecule modification, including nitric oxide (NO) precursor L‐arginine, endothelial glycocalyx heparin, and endothelial cell (EC) catcher vascular endothelial growth factor (VEGF). In our stent coating, the incorporated Cu acts as a sustainable catalyst for converting endogenous NO donors into NO, and the immobilized arginine serves as a precursor for NO generation under the effect of endothelial nitric oxide synthase (eNOS). The presence of heparin endows the stent coating with anticoagulant ability and enhances eNOS activity, whilst rapid capture of EC by VEGF accelerates re‐endothelialization. After in vivo implantation, the antioxidant elements and produced NO alleviate the inflammatory response, establishing a favorable healing environment. The conjugated VEGF contributes to the formation of a new and intact endothelium on the stent surface to counteract inappropriate vascular cell behaviors. The long‐lasting NO flux inhibits smooth muscle cell (SMC) migration and prevents its excessive proliferation, reducing the risk of endothelial hyperplasia. This innovative coating enables the dual delivery of VEGF and NO to target procedural vascular repair phases: promoting rapid re‐endothelialization, effectively preventing thrombosis, and suppressing inflammation and restenosis. Ultimately, this innovative coating has the potential to improve therapeutic outcomes following stent implantation.

Pulmonary vascular remodeling in Fra-2 transgenic mice is driven by type 2 inflammation and accompanied by pulmonary vascular hyperresponsiveness.

Lung vessel remodeling leads to increased pulmonary vascular resistance, causing pulmonary arterial hypertension (PAH), and consequently right ventricular hypertrophy and failure. In patients suffering from systemic sclerosis (SSc), PAH can occur and is a life-threatening complication. Dysregulation of immune processes plays a crucial role in pulmonary vascular remodeling, as has previously been shown in Fos-related antigen-2 (Fra-2) transgenic (TG) mice, a model of SSc-PAH. Here, we investigate whether vascular remodeling in the Fra-2 TG model is driven by type 2 inflammation and is associated with vascular hyperresponsiveness, an important feature of PAH pathobiology. Basal pulmonary arterial pressure and pulmonary vascular responsiveness to hypoxic ventilation and serotonin were increased in isolated, perfused and ventilated lungs of Fra-2 TG mice compared to wild-type (WT) littermates. Similarly, contractile responses of isolated intrapulmonary arteries were elevated in Fra-2 TG mice. We also observed increased expression of contractile genes in Fra-2 overexpressing human pulmonary artery smooth muscle cells (PASMCs) with elevated intracellular calcium levels after IL-13 stimulation. These findings were corroborated by transcriptomic data highlighting dysregulation of vascular smooth muscle cell contraction and type 2 inflammation in Fra-2 TG mice. In vivo, type 2-specific anti-inflammatory treatment with IL-13 neutralizing antibodies improved vascular remodeling in Fra-2 TG mice, similar to corticosteroid treatment with budesonide. Our results underscore the importance of type 2 inflammation and its potential therapeutic value in PAH-associated pulmonary vascular remodeling and hyperresponsiveness in SSc-PAH.

Virgin and photo-degraded microplastics induce the activation of human vascular smooth muscle cells

Microplastics (MPs) are an emerging environmental issue due to their accumulation in ecosystems and living organisms. Increasing evidence shows that MPs impact vascular function, with recent studies finding MPs in atheromas linked to cardiovascular events. Since vascular smooth muscle cells (VSMCs) are crucial to maintaining vascular function, this study examined how MPs activate VSMCs, leading to cardiovascular diseases like atherosclerosis and vascular calcification. The study used polyethylene (PE) and polystyrene (PS), common in food packaging, as “virgin” or photo-degraded to simulate environmental conditions. VSMC viability, apoptosis, cytotoxicity, inflammation, and activation markers were evaluated. PE and PS affected VSMC viability, induced apoptosis, and triggered pathological changes such as altered migration and proliferation. Key markers like RUNX-2 and galectin-3, which regulate cardiovascular pathology, were activated, alongside the inflammasome complex. In conclusion, MPs can induce harmful activation of VSMCs, posing potential health risks through inflammation, cell damage, and phenotypic changes. Understanding these toxic mechanisms may reveal critical pathways for intervention and prevention.