Remodeling In Mice Research Articles

Hyperuricemia suppresses lumican, exacerbating adverse remodeling after myocardial infarction by promoting fibroblast phenotype transition

BackgroundHyperuricemia is independently associated with a poor prognosis in patients with myocardial infarction (MI). Furthermore, MI induces activation of the repair response in local fibroblasts, resulting in extracellular matrix accumulation that generates a stable fibrotic scar in the infarcted area. However, researchers have not determined whether hyperuricemia affects fibroblast activation and its involvement in postinfarction cardiac remodeling.ObjectivesWe aimed to trigger hyperuricemia by administering potassium oxonate in a mouse model of MI to evaluate the role of hyperuricemia in MI pathogenesis.MethodsMicroarray datasets and single-cell sequencing data from gout patients, heart failure patients, and model mice were used to identify the underlying mechanisms responsible for the effect of hyperuricemia on MI progression. A hyperuricemia-related MI mouse model was established. Cardiac function was assessed, followed by sample collection and a uric acid assay. We conducted an enzyme-linked immunosorbent assay, histological detection, immunofluorescence, sequencing data processing, single-cell RNA-seq, and functional enrichment analysis. We then isolated and cultured cardiac fibroblasts and performed Western blotting, quantitative real-time polymerase chain reaction, and shRNA-mediated lumican knockdown assays.ResultsHyperuricemia decreased cardiac function, increased mortality, and aggravated adverse fibrosis remodeling in mice after MI. These outcomes were closely related to reduced levels of fibroblast-derived lumican. This reduction activated the TGF-β/SMAD signaling pathway to induce aberrant myofibroblast activation and extracellular matrix deposition in the infarcted area. Furthermore, lumican supplementation or uric acid-lowering therapy with allopurinol alleviated hyperuricemia-mediated abnormal cardiac remodeling.ConclusionHyperuricemia aggravates postinfarction cardiac remodeling by reducing lumican expression and promoting fibroblast phenotype transition. We highlight the clinical importance of lowering uric acid levels in hyperuricemia-related MI to prevent adverse ventricular remodeling.

Kidney and vascular involvement in Alagille syndrome.

Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disease with a high interindividual variability. The two causative genes JAG1 and NOTCH2 are expressed during kidney development, can be reactivated during adulthood kidney disease, and Notch signalling is essential for vascular morphogenesis and remodelling in mice. Liver disease is the most frequent and severe involvement; neonatal cholestasis occurs in 85% of cases, pruritus in 74%, xanthomas in 24% of cases, and the cumulative incidences of portal hypertension and liver transplantation are 66% and 50% respectively at 18years of age. Stenosis/hypoplasia of the branch pulmonary arteries is the most frequent vascular abnormality reported in ALGS. Kidney involvement is present in 38% of patients, and can reveal the disease. Congenital anomalies of the kidney and urinary tract is reported in 22% of patients, hyperchloremic acidosis in 9%, and glomerulopathy and/or proteinuria in 6%. A decreased glomerular filtration rate is reported in 10% of patients and is more frequent after liver transplantation for ALGS than for biliary atresia. Kidney failure has been frequently reported in childhood and adulthood. Renal artery stenosis and mid aortic syndrome have also frequently been reported, often associated with hypertension and stenosis and/or aneurysm of other large arteries. ALGS patients require kidney assessment at diagnosis, long-term monitoring of kidney function and early detection of vascular complications, notably if they have undergone liver transplantation, to prevent progression of chronic kidney disease and vascular complications, which account for 15% of deaths at a median age of 2.2years in the most recent series.

Pancreatic islet α cells regulate microtubule stability in neighboring β cells to tune insulin secretion and induce functional heterogeneity in individual mouse and human islets.

Gcg sensitizes glucose-induced MT remodeling in mouse and human β cellsMT density in single islets anti-correlates with α/β cell ratioGSIS levels in single islets positively correlate with α/β cell ratioDifferent α/β cell ratio contributes to heterogeneity of single islet GSIS.

A digital CRISPR-dCas9-based gene remodeling biocomputer programmed by dietary compounds in mammals

CRISPR-dCas9 (dead Cas9 protein) technology, combined with chemical molecules and light-triggered genetic switches, offers customizable control over gene perturbation. However, these simple ON/OFF switches cannot precisely determine the sophisticated perturbation process. Here, we developed a resveratrol and protocatechuic acid-programmed CRISPR-mediated gene remodeling biocomputer (REPACRISPR) for conditional endogenous transcriptional regulation of genes invitro and invivo. Two REPACRISPR variants, REPACRISPRi and REPACRISPRa, were designed for the logic control of gene inhibition and activation, respectively. We successfully demonstrated the digital computations of single or multiplexed endogenous gene transcription by using REPACRISPRa. We also established mathematical models to predict the dose-responsive transcriptional levels of a target endogenous gene controlled by REPACRISPRa. Moreover, high levels of endogenous gene activation in mice mediated by the AND logic gate demonstrated computational control of CRISPR-dCas9-based epigenome remodeling in mice. This CRISPR-based biocomputer expands the synthetic biology toolbox and can potentially advance gene-based precision medicine. A record of this paper's transparent peer review process is included in the supplemental information.

Microparticle Mediated Delivery of Apelin Improves Heart Function in Post Myocardial Infarction Mice.

Apelin is an endogenous prepropeptide that regulates cardiac homeostasis and various physiological processes. Intravenous injection has been shown to improve cardiac contractility in patients with heart failure. However, its short half-life prevents studying its impact on left ventricular remodeling in the long term. Here, we aim to study whether microparticle-mediated slow release of apelin improves heart function and left ventricular remodeling in mice with myocardial infarction (MI). A cardiac patch was fabricated by embedding apelin-containing microparticles in a fibrin gel scaffold. MI was induced via permanent ligation of the left anterior descending coronary artery in adult C57BL/6J mice followed by epicardial patch placement immediately after (acute MI) or 28 days (chronic MI) post-MI. Four groups were included in this study, namely sham, MI, MI plus empty microparticle-embedded patch treatment, and MI plus apelin-containing microparticle-embedded patch treatment. Cardiac function was assessed by transthoracic echocardiography. Cardiomyocyte morphology, apoptosis, and cardiac fibrosis were evaluated by histology. Cardioprotective pathways were determined by RNA sequencing, quantitative polymerase chain reaction, and Western blot. The level of endogenous apelin was largely reduced in the first 7 days after MI induction and it was normalized by day 28. Apelin-13 encapsulated in poly(lactic-co-glycolic acid) microparticles displayed a sustained release pattern for up to 28 days. Treatment with apelin-containing microparticle-embedded patch inhibited cardiac hypertrophy and reduced scar size in both acute and chronic MI models, which is associated with improved cardiac function. Data from cellular and molecular analyses showed that apelin inhibits the activation and proliferation of cardiac fibroblasts by preventing transforming growth factor-β-mediated activation of Smad2/3 (supporessor of mothers against decapentaplegic 2/3) and downstream profibrotic gene expression. Poly(lactic-co-glycolic acid) microparticles prolonged the apelin release time in the mouse hearts. Epicardial delivery of the apelin-containing microparticle-embedded patch protects mice from both acute and chronic MI-induced cardiac dysfunction, inhibits cardiac fibrosis, and improves left ventricular remodeling.

Traditional Chinese medicine Ze-Qi-Tang formula reduces inflammation in mice with asthma by inhibiting PI3K/AKT/NF-κB signaling pathway.

Asthma is a chronic airway inflammatory disease. The excessive proliferation of airway smooth muscle cells (ASMCs) is associated with airway remodeling. Ze-Qi-Tang (ZQT) is a popular traditional Chinese medicine preparation and has been confirmed to have therapeutic effects on lung diseases. This study is aimed to probe the biological function of ZQT in asthma. RT-qPCR and ELISA were utilized for testing the mRNA levels and concentrations of pro-inflammatory factors. Colony formation and transwell assay were applied to test cell viability and migration. The mouse model with asthma was established by ovalbumin (OVA) induction. Western blot was utilized for detecting the activation of PI3K/AKT/NF-κB pathway. We found that the concentrations of proinflammatory factors in cells induced by PDGF-BB could been suppressed by ZQT. ZQT-H treatment notably repressed cell viability and proliferation. Furthermore, we proved the suppressive effect of ZQT on airway inflammation in asthma mice. Additionally, we discovered that ZQT could suppress the PI3K/AKT/NF-κB pathway in PDGF-BB-induced ASMCs. To sum up, ZQT reduced airway inflammation and remodeling in mice with asthma via inactivating PI3K/AKT/NF-κB pathway.

Light-phase time-restricted feeding disrupts the muscle clock and insulin sensitivity yet potentially induces muscle fiber remodeling in mice

Skeletal muscle plays a critical role in regulating systemic metabolic homeostasis. It has been demonstrated that time-restricted feeding (TRF) during the rest phase can desynchronize the suprachiasmatic nucleus (SCN) and peripheral clocks, thereby increasing the risk of metabolic diseases. However, the impact of dietary timing on the muscle clock and health remains poorly understood. Here, through the analysis of cycling genes and differentially expressed genes in the skeletal muscle transcriptome, we identified disruptions in muscle diurnal rhythms by 2 weeks of light-phase TRF. Furthermore, compared with ad libitum (AL) feeding mice, 2 weeks of light-phase TRF was found to induce insulin resistance, muscle fiber type remodeling, and changes in the expression of muscle growth-related genes, while both light-phase and dark-phase TRF having a limited impact on bone quality relative to AL mice. In summary, our research reveals that the disruption of the skeletal muscle clock may contribute to the abnormal metabolic phenotype resulting from feeding restricted to the inactive period. Additionally, our study provides a comprehensive omics atlas of the diurnal rhythms in skeletal muscle regulated by dietary timing.

Effects of liver X receptor in O3-induced airway inflammation and remodeling in mice.

The current clinical treatment of chronic obstructive pulmonary disease (COPD) mainly uses drugs to improve symptoms, but these drugs cannot reverse the progression of the disease and the pathological changes in lung tissue. This study aimed to investigate the effects and mechanisms of Liver X receptors (LXRs) in ozone (O3)-induced airway inflammation and remodeling in mice. Wild mice and LXR deficient mice were exposed to O3 twice a week for 6 weeks. Some wild mice were intraperitoneally injected with T0901317 (a LXR agonist) before O3 exposure. Wild mice were exposed to ambient air and intraperitoneally injected with normal saline (NS) as control group. The lung tissues and bronchoalveolar lavage fluid (BALF) were collected to evaluate airway inflammation, airway remodeling and lipid disorder. After O3 exposure, LXR deficient mice showed severe airway inflammation and airway remodeling compared with the wild mice. There were a lot of foamy macrophages appeared in BALF of LXR deficient mice. The inflammatory proteins such as myeloid differentiation primary response protein 88 (MyD88) and interleukin-1 receptor-associated kinase (IRAK) in the lung tissues of LXR deficient mice were significantly increased compared with the wild mice. In wild mice exposed to O3, T0901317 treatment can alleviate airway inflammation, airway remodeling and foamy macrophages in BALF. And MyD88 and IRAK expression in lung tissue were also attenuated by T0901317 treatment. LXRs play protective roles in O3-induced lipid accumulation, airway inflammation and airway remodeling.

Mechanism of cigarette smoke in promoting small airway remodeling in mice via STAT 3 / PINK 1-Parkin / EMT

BackgroundAirway remodeling is an important pathological of airflow limitation in chronic obstructive pulmonary disease (COPD).However,its mechanism still needs to be further clarify. MethodsAnimals:Healthy male C57BL/6 mice aged 4–6 weeks were randomly divided into control group and cigarette smoke(CS)group. Mice in the CS group were placed in a homemade glass fumigator, 5 cigarettes/time, 40 min/time, 4 times/day, 5 days/week, for 24 weeks. Mice in the control group were placed in a normal air environment.Cells:BEAS-2B cells were stimulated with 0.1%cigarette smoke extract(CSE).HE staining, immunohistochemical staining and Masson staining were used to observe the pathological of lung tissues, transmission electron microscopy was used to observe the structural of mitochondria in bronchial epithelial cells.Western blotting was used to detect the expression of STAT3,transforming growth factor-β1(TGF-β1),microtubule-associated protein 1A/1B-light chain3(LC3),PINK1,Parkin,E-cadherin,zonula occludens1(ZO-1),vimentin and snail family transcriptional inhibitor1 (Snail1),and MitoSOX Red was used to detect mitochondrial reactive oxygen species(mtROS). ResultsCS exposure causes lung parenchymal destruction and airway remodeling in mice.Compared to the control group,the expression of p-STAT3,TGF-β1 and EMT in the whole lung homogenate of the CS group was increased.Mitochondrial architecture disruption in bronchial epithelial cells of CS mice, with impaired PINK1-Parkin-dependent mitophagy.In vitro experiments showed that CSE exposure led to STAT3 activation, increased TGF-β1,EMT and enhanced PINK1-Parkin-mediated mitophagy.STAT3 inhibition reversed TGF-β1 upregulation induced by CSE and improved CSE-induced EMT and mitophagy.Inhibition of mitophagy improves EMT induced by CSE. Inhibition of mitophagy reduces STAT3-induced EMT. ConclusionCS activates the STAT3,and activated STAT3 promotes EMT in bronchial epithelial cells by enhancing PINK1-Parkin-mediated mitophagy and TGF-β1 signaling.Moreover, activated STAT3 can promote EMT directly.This may be one of the mechanisms by which CS causes small airway remodeling in COPD.

Lumican is Both a Novel Risk Factor and Potential Plasma Biomarker for Vascular Aging, Capable of Promoting VSMCs Senescence through Interacting with Integrin α2β1.

Vascular aging, a common pathogenesis of senile chronic diseases, significantly increases morbidity and mortality in older adults; its intricate cellular and molecular mechanisms necessitate further investigation. Lumican (LUM) and integrin α2β1(ITGα2β1) are profibrotic extracellular matrix proteins and vital cell regulatory receptors, respectively. However, their roles in vascular aging remain unclear. This study sought to elucidate the connection between LUM and vascular aging as well as the biological mechanism of LUM/ITGα2β1 in this process. Using an enzyme-linked immunosorbent assay, we discovered that plasma LUM was elevated in vascular aging individuals and was positively correlated with brachial-ankle pulse wave velocity. Additionally, immunohistochemical and western blot analyses confirmed LUM upregulation in arteries of older adults and aged mice, as well as in senescent vascular smooth cells (VSMCs). Wild-type and LUM semiknockout (Lum-/+) mice, along with primary VSMCs extracted from these mice, were exposed to angiotensin II (Ang II) to induce stress-induced senescence model. LUM semiknockout mitigated Ang Ⅱ-induced arteriosclerosis, hypertension, vascular aging and remodeling in mice. Both in vitro and in vivo studies revealed that LUM deficiency suppressed p53, p21, collagen 1 and collagen 3 upregulation and synthetic phenotype formation in VSMCs stimulated by Ang Ⅱ. Treating VSMCs with a ITGα2β1 antagonist reversed the aforementioned changes triggered by LUM proteins. Briefly, LUM functions as a potential marker and risk factor for vascular aging and promotes pathological changes by affecting ITGα2β1 in VSMCs. This study introduces a novel molecular target for the early diagnosis and treatment of vascular aging and age-related vascular diseases.

Inhibition of RUNX1 slows the progression of pulmonary hypertension by targeting CBX5.

Pulmonary artery smooth muscle cell (PASMC) dysfunction is the central pathogenic mechanism in pulmonary hypertension (PH). This study explored the mechanism of action of RUNX1, a potential therapeutic target for PH, in PASMCs. A PH mouse model was used to investigate the impacts of RUNX1 knockdown on hemodynamics, right ventricular hypertrophy (RVH), and pulmonary artery remodeling (HE staining). Isolated PASMCs were transfected with RUNX1- or CBX5-related vectors and then subjected to cell function assays. Immunoprecipitation was used to detect molecular binding and ubiquitination. RUNX1 knockdown reduced right ventricular systolic pressure, RVH, and pulmonary artery remodeling in mice with PH. Knockdown of RUNX1 or CBX5 suppressed proliferation, invasion, and migration and stimulated apoptosis in PASMCs under hypoxia. RUNX1 enhanced USP15 promoter activity. USP15 bound to CBX5 and reduced CBX5 ubiquitination, thereby promoting CBX5 expression. CBX5 overexpression promoted the proliferation and movement of hypoxic PASMCs with reduced RUNX1 expression and decreased their apoptosis. In conclusion, RUNX1 knockdown alleviates PH in mice and reduces hypoxia-induced PASMC dysfunction by inhibiting USP15 transcription, thereby promoting the ubiquitination and degradation of CBX5.

Endothelial derived, secreted long non-coding RNAs Gadlor1 and Gadlor2 aggravate cardiac remodeling

Pathological cardiac remodeling predisposes individuals to developing heart failure. Here, we investigated two co-regulated long non-coding (lnc) RNAs, termed Gadlor1 and Gadlor2, which are upregulated in failing hearts of patients and mice. Cardiac overexpression of Gadlor1 and Gadlor2 aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. Compound Gadlor1/2 knock-out mice showed markedly reduced myocardial hypertrophy, fibrosis, and dysfunction, while exhibiting increased angiogenesis during short and prolonged periods of pressure overload. Paradoxically, Gadlor1/2 knock-out mice suffered from sudden death during prolonged overload, possibly due to cardiac arrhythmia. Gadlor1 and Gadlor2, which are mainly expressed in endothelial cells (ECs) in the heart, where they inhibit pro-angiogenic gene-expression, are strongly secreted within extracellular vesicles (EVs). These EVs transfer Gadlor lncRNAs to cardiomyocytes, where they bind and activate calmodulin-dependent kinase II, and impact pro-hypertrophic gene-expression and calcium homeostasis. Therefore, we reveal a crucial lncRNA-based mechanism of EC-cardiomyocyte crosstalk during heart failure, which could be specifically modified in the future for therapeutic purposes.

Unveiling the role of RhoA and ferroptosis in vascular permeability: Implications for osteoarthritis.

Abnormal angiogenesis and increased vascular permeability of subchondral bone are key mechanisms related to osteoarthritis (OA). However, the precise mechanisms responsible for heightened vascular permeability in OA remain unclear. The present study used proteomics to identify protein expression in damaged subchondral bone compared with normal subchondral bone. The results suggest that Ras homolog family member A (RhoA) may be associated with the vascular permeability of subchondral bone and ferroptosis in OA. The results of analysis of clinical samples indicated a significant increase in expression of RhoA in the subchondral bone of OA. This were consistent with the proteomics findings. We found through western blotting, RT‑PCR, and immunofluorescence that RhoA significantly increased the permeability of endothelial cells (ECs) by inhibiting inter‑EC adhesion proteins (zona occludens‑1, connexin 43 and Vascular endothelial‑Cadherin) and actin filaments. Furthermore, RhoA induced ferroptosis core proteins (glutathione peroxidase 4, solute carrier family 7 member 11 and acyl‑CoA synthase long‑chain family member 4, ACSL4) by influencing lipid peroxidation and mitochondrial function, leading to ferroptosis of ECs. This suggested an association between RhoA, ferroptosis and vascular permeability. Ferroptosis significantly increased permeability of ECs by inhibiting inter‑EC adhesion proteins. RhoA increased vascular permeability by inducing ferroptosis of ECs. In vivo, inhibition of RhoA and ferroptosis significantly mitigated progression of OA by alleviating cartilage degeneration and subchondral bone remodeling in mice with destabilization of the medial meniscus. In conclusion, the present findings indicated that RhoA enhanced vascular permeability in OA by inducing ferroptosis. This may serve as a novel strategy for the early prevention and treatment of OA.

AT1b receptors contribute to regional disparities in angiotensin II mediated aortic remodelling in mice.

The renin-angiotensin system plays a key role in regulating blood pressure, which has motivated many investigations of associated mouse models of hypertensive arterial remodelling. Such studies typically focus on histological and cell biological changes, not wall mechanics. This study explores tissue-level ramifications of chronic angiotensin II infusion in wild-type (WT) and type 1b angiotensin II (AngII) receptor null (Agtr1b -/-) mice. Biaxial biomechanical and immunohistological changes were quantified and compared in the thoracic and abdominal aorta in these mice following 14 and 28 days of angiotensin II infusion. Preliminary results showed that changes were largely independent of sex. Associated thickening and stiffening of the aortic wall in male mice differed significantly between thoracic and abdominal regions and between genotypes. Notwithstanding multiple biomechanical changes in both WT and Agtr1b -/- mice, AngII infusion caused distinctive wall thickening and inflammation in the descending thoracic aorta of WT, but not Agtr1b -/-, mice. Our study underscores the importance of exploring differential roles of receptor-dependent angiotensin II signalling along the aorta and its influence on distinct cell types involved in regional histomechanical remodelling. Disrupting the AT1b receptor primarily affected inflammatory cell responses and smooth muscle contractility, suggesting potential therapeutic targets.

SCD4 deficiency decreases cardiac steatosis and prevents cardiac remodeling in mice fed a high-fat diet

Stearoyl-CoA desaturase (SCD) is a lipogenic enzyme that catalyzes formation of the first double bond in the carbon chain of saturated fatty acids. Four isoforms of SCD have been identified in mice, the most poorly characterized of which is SCD4, which is cardiac-specific. In the present study, we investigated the role of SCD4 in systemic and cardiac metabolism. We used WT and global SCD4 KO mice that were fed standard laboratory chow or a high-fat diet (HFD). SCD4 deficiency reduced body adiposity and decreased hyperinsulinemia and hypercholesterolemia in HFD-fed mice. The loss of SCD4 preserved heart morphology in the HFD condition. Lipid accumulation decreased in the myocardium in SCD4-deficient mice and in HL-1 cardiomyocytes with knocked out Scd4 expression. This was associated with an increase in the rate of lipolysis and, more specifically, adipose triglyceride lipase (ATGL) activity. Possible mechanisms of ATGL activation by SCD4 deficiency include lower protein levels of the ATGL inhibitor G0/G1 switch protein 2 and greater activation by protein kinase A under lipid overload conditions. Moreover, we observed higher intracellular Ca2+ levels in HL-1 cells with silenced Scd4 expression. This may explain the activation of protein kinase A in response to higher Ca2+ levels. Additionally, the loss of SCD4 inhibited mitochondrial enlargement, NADH overactivation, and reactive oxygen species overproduction in the heart in HFD-fed mice. In conclusion, SCD4 deficiency activated lipolysis, resulting in a reduction of cardiac steatosis, prevented the induction of left ventricular hypertrophy, and reduced reactive oxygen species levels in the heart in HFD-fed mice.

RNA Helicase DDX5 Maintains Cardiac Function by Regulating CamkIIδ Alternative Splicing.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. RNA-binding proteins are identified as regulators of cardiac disease; DDX5 (dead-box helicase 5) is a master regulator of many RNA processes, although its function in heart physiology remains unclear. We assessed DDX5 expression in human failing hearts and a mouse HF model. To study the function of DDX5 in heart, we engineered cardiomyocyte-specific Ddx5 knockout mice. We overexpressed DDX5 in cardiomyocytes using adeno-associated virus serotype 9 and performed transverse aortic constriction to establish the murine HF model. The mechanisms underlined were subsequently investigated using immunoprecipitation-mass spectrometry, RNA-sequencing, alternative splicing analysis, and RNA immunoprecipitation sequencing. We screened transcriptome databases of murine HF and human dilated cardiomyopathy samples and found that DDX5 was significantly downregulated in both. Cardiomyocyte-specific deletion of Ddx5 resulted in HF with reduced cardiac function, an enlarged heart chamber, and increased fibrosis in mice. DDX5 overexpression improved cardiac function and protected against adverse cardiac remodeling in mice with transverse aortic constriction-induced HF. Furthermore, proteomics revealed that DDX5 is involved in RNA splicing in cardiomyocytes. We found that DDX5 regulated the aberrant splicing of Ca2+/calmodulin-dependent protein kinase IIδ (CamkIIδ), thus preventing the production of CaMKIIδA, which phosphorylates L-type calcium channel by serine residues of Cacna1c, leading to impaired Ca2+ homeostasis. In line with this, we found increased intracellular Ca2+ transients and increased sarcoplasmic reticulum Ca2+ content in DDX5-depleted cardiomyocytes. Using adeno-associated virus serotype 9 knockdown of CaMKIIδA partially rescued the cardiac dysfunction and HF in Ddx5 knockout mice. These findings reveal a role for DDX5 in maintaining calcium homeostasis and cardiac function by regulating alternative splicing in cardiomyocytes, identifying the DDX5 as a potential target for therapeutic intervention in HF.

Intervention of Asprosin Attenuates Oxidative Stress and Neointima Formation in Vascular Injury.

Aims: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cell (VSMC) proliferation, migration, oxidative stress, and neointima formation of vascular injury. Methods: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation, and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of the carotid artery in mice. Results: Asprosin overexpression promoted VSMC oxidative stress, proliferation, and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant (N-Acetylcysteine, NAC), NADPH oxidase 1 (NOX1) inhibitor ML171, or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, whereas asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation, and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation, and migration were enhanced by Nrf2 inhibitor ML385 but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation, and vascular remodeling in mice. Innovation and Conclusion: Asprosin promotes oxidative stress, proliferation, and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress, and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury. Antioxid. Redox Signal. 41, 488-504.

Exercise mitigates reductive stress-induced cardiac remodeling in mice

The endoplasmic reticulum (ER) regulates protein folding and maintains proteostasis in cells. We observed that the ER transcriptome is impaired during chronic reductive stress (RS) in cardiomyocytes. Here, we hypothesized that a prolonged moderate treadmill exercise mitigates the RS-induced ER dysfunction and cardiac remodeling in cardiac-specific constitutively active Nrf2 mice (CaNrf2-TG). RNA sequencing showed notable alterations in the ER transcriptome of TG hearts at 4, 12, and 24 weeks (16, 28, and 35 genes, respectively). Notably, the downregulation of ER genes was significant at 12 weeks, and further pronounced at 24 weeks, at which the cardiac pathology is evident. We also observed increased levels of ubiquitinated proteins in CaNrf2-TG hearts across all ages, along with VCP, a marker of ERAD function, at 24 weeks. These findings indicate that constitutive Nrf2 activation and RS impair protein-folding activity and augments ERAD function over time. Exercise intervention for 20 weeks (beginning at 6 weeks of age), reduced cardiomyocyte hypertrophy (from 448 μm2 to 280 μm2) in TG mice, through adaptive remodeling, and preserved the cardiac function. However, while exercise did not influence antioxidants or ER stress protein levels, it significantly improved ERAD function and autophagy flux (LC-I to LC-II) in the TG-EXE hearts. Collectively, our findings underscore the prophylactic potential of exercise in mitigating RS-associated pathology, highlighting its essential role in maintaining cellular proteostasis through ER-independent mechanisms.

Aerobic training attenuates cardiac remodeling in mice post-myocardial infarction by inhibiting the p300/CBP-associated factor.

Aerobic training (AT), an effective form of cardiac rehabilitation, has been shown to be beneficial for cardiac repair and remodeling after myocardial infarction (MI). The p300/CBP-associated factor (PCAF) is one of the most important lysine acetyltransferases and is involved in various biological processes. However, the role of PCAF in AT and AT-mediated cardiac remodeling post-MI has not been determined. Here, we found that the PCAF protein level was significantly increased after MI, while AT blocked the increase in PCAF. AT markedly improved cardiac remodeling in mice after MI by reducing endoplasmic reticulum stress (ERS). Invivo, similar to AT, pharmacological inhibition of PCAF by Embelin improved cardiac recovery and attenuated ERS in MI mice. Furthermore, we observed that both IGF-1, a simulated exercise environment, and Embelin protected from H2O2-induced cardiomyocyte injury, while PCAF overexpression by viruses or the sirtuin inhibitor nicotinamide eliminated the protective effect of IGF-1 in H9C2 cells. Thus, our data indicate that maintaining low PCAF levels plays an essential role in AT-mediated cardiac protection, and PCAF inhibition represents a promising therapeutic target for attenuating cardiac remodeling after MI.

LincR-PPP2R5C Deficiency Alleviates Airway Remodeling by Inhibiting Epithelial-Mesenchymal Transition Through the PP2A/TGF-β1 Signaling Pathway in Chronic Experimental Allergic Asthma.

Airway remodeling is a key characteristic of allergic asthma. Epithelial-mesenchymal transition (EMT) induced by various factors, particularly transforming growth factor (TGF)-β1, orchestrates airway remodeling. Protein phosphatase 2A (PP2A), an important serine-threonine phosphatase, is involved in TGF-β1 production and EMT. Long noncoding RNAs (lncRNAs) have emerged as novel players in regulating EMT. Here, we aimed to explore the effects and mechanisms of action of lincR-PPP2R5C, a lncRNA that affects PP2A activity, on airway remodeling in a mouse model of chronic allergic asthma. LincR-PPP2R5C knockout (KO) alleviated inflammatory responses in house dust mite (HDM)-induced chronic allergic asthma. Moreover, airway remodeling and EMT were reduced in lung tissues of lincR-PPP2R5C KO mice. HDM extract induced EMT in airway epithelial cells, which was decreased following lincR-PPP2R5C KO. Mechanistically, lincR-PPP2R5C deficiency enhanced PP2A activity, which inhibited TGF-β1 production in epithelial cells. In conclusion, lincR-PPP2R5C deficiency prevented HDM-induced airway remodeling in mice by reversing EMT, which was mediated by the PP2A/TGF-β1 signaling pathway. Thus, lncRNAs, i.e., lincR-PPP2R5C, may be potential targets to prevent airway remodeling in allergic asthma.