Mechanisms Of Remodeling Research Articles

Extracellular Matrix Recycling as a Novel Plasticity Mechanism With a Potential Role in Disease.

The extracellular matrix (ECM) stabilizes neural circuits and synapses in the healthy brain, while also retaining the ability to be remodeled, to allow synapses to be plastic. A well-described mechanism for ECM remodeling is through the regulated secretion of proteolytic enzymes at the synapse, together with the synthesis of new ECM molecules. The importance of this process is evidenced by the large number of brain disorders that are associated with a dysregulation of ECM-cleaving protease activity. While most of the brain ECM molecules are indeed stable for remarkable time periods, evidence in other cell types, as cancer cells, suggests that at least a proportion of the ECM molecules may be endocytosed regularly, and could even be recycled back to the ECM. In this review, we discuss the involvement of such a mechanism in the brain, under physiological activity conditions and in relation to synapse and brain disease.

Atrial remodelling comparison after maze-3 and cryo-maze procedures in combined cardiac interventions: a retrospective study

Background. The maze procedure aims to eliminate atrial fibrillation (AF), restore sinus rhythm (SR) and atrial contractility. However, conflicting evidence exists regarding the extent of atrial remodelling in various techniques, which directed the focus of our study.Objectives. An atrial remodelling comparison after a cut-and-sew maze-3 surgery and its biatrial cryo-maze modification using 2D echocardiography.Methods. The study is a retrospective uncontrolled interrupted two-cohort time-series trial, with patients selected by pseudorandomisation according to a normal sinus rhythm-maintaining AF surgery method. A total of 217 maze-3 and 113 cryo-maze combined cardiac interventions have been performed within 2012–2021. The interventions included valve repair, coronary artery bypass grafting and their combination. Due to differences in long-term follow-up, the cohorts were pseudorandomised to select by 50 restored vs. maintained sinus rhythm patients using a nearest-neighbour classifier coupled with logistic regression. Mean follow-up period was 6 (1–17) months. The patients had paroxysmal, persistent and longstanding persistent AF. Echocardiography values prior to and long-term post-surgery were further analysed to determine the atrial remodelling dynamics. Results. A statistically significant atrial volume reduction is evident in a long-term within-cohort comparison. Meanwhile, a statistically more pronounced remodelling is observed between cohorts after maze-3 procedure. The cohort 1 vs. 2 estimates are: mean left atrial volume 120/125 mL3 (p = 0.011), left atrial size in apical view 52/53 mm (p = 0.023), right atrial size in apical view 58/62 mm (p = 0.004), right atrial size in parasternal short axis view 43/45 mm (p = 0.004), right atrial area in apical 4-chamber view 25/28 cm2 (p = 0.007). Maintained atrial pacing patients had positive systolic atrial function recovery rates (E/A ratio increased to average 1.5) in the long-term in both comparison cohorts.Conclusion. Remodelling is biatrial after all the maze procedures compared. A more pronounced atrial volume reduction occurs after maze-3 surgery. The presence of sinus rhythm is facilitated by cardiac conduction leading to mechanical and electrical remodelling of the atria.

Transcriptome profiling of the nonlactating mammary glands of dairy goats reveals the molecular genetic mechanism of mammary cell remodeling

The mammary gland redevelops to the prepregnancy state during involution, which shows the mammary cells have the characteristics of remodeling. The rapidity and degree of mammary gland involution vary across species (e.g., between model organism mice and dairy livestock). However, the molecular genetic mechanism of involution and remodeling of goat mammary gland has not yet been clarified. This work investigated the structural changes and transcriptome characteristics of the mammary gland tissue of nonlactating dairy goats during the late lactation (LL), the dry period (DP), and late gestation (LG). Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining revealed significant changes in the structure of the nonlactating goat mammary gland, and obvious cell apoptosis occurred at LL and DP. Sequencing identified 1,381 genes that are differentially expressed in mammary gland tissue at the 3 developmental stages. Genes related to cell growth, apoptosis, immunity, nutrient transport, synthesis, and metabolism exhibited adaptive transcriptional changes to meet the needs of a new set of mammary gland lactation functions. The significant enrichment of Gene Ontology terms such as humoral immune response, complement activation, and neutrophil-mediated immunity indicates that the innate immune system plays an important role in maintaining the health of degenerative mammary glands and eliminating apoptotic cells. The peroxisome proliferator-activated receptor signaling pathway plays an important regulatory role in lipid metabolism, especially the adaptive changes in expression of genes encoded lipid transport and enzymes, which promote the formation of milk fat during the lactation. The mammary gland development gene module revealed that pregnancy hormone receptors, cell growth factors and their receptors, and genes encoding insulin-like growth factor binding proteins regulate the physiological process of mammary gland involution through adaptive transcriptional changes. Interestingly, ERBB4 was identified as the hub gene of the network that regulates mammary gland growth and development. Overexpression of ERBB4 in mammary epithelial cells cultured in vitro can reduce cell cycle arrest in G1/S phase and apoptosis by regulating the PI3K/Akt signaling pathway and promote the proliferation of mammary epithelial cells. The gene ERBB4 also affects the expression of genes that initiate mammary gland involution and promote mammary gland remodeling. These findings contribute to an in-depth understanding of the molecular mechanisms involved in mammary gland involution and remodeling.

Complete electrical reverse remodeling of native conduction after resynchronization therapies

BackgroundElectrical reverse remodeling of native conduction is associated with better clinical outcome following cardiac resynchronization therapy (CRT). We aimed to describe characteristics, time course and long-term outcome of patients with complete electrical reverse remodeling (CERR) after resynchronization therapies. MethodsCRT candidates were treated with bi-ventricular, His bundle or left bundle branch pacing. CERR was defined if native QRS duration post-implantation was narrowed to ≤120 ms. ResultsA total of 322 patients met the inclusion criteria. Among them, 66 were super-responders and 12 exhibited CERR. All 12 patients were diagnosed of non-ischemic cardiomyopathy with left bundle branch block (LBBB) meeting the Strauss criteria. The mean native QRS duration when CERR was achieved was 110.8 ± 10.0 ms, significantly shorter than the baseline (175.0 ± 18.8 ms). The occurrence of CERR varied from several days post-implantation to 18-month follow-up. The persistence of CERR also showed great variations. Eleven patients (91.7%, 11/12) showed echocardiographic super-response. Patients with CERR showed similar baseline characteristics compared to those with echocardiographic super-response but without CERR. Two patients with CERR showed different responses after bi-ventricular pacing was turned off. One patient remained stable with narrow QRS complex and great response. The other patient had reappearance of LBBB and decreased cardiac function, but recovered by turning on the device again. ConclusionsPatients with CERR exhibited great response to different resynchronization therapies. The time course of CERR and echocardiographic super-response varied greatly. The variability of native conduction system and accompanied changes of mechanical remodeling suggest the mechanisms of electrical-disorder related cardiomyopathy.

IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling

RationaleEndoplasmic reticulum (ER) stress and mitochondrial dysfunction are important mechanisms of atrial remodeling, predisposing to the development of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). However, the molecular mechanisms underlying these processes especially their interactions have not been fully elucidated. ObjectiveTo explore the potential role of ER stress–mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes. Methods and resultsMouse atrial cardiomyocytes (HL-1 cells) and rats with T2DM were used as study models. Significant ER stress was observed in the diabetic rat atria. After treatment with tunicamycin (TM), an ER stress agonist, mass spectrometry (MS) identified several known ER stress and calmodulin proteins, including heat shock protein family A (HSP70) member [HSPA] 5 [GRP78]) and HSPA9 (GRP75, glucose-regulated protein 75). In situ proximity ligation assay indicated that TM led to increased protein expression of the IP3R1–GRP75–VDAC1 (inositol 1,4,5-trisphosphate receptor 1–glucose-regulated protein 75–voltage-dependent anion channel 1) complex in HL-1 cells. Small interfering RNA silencing of GRP75 in HL-1 cells and GRP75 conditional knockout in a mouse model led to impaired calcium transport from the ER to the mitochondria and alleviated mitochondrial oxidative stress and calcium overload. Moreover, GRP75 deficiency attenuated atrial remodeling and AF progression in Myh6-Cre+/Hspa9flox/flox + TM mice. ConclusionsThe IP3R1–GRP75–VDAC1 complex mediates ER stress–mitochondrial oxidative stress and plays an important role in diabetic atrial remodeling.

Structural Remodeling and Rotational Activity in Persistent/Long-Lasting Atrial Fibrillation: Gender-Effect Differences and Impact on Post-ablation Outcome.

BackgroundStructural and post-ablation gender differences are reported in atrial fibrillation (AF). We analyzed the gender differences in structural remodeling and AF mechanisms in patients with persistent/long-lasting AF who underwent wide area circumferential pulmonary vein isolation (WACPVI).Materials and MethodsUltra-high-density mapping was used to study atrial remodeling and AF drivers in 85 consecutive patients. Focal and rotational activity (RAc) were identified with the CartoFinder system and activation sequence analysis. The impact of RAc location on post-ablation outcomes was analyzed.ResultsThis study included 64 men and 21 women. RAc was detected in 73.4% of men and 38.1% of women (p = 0.003). RAc patients had higher left atrium (LA) voltage (0.64 ± 0.3 vs. 0.50 ± 0.2 mV; p = 0.01), RAc sites had higher voltage than non-RAc sites 0.77 ± 0.46 vs. 0.53 ± 0.37 mV (p < 0.001). Women had lower LA voltage than men (0.42 vs. 0.64 mV; p < 0.001), including pulmonary vein (PV) antra (0.16 vs. 0.30 mV; p < 0.001) and posterior wall (0.34 vs. 0.51 mV; p < 0.001). RAc in the posterior atrium was recorded in few women (23.8 vs. 54.7% in men; p = 0.014). AF recurrence rate was higher in patients with RAc outside WACPVI than those with all RAc inside WACPVI or no RAc (63.4 vs. 11.1 and 31.0%; p = 0.008 and p = 0.01). Comparison of selected patients using propensity score matching confirmed lower atrial voltage (0.4 ± 0.2 vs. 0.7 ± 0.3 mV; p = 0.007) and less RAc (38 vs. 75%; p = 0.02) in women.ConclusionWomen have shown more advanced structural remodeling at ablation, which is associated with a lower incidence of RAc (usually located outside the WACPVI). These findings could explain post-ablation gender differences.

Nrf2 attenuates the innate immune response after experimental myocardial infarction

BackgroundThere is compelling evidence implicating dysregulated inflammation in the mechanism of ventricular remodeling and heart failure (HF) after MI. The transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2, encoded by Nfe2l2) is a promising target in this context since it impedes transcriptional upregulation of pro-inflammatory cytokines and is anti-inflammatory in various murine models. ObjectivesWe aimed to investigate the contribution of Nrf2 to the inflammatory response after experimental myocardial infarction (MI). MethodsWe subjected Nrf2−/− mice and wild type (WT) controls to permanent left coronary artery (LCA) ligation. The inflammatory response was investigated with fluorescence-activated cell sorting (FACS) analysis of peripheral blood and heart cell suspensions, together with qRT-PCR of infarcted tissue for chemokines and their receptors. To investigate whether Nrf2-mediated transcription is a dedicated function of leukocytes, we interrogated publicly available RNA-sequencing (RNA-seq) data from mouse hearts after permanent LCA ligation for Nrf2-regulated gene (NRG) expression. ResultsFACS analysis demonstrated a profoundly inflamed phenotype in the hearts of global Nrf2−/− mice as compared to WT mice after MI. Moreover, infarcted tissue from Nrf2−/− mice displayed higher expression of mRNA coding for inflammatory cytokines, chemokines, and their receptors, including IL-6, Ccl2, and Cxcr4. RNA-seq analysis showed upregulated NRG expression in WT mice after MI compared to naive mice, which was significantly higher in bioinformatically isolated CCR2+ cells. ConclusionsTaken together, the results suggest that Nrf2 signalling in leukocytes, and possibly CCR2+ monocytes and monocyte-derived cardiac resident macrophages, may be potential targets to prevent post-MI ventricular remodeling.

Sodium-Glucose Cotransporter 2 Inhibitors and Cardiac Remodeling.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have evident cardiovascular benefits in patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction (only empagliflozin and dapagliflozin have been investigated in this group so far), and chronic kidney disease. Prevention and reversal of adverse cardiac remodeling is one of the mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits, especially heart failure-related outcomes. Cardiac remodeling encompasses molecular, cellular, and interstitial changes that result in favorable changes in the mass, geometry, size, and function of the heart. The pathophysiological mechanisms of adverse cardiac remodeling are related to increased apoptosis and necrosis, decreased autophagy, impairments of myocardial oxygen supply and demand, and altered energy metabolism. Herein, the accumulating evidence from animal and human studies is reviewed investigating the effects of SGLT2 inhibitors on these mechanisms of cardiac remodeling.

Metabolic Landscape of Bronchoalveolar Lavage Fluid in Coronavirus Disease 2019 at Single Cell Resolution

Abnormal function of immune cells is one of the key mechanisms leading to severe clinical symptoms in coronavirus disease 2019 patients, and metabolic pathways can destroy the function of the immune system by affecting innate and adaptive immune responses. However, the metabolic characteristics of the immune cells of the SARS-CoV-2 infected organs in situ remaining elusive. We reanalyzed the metabolic-related gene profiles in single-cell RNA sequencing data, drew the metabolic landscape in bronchoalveolar lavage fluid immune cells, and elucidated the metabolic remodeling mechanism that might lead to the progression of COVID-19 and the cytokine storm. Enhanced glycolysis is the most important common metabolic feature of all immune cells in COVID-19 patients. CCL2+ T cells, Group 2 macrophages with high SPP1 expression and myeloid dendritic cells are among the main contributors to the cytokine storm produced by infected lung tissue. Two metabolic analysis methods, including Compass, showed that glycolysis, fatty acid metabolism, bile acid synthesis and purine and pyrimidine metabolism levels of CCL2+ T cells, Group 2 macrophages and myeloid dendritic cells were upregulated and correlated with cytokine storms of COVID-19 patients. This might be the key metabolic regulatory factor for immune cells to produce large quantities of cytokines.

Neutrophil Extracellular Traps in Cancer Therapy Resistance.

Simple SummaryNeutrophils are a type of white blood cell that also play a role in cancer. They have been shown to influence various aspects of the disease, including resistance to therapy. The role of neutrophils in cancer is now known to involve the extrusion of their DNA in a process called NETosis. The resulting protein-covered DNA webs are called neutrophil extracellular traps (NETs), which have been shown to interact with cancer cells. This interaction is now thought to drive resistance to various cancer therapies, including chemotherapy, immunotherapy, and radiation therapy. The evidence now suggests that NETs may be central facilitators of therapy resistance, bringing cancer cells into proximity with various proteins and factors, and driving multiple mechanisms concurrently. This paper will therefore provide an overview of current evidence implicating NETs in cancer therapy resistance and potential clinical applications.Neutrophils and their products are increasingly recognized to have a key influence on cancer progression and response to therapy. Their involvement has been shown in nearly every aspect of cancer pathophysiology with growing evidence now supporting their role in resistance to a variety of cancer therapies. Recently, the role of neutrophils in cancer progression and therapy resistance has been further complicated with the discovery of neutrophil extracellular traps (NETs). NETs are web-like structures of chromatin decorated with a variety of microbicidal proteins. They are released by neutrophils in a process called NETosis. NET-dependent mechanisms of cancer pathology are beginning to be appreciated, particularly with respect to tumor response to chemo-, immuno-, and radiation therapy. Several studies support the functional role of NETs in cancer therapy resistance, involving T-cell exhaustion, drug detoxification, angiogenesis, the epithelial-to-mesenchymal transition, and extracellular matrix remodeling mechanisms, among others. Given this, new and promising data suggests NETs provide a microenvironment conducive to limited therapeutic response across a variety of neoplasms. As such, this paper aims to give a comprehensive overview of evidence on NETs in cancer therapy resistance with a focus on clinical applicability.

Molecular feature of arterial remodeling in the brain arteriovenous malformation revealed by arteriovenous shunt rat model and RNA sequencing

PurposeMorphological research suggested the feeding artery of brain arteriovenous malformation (bAVM) had vascular remodeling under the high blood flow; however, the underlying molecular mechanisms were unclear. MethodsWe constructed 32 simplified AVM rat models in four groups: the control group (n = 6), 1-week high-blood-flow group (n = 9), 3-week high-blood-flow group (n = 7) and 6-week high-blood-flow group (n = 10). The circumference, blood velocity, blood flow, pressure, and wall shear of the feeding artery were measured or calculated. The arterial wall change was observed by Masson staining. RNA sequencing (RNA-seq) of feeding arteries was performed, followed by bioinformatics analysis to detect the potential molecular mechanism for bAVM artery remodeling under the high blood flow. ResultsWe observed hemodynamic injury and vascular remodeling on the feeding artery under the high blood flow. RNA-seq showed immune/inflammation infiltration and vascular smooth muscle cell (VSMC) phenotype transformation during remodeling. Weighted gene co-expression network analysis (WGCNA) and time series analysis further identified 27 key genes and pathways involved in remodeling. Upstream miRNA and molecular drugs were predicted targeting these key genes. ConclusionsWe depicted molecular change of bAVM arterial remodeling via RNA-seq in high-blood-flow rat models. Twenty-seven key genes may regulate immune/inflammation infiltration and VSMC phenotype transform in bAVM arterial remodeling.

A Model of Reverse Vascular Remodeling in Pulmonary Hypertension Due to Left Heart Disease by Aortic Debanding in Rats.

Pulmonary hypertension due to left heart disease (PH-LHD) is the most common form of PH, yet its pathophysiology is poorly characterized than pulmonary arterial hypertension (PAH). As a result, approved therapeutic interventions for the treatment or prevention of PH-LHD are missing. Medications used to treat PH in PAH patients are not recommended for treatment of PH-LHD, as reduced pulmonary vascular resistance (PVR) and increased pulmonary blood flow in the presence of increased left-sided filling pressures may cause left heart decompensation and pulmonary edema. New strategies need to be developed to reverse PH in LHD patients. In contrast to PAH, PH-LHD develops due to increased mechanical load caused by congestion of blood into the lung circulation during left heart failure. Clinically, mechanical unloading of the left ventricle (LV) by aortic valve replacement in aortic stenosis patients or by implantation of LV assist devices in end-stage heart failure patients normalizes not only pulmonary arterial and right ventricular (RV) pressures but also PVR, thus providing indirect evidence for reverse remodeling in the pulmonary vasculature. Using an established rat model of PH-LHD due to left heart failure triggered by pressure overload with subsequent development of PH, a model is developed to study the molecular and cellular mechanisms of this physiological reverse remodeling process. Specifically, an aortic debanding surgery was performed, which resulted in reverse remodeling of the LV myocardium and its unloading. In parallel, complete normalization of RV systolic pressure and significant but incomplete reversal of RV hypertrophy was detectable. This model may present a valuable tool to study the mechanisms of physiological reverse remodeling in the pulmonary circulation and the RV, aiming to develop therapeutic strategies for treating PH-LHD and other forms of PH.

Shaping the root system architecture in plants for adaptation to drought stress.

Root system architecture plays an important role in plant adaptation to drought stress. The root system architecture (RSA) consists of several structural features, which includes number and length of main and lateral roots along with the density and length of root hairs. These features exhibit plasticity under water-limited environments and could be critical to developing crops with efficient root systems for adaptation under drought. Recent advances in the omics approaches have significantly improved our understanding of the regulatory mechanisms of RSA remodeling under drought and the identification of genes and other regulatory elements. Plant response to drought stress at physiological, morphological, biochemical, and molecular levels in root cells is regulated by various phytohormones and their crosstalk. Stress-induced reactive oxygen species play a significant role in regulating root growth and development under drought stress. Several transcription factors responsible for the regulation of RSA under drought have proven to be beneficial for developing drought tolerant crops. Molecular breeding programs for developing drought-tolerant crops have been greatly benefitted by the availability of quantitative trait loci (QTLs) associated with the RSA regulation. In the present review, we have discussed the role of various QTLs, signaling components, transcription factors, microRNAs and crosstalk among various phytohormones in shaping RSA and present future research directions to better understand various factors involved in RSA remodeling for adaptation to drought stress. We believe that the information provided herein may be helpful in devising strategies to develop crops with better RSA for efficient uptake and utilization of water and nutrients under drought conditions.

The Molecular Mechanism of Aerobic Exercise Improving Vascular Remodeling in Hypertension.

The treatment and prevention of hypertension has been a worldwide medical challenge. The key pathological hallmark of hypertension is altered arterial vascular structure and function, i.e., increased peripheral vascular resistance due to vascular remodeling. The aim of this review is to elucidate the molecular mechanisms of vascular remodeling in hypertension and the protective mechanisms of aerobic exercise against vascular remodeling during the pathological process of hypertension. The main focus is on the mechanisms of oxidative stress and inflammation in the pathological condition of hypertension and vascular phenotypic transformation induced by the trilaminar structure of vascular endothelial cells, smooth muscle cells and extracellular matrix, and the peripheral adipose layer of the vasculature. To further explore the possible mechanisms by which aerobic exercise ameliorates vascular remodeling in the pathological process of hypertension through anti-proliferative, anti-inflammatory, antioxidant and thus inhibiting vascular phenotypic transformation. It provides a new perspective to reveal the intervention targets of vascular remodeling for the prevention and treatment of hypertension and its complications.

Histochemical changes, cellular dynamics and antioxidant responses in the corpuscles of Stannius of the female Lake Van fish ( Alburnus tarichi Güldenstädt, 1814) (Cyprinidae) during migration from highly alkaline and brackish water to freshwater

The Lake Van fish (Alburnus tarichi) is an anadromous species, which is endemic to Lake Van Basin of Turkey. In spring, the fish migrates from Lake Van, which has highly alkaline and brackish water, to freshwater to spawn. During the anadromous migration of the female Lake Van fish, histochemical changes in the cell types, cellular dynamics, apoptosis, cell proliferation and antioxidant responses in the corpuscles of Stannius (CS) which are tiny endocrine glands related with calcium homeostasis were examined. When compared to the lake, calcium concentrations of ambient water and plasma increased considerably in freshwater. Freshwater dramatically increased the number of predominant type-I cells in the gland while decreased the type-II cells. A reduction in the cytoplasmic periodic acid-Schiff content of type-I cells was observed in freshwater. No cytoplasmic staining was found in cytoplasm of type-II cells in both lake and freshwater. Apoptotic cells were detected in fish sampled from both the lake and freshwater and a nonsignificant increase was observed in freshwater. The number of proliferating cells increased significantly in the freshwater, as well as antioxidant defences such as catalase, glutathione peroxidase and glutathione s-transferase activities, which indicates an elevated oxidative status. The findings suggest that type-I cells are possible source of a hypocalcin hormone and type-II cells are considered to be a likely precursor of type-I cells. Apoptosis and cell proliferation are basic mechanisms of gland remodelling. In addition antioxidant mechanisms play a role during the acclimation of the gland in different environments.

Controlling Mesenchyme Tissue Remodeling via Spatial Arrangement of Mechanical Constraints.

Tissue morphogenetic remodeling plays an important role in tissue repair and homeostasis and is often governed by mechanical stresses. In this study, we integrated an in vitro mesenchymal tissue experimental model with a volumetric contraction-based computational model to investigate how geometrical designs of tissue mechanical constraints affect the tissue remodeling processes. Both experimental data and simulation results verified that the standing posts resisted the bulk contraction of the tissues, leading to tissue thinning around the posts as gap extension and inward remodeling at the edges as tissue compaction. We changed the geometrical designs for the engineered mesenchymal tissues with different shapes of posts arrangements (triangle vs. square), different side lengths (6 mm vs. 8 mm), and insertion of a center post. Both experimental data and simulation results showed similar trends of tissue morphological changes of significant increase of gap extension and deflection compaction with larger tissues. Additionally, insertion of center post changed the mechanical stress distribution within the tissues and stabilized the tissue remodeling. This experimental-computational integrated model can be considered as a promising initiative for future mechanistic understanding of the relationship between mechanical design and tissue remodeling, which could possibly provide design rationale for tissue stability and manufacturing.

Dynamic alteration in myocardium creatine during acute infarction using MR CEST imaging.

Creatine (Cr) is an essential metabolite in the creatine kinase reaction, which plays a critical role in maintaining normal cardiac function. Chemical exchange saturation transfer (CEST) MRI offers a novel way to map myocardium Cr. This study aims to investigate the dynamic alteration in myocardium Cr during acute infarction using CEST MRI, which may facilitate understanding of the heart remodeling mechanism at the molecular level. Seven adult Bama pigs underwent cardiac cine, Cr CEST, and late gadolinium-enhanced (LGE) T1 -weighted (T1 w) imaging three and 14 days after myocardial infarction induction on a 3 T scanner. Cardiac structural and functional indices, including myocardium mass (MM), end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and ejection fraction (EF), were measured from cines. Infarct angle was determined from LGE T1 w images, based on which myocardium was classified into infarct, adjacent, and remote regions. Cr-weighted CEST signal was quantified from a three-pool Lorentzian fitting model and measured within each region and the entire myocardium. Student's t-test was conducted to evaluate any significant differences in measurements between the two time points. Correlation was assessed with Pearson correlation. P values less than 0.05 were considered statistically significant. Over the studied period, MM, EDV, and ESV did not alter significantly (P> 0.05), whereas significant increases of SV and EF and decrease of infarct angle were observed (P< 0.05). Meanwhile, the Cr-weighted CEST signal elevated significantly on Day 14 compared with Day 3 in the infarct (10.00 ± 1.28% versus 6.91 ± 1.54%, P< 0.01), adjacent (11.17 ± 2.00% versus 8.01 ± 1.58%, P= 0.01), and entire myocardium (11.03 ± 1.36% versus 8.19 ± 1.28%, P< 0.01). Moderate negative correlations were shown between the infarct angle and Cr-weighted CEST signals in the infarct (r= -0.80, P< 0.001), adjacent (r= -0.58, P= 0.03), and entire myocardium (r= -0.76, P< 0.01). In conclusion, the dynamic increase of myocardium Cr during acute infarction may interact with cardiac structural and functional recovery. The study provides supplementary insights into the heart remodeling process from the metabolic viewpoint.

Role of N6-methyladenosine Modification in Cardiac Remodeling.

Cardiac remodeling is the critical process in heart failure due to many cardiovascular diseases including myocardial infarction, hypertension, cardiovascular disease and cardiomyopathy. However, treatments for heart failure focusing on cardiac remodeling show relatively limited effectiveness. In recent decades, epitranscriptomic modifications were found abundantly present throughout the progression of cardiac remodeling, and numerous types of biochemical modifications were identified. m6A modification is the methylation of the adenosine base at the nitrogen-6 position, and dysregulation of m6A modification has been implicated in a wide range of diseases. However, function of m6A modifications still remain largely unknown in cardiac diseases, especially cardiac remodeling. LncRNAs are also shown to play a vital role in the pathophysiology of cardiac remodeling and heart failure. The crosstalk between lncRNAs and m6A modification provides a novel prospective for exploring possible regulatory mechanism and therapeutic targets of cardiac remodeling. This review summarizes the role of m6A modification in cardiac remodeling in the current researches.

Gravity-Vector Induces Mechanical Remodeling of rMSCs via Combined Substrate Stiffness and Orientation.

Distinct physical factors originating from the cellular microenvironment are crucial to the biological homeostasis of stem cells. While substrate stiffness and orientation are known to regulate the mechanical remodeling and fate decision of mesenchymal stem cells (MSCs) separately, it remains unclear how the two factors are combined to manipulate their mechanical stability under gravity vector. Here we quantified these combined effects by placing rat MSCs onto stiffness-varied poly-dimethylsiloxane (PDMS) substrates in upward (180°), downward (0°), or edge-on (90°) orientation. Compared with those values onto glass coverslip, the nuclear longitudinal translocation, due to the density difference between the nucleus and the cytosol, was found to be lower at 0° for 24 h and higher at 90° for 24 and 72 h onto 2.5 MPa PDMS substrate. At 0°, the cell was mechanically supported by remarkably reduced actin and dramatically enhanced vimentin expression. At 90°, both enhanced actin and vimentin expression worked cooperatively to maintain cell stability. Specifically, perinuclear actin stress fibers with a large number, low anisotropy, and visible perinuclear vimentin cords were formed onto 2.5 MPa PDMS at 90° for 72 h, supporting the orientation difference in nuclear translocation and global cytoskeleton expression. This orientation dependence tended to disappear onto softer PDMS, presenting distinctive features in nuclear translocation and cytoskeletal structures. Moreover, cellular morphology and focal adhesion were mainly affected by substrate stiffness, yielding a time course of increased spreading area at 24 h but decreased area at 72 h with a decrease of stiffness. Mechanistically, the cell tended to be stabilized onto these PDMS substrates via β1 integrin–focal adhesion complexes–actin mechanosensitive axis. These results provided an insight in understanding the combination of substrate stiffness and orientation in defining the mechanical stability of rMSCs.

Rhinovirus infection of bronchial epithelium induces specific bronchial smooth muscle cell migration of severe asthmatic patients

Patients with severe asthma show an increase in both exacerbation frequency and bronchial smooth muscle (BSM) mass. Rhinovirus (RV) infection of the bronchial epithelium (BE) is the main trigger of asthma exacerbations. Histological analysis of biopsies shows that a close connection between BE and hypertrophic BSM is a criterion for severity of asthma. We hypothesized that RV infection of BE specifically increases BSM-cell migration from patients with asthma. Serum samples, biopsies, or BSM cells were obtained from 86 patients with severe asthma and 31 subjects without asthma. BE cells from subjects without asthma were cultured in an air-liquid interface and exposed to RV-16. Migration of BSM cells was assessed in response to BE supernatant using chemotaxis assays. Chemokine concentrations were analyzed by transcriptomics and ELISAs. Immunocytochemistry, western blotting, and flow cytometry were used to quantify CXCR3 isoform distribution. CXCR3 downstream signaling pathways were assessed by calcium imaging and western blots. BSM cells from patients with severe asthma specifically migrated toward RV-infected BE, whereas those from subjects without asthma did not. This specific migration is driven by BE C-X-C motif chemokine ligand 10, which was increased invitro in response to RV infection as well as invivo in serum from exacerbating patients with severe asthma. The mechanism is related to both decreased expression and activation of the CXCR3-B-specific isoform in BSM cells from those with severe asthma. We have demonstrated a novel mechanism of BSM remodeling in patients with severe asthma following RV exacerbation. This study highlights the C-X-C motif chemokine ligand 10/CXCR3-A axis as a potential therapeutic target in severe asthma.