Structural Remodeling Research Articles

Left Ventricular Dilation Resulting from the Absence of Either Rgs2 or Rgs5 Is Associated with Increased Immune Cell Infiltration in the Myocardium

Sustained sympathoexcitation is a hallmark of heart failure, with equally sustained activation of downstream signaling pathways involving Gs- and Gi/o-coupled β-adrenergic receptors (βAR) stimulating cAMP production and PKA activation. A critical mechanism controlling G protein-mediated βAR signaling is the activity of regulator of G protein signaling (RGS) proteins, including members of the B/R4 subfamily, which accelerate the termination of Gq/11 and Gi/o protein signaling. Previous studies by us and others reported that moderation of Gi/o activity separately by RGS2 and RGS5 of the R4 subfamily is key to maintaining normal ventricular rhythm. The loss of one or both R4 RGS proteins also results in left ventricular (LV) dilation and reduced ejection fraction. Here, we tested the hypothesis that the LV structural remodeling is due to the disruption of the coordinated activity of RGS2 and 5 resulting in sensitization of βAR signaling. To test this hypothesis, we challenged wild type (WT), Rgs2 KO ,Rgs5 KO, and Rgs2/5 double knockout (dbKO) adult male mice with sub-chronic infusion of isoproterenol (ISO, 30 mg/kg/day, 3 days) via a peritoneal osmotic minipump implantation. Rgs2 KO and Rgs5 KO mice showed increased LV chamber size at baseline, which was unchanged by ISO administration. In saline-treated animals, the loss of Rgs2 increased Rgs5 mRNA expression, while Rgs5 absence increased Rgs4 mRNA expression. ISO infusion induced concentric cardiac hypertrophy in WT mice, as evidenced by increased heart weight/tibia length (HW/TL) ratio and cardiomyocyte cross sectional area. While ISO infusion increased interstitial fibrosis in midventricular tissue and HW/TL ratio in dbKO mice, it did not affect cardiomyocyte cross sectional area or exacerbate LV dilation, despite increased expression of the cardiac fetal gene Nppa as well as the sarcomeric protein α-actinin and Ca2+/calmodulin-dependent kinase II (CaMKII). Cardiact tissue from saline-treated Rgs2 KO and Rgs5 KO mice had markedly increased CD45+ cells vs WT, while tissue from Rgs5 KO mice showed increased CD68+ cells, as revealed by immunohistochemistry. Taken together, these results indicate that ventricular remodeling seen in Rgs2 KO, Rgs5 KO, and Rgs2/5 dbKO mice is insensitive to sustained βAR stimulation but may be due to increased cardiac resident immune cell population. This work was supported by NIH R56 DK132859-01A1 and R01 HL139754, and Craig H. Neilsen Foundation Grant 382566 to Patrick Osei-Owusu. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

DISPARATE IMPACT OF PRIMARY HYPERTENSION ON RIGHT VERSUS LEFT HEART VENTRICLES OF MALES AND FEMALES WILD TYPE AND HAIRLESS STRAIN OF SPONTANEOUSLY HYPERTENSIVE RATS

Objective: Poor adherence to lifestyle changes and antihypertensive drugs contributes to increase a risk for malignant cardiac arrhythmias. Hypertension contributes to myocardial structural remodeling, abnormalities in connexin43 (Cx43) which promote electrical instability and mechanical dysfunction. However, it is not known whether changes are confined solely to left heart ventricle (LV) or there is response of right heart ventricle (RV). SHR mimic human primary hypertension and hairless SHR is model of temperature acclimation characterized by increase thermogenesis. Aim of the study was to explore key factors involved in development of malignant arrhythmias and progression to heart failure, in left and right heart ventricles, of males and females wild type (WT) and hairless SHR. Design and method: 6-month-old males and females WT and hairless SHR and normotensive WKY strain of rats were housed at standard 22°C. Biometric parameters, including electro- and echo-cardiographic were registered. LV and RV tissue was used for immuno-labelling of Cx43 to detect its topology and western blotting for determination protein levels of Cx43, PKA, PKC∊, PKCδ and markers of extracellular matrix (ECM) remodelling: TGFβ, SMAD2/3, MMP-2 and collagen-1. Susceptibility of the heart to electrically-inducible VF was tested using isolated perfused heart technique. Results: Comparing to WKY, QT and QRS intervals were prolonged in WT SHR with normalisation in hairless SHR. Hypertension resulted in decrease in Cx43 with its abnormal topology in LV of males and less in hairless SHR but not in females. Cx43 levels and its topology were preserved in RV regardless rat strain and sex. There were no differences in protein levels of ECM-markers when comparing LV and RV in all strains. PKC∊ and PKCδ were increased in RV versus LV in both SHR strains. Hairless SHR males and females were less prone to inducible VF compared to WT SHR. Conclusions: Findings point out that hypertension-induced pro-arrhythmic disorders of Cx43 are related to the left while not to right heart ventricle in both hypertensive strains. There is a benefit of cold acclimation in hypertension that may contribute, to the protection from malignant cardiac arrhythmias and mechanical dysfunction. Supported by Vega2/0002/20,2/0006/23 and APVV21-0410.

Load-Dependent Arterial Stiffness Mechanisms are Responsible for Increased Large Artery Stiffness Observed among Women with a History of Preeclampsia

Introduction: Preeclampsia is a pregnancy complication characterized by hypertension and multi-organ dysfunction and is a leading cause of maternal morbidity and mortality. Preeclampsia results in a two-four fold increased risk of developing hypertension and cardiovascular disease later in life. Large artery stiffness (LAS), a robust risk factor for hypertension and cardiovascular disease, and blood pressure (BP) are elevated after pregnancy in women with a history of preeclampsia (hxPE) and is associated with reduced cardiovagal baroreflex sensitivity (BRS). Whether elevated LAS in women with a hxPE is a consequence of structural remodeling of the arterial wall or the load applied to the arterial wall by the blood (i.e., BP) is unclear. Furthermore, it is unknown whether one or both LAS mechanisms are associated with differences in BRS. Therefore, we hypothesized that 1) structural- and load- dependent LAS would be elevated in women with a hxPE versus no hxPE postpartum controls, and 2) structural- and load- dependent LAS would be associated with BRS in women with hxPE.Methods: LAS was measured via carotid-femoral pulse wave velocity (aortic LAS), and carotid ultrasonography/tonometry (carotid LAS) among 115 women 1-5 years postpartum (age 34 ±4yrs; hxPE n=51; controls n=64). Participant-specific exponential models were used to standardize LAS measurements to a ‘reference’ BP (aortic: 90mmHg mean arterial pressure; carotid: BP 120/80mmHg) and used to calculate structural LAS. Load-dependent LAS was calculated as total minus structural LAS. Spontaneous cardiovagal BRS was measured using the sequence technique. Results: Systolic and diastolic BP were higher in women with hxPE compared with controls (all p<0.001). Aortic, but not carotid, LAS was 0.57 m/s higher in women with hxPE compared with controls (p=0.025). Load-dependent LAS was 0.39 m/s (aortic) and 0.5 m/s (carotid) higher in women with hxPE (p<0.001 for aortic and carotid), but no difference was observed for structural LAS measures (p>0.14 for both). Women with hxPE had 4.13 ms/mmHg lower BRS compared to controls (p=0.042). In women with hxPE, BRS was negatively associated with both aortic and carotid LAS (r=-0.37, p=0.042 and r=-0.38, p=0.025, respectively), and aortic load-dependent LAS (r=-0.39, p=0.033), after adjusting for age and body mass index. Conclusion: Load-dependent LAS mechanisms explained the higher aortic and carotid LAS observed among women with a hxPE and was associated with lower BRS. Our findings suggest that changes in BP and cardiovagal BRS may underpin in part the higher LAS observed in women with a hxPE. Grant funding: American Heart Association 22TPA969732 (to GLP) and 18SCG34350001 (to MKS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Enhancing efficiency and user-centricity in architectural remodeling: A comprehensive system design for structural renovation

The home renovation industry has witnessed remarkable growth, driven by shifts in lifestyle necessitating adjustments in living spaces. This paper addresses critical gaps in the domain of architectural remodeling, with a particular focus on improving efficiency, referenceability, and user-centricity in structural remodeling. This research introduces a system design tailored for structural remodeling within house renovation, catering to both comprehensive and partial projects to facilitate the creation of structurally viable renovation options and optimizing them to align precisely with user requirements. The proposed system's accessibility and consideration of architectural factors set it apart. While offering substantial benefits, the system has limitations, such as the exclusion of interior furnishing styles in output solutions. In conclusion, contributes to the improvement of remodeling projects and offers a promising approach, particularly in the early stages of these endeavors.

The SK4 channel allosteric blocker, BA6b9, reduces atrial fibrillation substrate in rats with reduced ejection fraction.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is strongly associated with several comorbidities including heart failure (HF). AF in general, and specifically in the context of HF, is progressive in nature and associated with poor clinical outcomes. Current therapies for AF are limited in number and efficacy and do not target the underlying causes of atrial remodeling such as inflammation or fibrosis. We previously identified the calcium-activated SK4 K+ channels, which are preferentially expressed in the atria relative to the ventricles in both rat and human hearts, as attractive druggable target for AF treatment. Here, we examined the ability of BA6b9, a novel allosteric inhibitor of SK4 channels that targets the specific calmodulin-PIP2 binding domain, to alter AF susceptibility and atrial remodeling in a systolic HF rat postmyocardial infarction (post-MI) model. Daily BA6b9 injection (20 mg/kg/day) for 3 weeks starting 1-week post-MI prolonged the atrial effective refractory period, reduced AF induction and duration, and dramatically prevented atrial structural remodeling. In the post-MI left atrium (LA), pronounced upregulation of the SK4 K+ channel was observed, with corresponding increases in collagen deposition, α-SMA levels, and NLRP3 inflammasome expression. Strikingly, BA6b9 treatment reversed these changes while also significantly reducing the lateralization of the atrial connexin Cx43 in the LA of post-MI rats. Our findings indicate that the blockade of SK4 K+ channels using BA6b9 not only favors rhythm control but also remarkably reduces atrial structural remodeling, a property that is highly desirable for novel AF therapies, particularly in patients with comorbid HF.

Sarcomere. The structural unit of the myofibrillar complex of typical cardiomyocytes. Isometric aspects of sarcomere organization

Background. The complexity of understanding the structure and function of cardiomyocytes in the myocardium is a fundamental problem in the field of heart morphology. Sarcomeres are the main structural and functional units of myofibrils. Understanding the organization and dynamics of sarcomeres in cardiomyocytes is crucial for establishing the mechanisms responsible for the process of forming the contractile system of cardiomyocytes. Objective. The main purpose of this study is a review of literary sources that complement and expand the essential findings about the construction of myofibrils and their components when studied by effective methods of microscopic techniques. Materials. Literature review databases, systematic search of primary sources related to the research topic. Methods of visual examination of the components of sarcomeres and elements of their organization. Results. Transmission electron microscopy provides high-resolution imaging of sarcomeres, which is necessary for detailed analysis of their ultrastructure, including visualization of sarcomere components such as Z-discs, M-lines, thick and thin filaments. Morphometric methods are crucial for studying the compaction and orientation of myofibrils in cardiomyocytes. Conclusion. Morphometric methods provide valuable information about the structural remodeling of myofibrils in response to physiological stimuli or pathological conditions. These techniques are needed to improve our understanding of the mechanisms underlying muscle contraction and to develop methods to study cardiac remodeling processes in response to the adaptive response.

Mechanisms of vibration-induced structural myocardial remodeling

The review analyzes literature data on structural changes in the heart of patients with vibration disease, as detected by echocardiographic methods. Particularly, it highlights concentric remodeling of the left ventricle chambers and disturbances in diastolic function. The review also discusses a 1.2-fold decrease in heart structure intensity compared to healthy individuals (p 0.05). Furthermore, it examines changes in morphometric and bioenergetic parameters of cardiomyocytes under different experimental vibration modes (7 and 56 sessions at a frequency of 8 Hz), confirming the disruptions in the relationship between the spatial configuration of the heart cavities, contractile ability, and energy supply potential. Loss of cardiac myofibrils represents the transition from myocardial hypertrophy to decompensation, accompanied by an increase in degenerative (dystrophic) signs such as the loss of sarcomeres in cardiomyocytes. Understanding these pathological (morphological) processes requires consideration of various mediators that regulate cell metabolism, proliferation, growth, and survival, including stromal interaction molecule, calcium ATPase of the endo(sarco)plasmic reticulum, inositol-1,4,5-triphosphate receptor, protein that forms CRAC channels, and transient receptor potential canonical. The degradation system of the extracellular matrix, including matrix metalloproteinases and tissue inhibitors, plays a crucial role in structural cardiac remodeling. This system regulates the rate of mRNA synthesis on the DNA matrix by binding to specific DNA regions that control cardiac nutrition and plasticity. The review suggests that these findings can help explain some patterns of cardiac remodeling development in patients with vibration disease and determine the direction of pathogenetically based therapy. This therapy should consider not only the vibration-protective effect of drugs but also their ability to inhibit and regress myocardial remodeling.

No Detectable Differences in microRNA Plasma Levels between Diabetic Hypertensive Patients with and without Incident Subclinical Atrial Fibrillation.

Background: Long-term rhythm monitoring (LTRM) can detect undiagnosed atrial fibrillation (AF) in patients at risk of AF and stroke. Circulating microRNAs (miRNAs), which have been shown to play a role in atrial electrical and structural remodelling, could help to select patients who would benefit most from LTRM. The aim of this study was to investigate whether patients with diabetes mellitus (DM) and hypertension and screen-detected subclinical AF (SCAF) using an insertable cardiac monitor (ICM) have significantly different plasma baseline levels of five selected miRNAs playing a role in the modulation of atrial electrical and structural remodelling (miR-21-5p, miR-29b-3p, miR-150-5p, miR-328-3p, and miR-432-5p) compared to those without SCAF. Methods: This study was performed at the outpatient clinic of a secondary academic teaching hospital between December 2013 and November 2015. Eligible patients were ≥65 years of age with DM and hypertension but without known heart diseases. All patients received an ICM. On the day of ICM implantation, blood samples for the measurement of plasma levels of the five miRNAs were drawn. In this post hoc analysis, we investigated their expression by reverse transcription-quantitative polymerase chain reaction. MiRNA plasma levels in patients with and without newly detected SCAF were compared. Results: We included 82 consecutive patients (median age of 71.3 years (IQR 67.4-75.1)), who were followed for a median of 588 days (IQR: 453-712 days). Seventeen patients (20.7%) had ICM-detected SCAF. Plasma levels of miR-328-3p, miR-29b-3p, miR-21-5p, miR-432-5p, and miR-150-5p were slightly but not significantly different in patients with incident SCAF compared with patients without. Conclusions: In patients with hypertension and DM, newly detected SCAF was not significantly associated with changes in expression levels of miR-21-5p, miR-29b-3p, miR-150-5p, miR-328-3p, and miR-432-5p.

Electrocardiographic manifestations in female team handball players: analyzing ECG changes in athletes.

Long-term intense training leads to structural, functional, and electrical remodeling of the heart. How different sports affect the heart has not been fully investigated, particularly for female athletes. The aim of the present study was to investigate the morphology of 12-lead resting electrocardiogram (ECG) in elite female handball players compared to non-athlete female subjects. Potential changes will be explored to see if they could be explained by differences in cardiac dimensions and exercise hours. A cross-sectional study of 33 elite female team handball players compared to 33 sex and age-matched, non-athletic controls (age range 18-26 years) was performed. All participants underwent a resting 12-lead ECG and an echocardiographic examination. ECG variables for left ventricular hypertrophy and durations were evaluated and adjusted for cardiac dimensions and exercise hours using ANCOVA analysis. A linear regression analysis was used to describe relation between echocardiographic and ECG measures and exercise hours. The female handball players had larger cardiac dimensions and significantly lower heart rate and QTc duration (Bazett's formula) as well as increased QRS and QT durations compared to controls. The 12-lead sum of voltage and the 12-lead sum of voltage ∗ QRS were significantly higher among handball players. Changes in ECG variables reflecting the left ventricle could in part be explained by left ventricular size and exercise hours. Correlation with exercise hours were moderately strong in most of the echocardiographic measures reflecting left ventricular (LV), left ventricular mass (LVM), left atrium (LA) and right atrium (RA) size. Poor to fair correlations were seen in the majority of ECG measures. Female team handball players had altered ECGs, longer QRS and QT durations, higher 12-lead sum of voltage and 12-lead sum of voltage ∗ QRS as well as shorter QTc (Bazett's formula) duration compared to non-athletic controls. These findings could only partly be explained by differences in left ventricular size. Despite larger atrial size in the athletes, no differences in P-wave amplitude and duration were found on ECG. This suggest that both structural, and to some degree electrical remodeling, occur in the female team handball players' heart and highlight that a normal ECG does not rule out structural adaptations. The present study adds knowledge to the field of sports cardiology regarding how the heart in female team handball players adapts to this type of sport.

Synergistic Effects of Weight Loss and Catheter Ablation: Can microRNAs Serve as Predictive Biomarkers for the Prevention of Atrial Fibrillation Recurrence?

In atrial fibrillation (AF), multifactorial pathologic atrial alterations are manifested by structural and electrophysiological changes known as atrial remodeling. AF frequently develops in the context of underlying cardiac abnormalities. A critical mechanistic role played by atrial stretch is played by abnormal substrates in a number of conditions that predispose to AF, including obesity, heart failure, hypertension, and sleep apnea. The significant role of overweight and obesity in the development of AF is known; however, the differential effect of overweight, obesity, cardiovascular comorbidities, lifestyle, and other modifiable risk factors on the occurrence and recurrence of AF remains to be determined. Reverse remodeling of the atrial substrate and subsequent reduction in the AF burden by conversion into a typical sinus rhythm has been associated with weight loss through lifestyle changes or surgery. This makes it an essential pillar in the management of AF in obese patients. According to recently published research, microRNAs (miRs) may function as post-transcriptional regulators of genes involved in atrial remodeling, potentially contributing to the pathophysiology of AF. The focus of this review is on their modulation by both weight loss and catheter ablation interventions to counteract atrial remodeling in AF. Our analysis outlines the experimental and clinical evidence supporting the synergistic effects of weight loss and catheter ablation (CA) in reversing atrial electrical and structural remodeling in AF onset and in recurrent post-ablation AF by attenuating pro-thrombotic, pro-inflammatory, pro-fibrotic, arrhythmogenic, and male-sex-associated hypertrophic remodeling pathways. Furthermore, we discuss the promising role of miRs with prognostic potential as predictive biomarkers in guiding approaches to AF recurrence prevention.

Smoking cessation only partially reverses cardiac metabolic and structural remodeling in mice.

Active cigarette smoking is a major risk factor for chronic obstructive pulmonary disease that remains elevated after cessation. Skeletal muscle dysfunction has been well documented after smoking, but little is known about cardiac adaptations to cigarette smoking. The underlying cellular and molecular cardiac adaptations, independent of confounding lifestyle factors, and time course of reversibility by smoking cessation remain unclear. We hypothesized that smoking negatively affects cardiac metabolism and induces local inflammation in mice, which do not readily reverse upon 2-week smoking cessation. Mice were exposed to air or cigarette smoke for 14 weeks with or without 1- or 2-week smoke cessation. We measured cardiac mitochondrial respiration by high-resolution respirometry, cardiac mitochondrial density, abundance of mitochondrial supercomplexes by electrophoresis, and capillarization, fibrosis, and macrophage infiltration by immunohistology, and performed cardiac metabolome and lipidome analysis by mass spectrometry. Mitochondrial protein, supercomplex content, and respiration (all p < 0.03) were lower after smoking, which were largely reversed within 2-week smoking cessation. Metabolome and lipidome analyses revealed alterations in mitochondrial metabolism, a shift from fatty acid to glucose metabolism, which did not revert to control upon smoking cessation. Capillary density was not different after smoking but increased after smoking cessation (p = 0.02). Macrophage infiltration and fibrosis (p < 0.04) were higher after smoking but did not revert to control upon smoking cessation. While cigarette-impaired smoking-induced cardiac mitochondrial function was reversed by smoking cessation, the remaining fibrosis and macrophage infiltration may contribute to the increased risk of cardiovascular events after smoking cessation.

Targeting NLRP3 signaling reduces myocarditis-induced arrhythmogenesis and cardiac remodeling

BackgroundMyocarditis substantially increases the risk of ventricular arrhythmia. Approximately 30% of all ventricular arrhythmia cases in patients with myocarditis originate from the right ventricular outflow tract (RVOT). However, the role of NLRP3 signaling in RVOT arrhythmogenesis remains unclear.MethodsRats with myosin peptide–induced myocarditis (experimental group) were treated with an NLRP3 inhibitor (MCC950; 10 mg/kg, daily for 14 days) or left untreated. Then, they were subjected to electrocardiography and echocardiography. Ventricular tissue samples were collected from each rat’s RVOT, right ventricular apex (RVA), and left ventricle (LV) and examined through conventional microelectrode and histopathologic analyses. In addition, whole-cell patch-clamp recording, confocal fluorescence microscopy, and Western blotting were performed to evaluate ionic currents, intracellular Ca2+ transients, and Ca2+-modulated protein expression in individual myocytes isolated from the RVOTs.ResultsThe LV ejection fraction was lower and premature ventricular contraction frequency was higher in the experimental group than in the control group (rats not exposed to myosin peptide). Myocarditis increased the infiltration of inflammatory cells into cardiac tissue and upregulated the expression of NLRP3; these observations were more prominent in the RVOT and RVA than in the LV. Furthermore, experimental rats treated with MCC950 (treatment group) improved their LV ejection fraction and reduced the frequency of premature ventricular contraction. Histopathological analysis revealed higher incidence of abnormal automaticity and pacing-induced ventricular tachycardia in the RVOTs of the experimental group than in those of the control and treatment groups. However, the incidences of these conditions in the RVA and LV were similar across the groups. The RVOT myocytes of the experimental group exhibited lower Ca2+ levels in the sarcoplasmic reticulum, smaller intracellular Ca2+ transients, lower L-type Ca2+ currents, larger late Na+ currents, larger Na+–Ca2+ exchanger currents, higher reactive oxygen species levels, and higher Ca2+/calmodulin-dependent protein kinase II levels than did those of the control and treatment groups.ConclusionMyocarditis may increase the rate of RVOT arrhythmogenesis, possibly through electrical and structural remodeling. These changes may be mitigated by inhibiting NLRP3 signaling.

Leukocyte Ig-like receptor B4 (Lilrb4a) alleviates cardiac dysfunction and isoproterenol-induced arrhythmogenic remodeling associated with cardiac fibrosis and inflammation

BackgroundHeart failure is usually accompanied by activation of the sympathetic nerve, and excessive activation of the sympathetic nerve promotes cardiac remodeling and cardiac dysfunction. In the isoproterenol (ISO)–induced animal model, it is often accompanied by myocardial hypertrophy, fibrosis, and inflammation. Leukocyte immunoglobulin-like receptor B4a (Lilrb4a), an immunosuppressive regulatory receptor, plays a vital role in cardiovascular disease. However, the effect of Lilrb4a on ventricular arrhythmia in an ISO-induced mouse model remains unclear. ObjectiveThe purpose of this study was to explore the role and molecular mechanism of Lilrb4a in ISO-induced arrhythmogenic remodeling. MethodsLilrb4a knockout mice and Lilrb4a overexpression mice were infused with ISO (15 mg/kg per 24 hours, 4 weeks). Echocardiography and histology evaluations of myocardial hypertrophy and cardiac structural remodeling were conducted. Surface electrocardiography and electrophysiologic examination were used to evaluate cardiac electrical remodeling and susceptibility to ventricular arrhythmias. Quantitative reverse transcriptase–polymerase chain reaction analysis and Western blotting were used to detect the expression levels of ion channel proteins and signal pathway proteins. ResultsThe results discovered that ISO induced cardiac hypertrophy, fibrosis, and inflammation and led to electrical remodeling and the occurrence of ventricular arrhythmias. Lilrb4a alleviated cardiac structural and electrical remodeling and protected against the occurrence of ventricular arrhythmias in ISO-induced mice by gain-of-function or loss-of-function approaches. The mechanism is that Lilrb4a inhibited NF-κB signaling and MAPK signaling activation mediated by transforming growth factor kinase 1. ConclusionLilrb4a alleviates cardiac dysfunction and ISO-induced arrhythmogenic remodeling associated with cardiac fibrosis and inflammation through the regulation of NF-κB signaling and MAPK signaling activation.

Exenatide reduces atrial fibrillation susceptibility by inhibiting hKv1.5 and hNav1.5 channels

Exenatide, a promising cardioprotective agent, protects against cardiac structural remodeling and diastolic dysfunction. Combined blockade of sodium and potassium channels is valuable for managing atrial fibrillation (AF). Here, we explored whether exenatide displayed anti-AF effects by inhibiting human Kv1.5 and Nav1.5 channels. We used the whole-cell patch-clamp technique to investigate the effects of exenatide on hKv1.5 and hNav1.5 channels expressed in human embryonic kidney 293 cells and studied the effects of exenatide on action potential (AP) and other cardiac ionic currents in rat atrial myocytes. Additionally, an electrical mapping system was used to explore the effects of exenatide on electrical properties and AF activity in isolated rat hearts. Finally, a rat AF model, established using acetylcholine and calcium chloride, was employed to evaluate the anti-AF potential of exenatide in rats. Exenatide reversibly suppressed IKv1.5 with IC50 of 3.08 μM, preferentially blocked hKv1.5 channel in its closed state, and positively shifted the voltage-dependent activation curve. Exenatide also reversibly inhibited INav1.5 with IC50 of 3.30 μM, negatively shifted the voltage-dependent inactivation curve, and slowed its recovery from inactivation with significant use-dependency at 5 and 10 Hz. Furthermore, exenatide prolonged AP duration and suppressed the sustained K+ current (Iss) and transient outward K+ current (Ito), but without inhibition of L-type Ca2+ current (ICa,L) in rat atrial myocytes. Exenatide prevented AF incidence and duration in rat hearts and rats. These findings demonstrate that exenatide inhibits IKv1.5 and INav1.5in vitro and reduces AF susceptibility in isolated rat hearts and rats.

Cellular and molecular mechanisms involved in the protective effects of Aerva Lanata Linn.on airways remodeling in experimental model of bronchial asthma in rats

Bronchial asthma is a chronic inflammatory respiratory disease characterized by bronchoconstriction and hyperresponsiveness of the bronchial airways. The treatment for bronchial asthma is mainly aimed at relieving symptoms by bronchodilators and controlling asthmatic attacks with anti-inflammatory agents. These therapeutic strategies are associated with several adverse drug effects and high cost that may negatively affect the compliance to therapy. Chronic asthma also results in structural remodeling of the airways which enhances the incidence of refractory asthma and increases morbidity/mortality. It is therefore important to explore adjuncts from alternative forms of therapy to compliment/supplement the conventional treatment. The study assessed the effects of Aerva Lanata Linn., a medicinal plant used in the traditional systems of medicine, on airway remodeling in an experimental model of asthma in rats. Wistar rats were immunized on day 0 with ovalbumin and Al(OH)3 and challenged with aerosolized ovalbumin from day 15 to 22. The rats were treated orally with various doses of standardized aqueous extract of whole plant of Aerva Lanata Linn. or prednisolone (10 mg/kg) for 22 days. After 24 hrs of last challenge, blood, bronchoalveolar lavage (BAL) fluid and lung tissue were collected and assayed for markers of structural remodeling viz, (a) cytokine levels (TGF-β and IL-13); (b) hydroxyproline content, and (c) histopathology. The results showed that Aerva Lanata Linn. markedly reduced the levels of TGF-β, IL-13 in both blood and BAL fluid and hydroxyproline content in lung homogenates. Histopathological examination of lung tissue confirmed the modulatory effects of Aerva Lanata Linn. on airway remodeling as evidenced by reductions in goblet cell hyperplasia, inflammatory cells infiltration and sub epithelial fibrosis, as compared to that in the experimental (disease control) group. The results showed that Aerva Lanata Linn. Attenuated the histopathological changes and biochemical markers of airway remodeling by altering the levels of IL-13 and TGFβ, and the study suggested that it could be beneficial in cases of chronic bronchial asthma.

Cytoskeletal rearrangement precedes nucleolar remodeling during adipogenesis

Differentiation of adipose progenitor cells into mature adipocytes entails a dramatic reorganization of the cellular architecture to accommodate lipid storage into cytoplasmic lipid droplets. Lipid droplets occupy most of the adipocyte volume, compressing the nucleus beneath the plasma membrane. How this cellular remodeling affects sub-nuclear structure, including size and number of nucleoli, remains unclear. We describe the morphological remodeling of the nucleus and the nucleolus during in vitro adipogenic differentiation of primary human adipose stem cells. We find that cell cycle arrest elicits a remodeling of nucleolar structure which correlates with a decrease in protein synthesis. Strikingly, triggering cytoskeletal rearrangements mimics the nucleolar remodeling observed during adipogenesis. Our results point to nucleolar remodeling as an active, mechano-regulated mechanism during adipogenic differentiation and demonstrate a key role of the actin cytoskeleton in defining nuclear and nucleolar architecture in differentiating human adipose stem cells.

Effect of Low-Level Tragus Stimulation on Cardiac Metabolism in Heart Failure with Preserved Ejection Fraction: A Transcriptomics-Based Analysis.

Abnormal cardiac metabolism precedes and contributes to structural changes in heart failure. Low-level tragus stimulation (LLTS) can attenuate structural remodeling in heart failure with preserved ejection fraction (HFpEF). The role of LLTS on cardiac metabolism is not known. Dahl salt-sensitive rats of 7 weeks of age were randomized into three groups: low salt (0.3% NaCl) diet (control group; n = 6), high salt diet (8% NaCl) with either LLTS (active group; n = 8), or sham stimulation (sham group; n = 5). Both active and sham groups received the high salt diet for 10 weeks with active LLTS or sham stimulation (20 Hz, 2 mA, 0.2 ms) for 30 min daily for the last 4 weeks. At the endpoint, left ventricular tissue was used for RNA sequencing and transcriptomic analysis. The Ingenuity Pathway Analysis tool (IPA) was used to identify canonical metabolic pathways and upstream regulators. Principal component analysis demonstrated overlapping expression of important metabolic genes between the LLTS, and control groups compared to the sham group. Canonical metabolic pathway analysis showed downregulation of the oxidative phosphorylation (Z-score: -4.707, control vs. sham) in HFpEF and LLTS improved the oxidative phosphorylation (Z-score = -2.309, active vs. sham). HFpEF was associated with the abnormalities of metabolic upstream regulators, including PPARGC1α, insulin receptor signaling, PPARα, PPARδ, PPARGC1β, the fatty acid transporter SLC27A2, and lysine-specific demethylase 5A (KDM5A). LLTS attenuated abnormal insulin receptor and KDM5A signaling. HFpEF is associated with abnormal cardiac metabolism. LLTS, by modulating the functioning of crucial upstream regulators, improves cardiac metabolism and mitochondrial oxidative phosphorylation.

The role of language-related functional brain regions and white matter tracts in network plasticity of post-stroke aphasia.

The neural mechanisms underlying language recovery after a stroke remain controversial. This review aimed to summarize the plasticity and reorganization mechanisms of the language network through neuroimaging studies. Initially, we discussed the involvement of right language homologues, perilesional tissue, and domain-general networks. Subsequently, we summarized the white matter functional mapping and remodeling mechanisms associated with language subskills. Finally, we explored how non-invasive brain stimulation (NIBS) promoted language recovery by inducing neural network plasticity. It was observed that the recruitment of right hemisphere language area homologues played a pivotal role in the early stages of frontal post-stroke aphasia (PSA), particularly in patients with larger lesions. Perilesional plasticity correlated with improved speech performance and prognosis. The domain-general networks could respond to increased "effort" in a task-dependent manner from the top-down when the downstream language network was impaired. Fluency, repetition, comprehension, naming, and reading skills exhibited overlapping and unique dual-pathway functional mapping models. In the acute phase, the structural remodeling of white matter tracts became challenging, with recovery predominantly dependent on cortical activation. Similar to the pattern of cortical activation, during the subacute and chronic phases, improvements in language functions depended, respectively, on the remodeling of right white matter tracts and the restoration of left-lateralized language structural network patterns. Moreover, the midline superior frontal gyrus/dorsal anterior cingulate cortex emerged as a promising target for NIBS. These findings offered theoretical insights for the early personalized treatment of aphasia after stroke.

Inhibitory effects of propylene glycol alginate sodium sulfate derivatives on atrial fibrosis in atrial fibrillation

Atrial fibrosis is the hallmark of structural remodeling in the pathogenesis of atrial fibrillation (AF). Meanwhile, AF causes a hypercoagulable state, and then provokes pro-fibrotic response. To discover a potential effective AF treatment targeting both coagulation and atrial fibrosis, this study investigated the structure–activity relationship of propylene glycol alginate sodium sulfate (PSS) derivatives with heparin-like activity on TGF-β1-induced atrial fibrosis. We found that PSS derivatives had significantly inhibitory effects on proliferation, migration, phenotypic transformation, and secretion/deposition of extracellular matrix of atrial fibroblasts. Among them, PGGS showed the optimal anti-atrial fibrotic activity by suppressing TGF-β1-induced activation of Smad2/3 signaling pathway. Furthermore, the study in vivo indicated that PGGS treatment displayed a reduced atrial fibrosis and AF inducibility, and attenuated the hypercoagulable state by decreasing D-dimer level and thrombin (FIIa) activity in MHC-TGF-β1 cys33ser transgenic mice, which had increased fibrosis in atrium but not in the ventricles. Our results demonstrated that PSS derivatives, especially PGGS, were potential anti-atrial fibrosis and anti-coagulant agents for AF prevention. Our study is beneficial in extending the current understandings of the function of PSS on atrial fibrosis and vulnerability to AF.

Chronic intermittent hypoxia elicits distinct transcriptomic responses among neurons and oligodendrocytes within the brainstem of mice.

Chronic intermittent hypoxia (CIH) is a prevalent condition characterized by recurrent episodes of oxygen deprivation, linked to respiratory and neurological disorders. Prolonged CIH is known to have adverse effects, including endothelial dysfunction, chronic inflammation, oxidative stress, and impaired neuronal function. These factors can contribute to serious comorbidities, including metabolic disorders and cardiovascular diseases. To investigate the molecular impact of CIH, we examined male C57BL/6J mice exposed to CIH for 21 days, comparing with normoxic controls. We used single-nucleus RNA sequencing to comprehensively examine the transcriptomic impact of CIH on key cell classes within the brainstem, specifically excitatory neurons, inhibitory neurons, and oligodendrocytes. These cell classes regulate essential physiological functions, including autonomic tone, cardiovascular control, and respiration. Through analysis of 10,995 nuclei isolated from pontine-medullary tissue, we identified seven major cell classes, further subdivided into 24 clusters. Our findings among these cell classes, revealed significant differential gene expression, underscoring their distinct responses to CIH. Notably, neurons exhibited transcriptional dysregulation of genes associated with synaptic transmission, and structural remodeling. In addition, we found dysregulated genes encoding ion channels and inflammatory response. Concurrently, oligodendrocytes exhibited dysregulated genes associated with oxidative phosphorylation and oxidative stress. Utilizing CellChat network analysis, we uncovered CIH-dependent altered patterns of diffusible intercellular signaling. These insights offer a comprehensive transcriptomic cellular atlas of the pons-medulla and provide a fundamental resource for the analysis of molecular adaptations triggered by CIH.NEW & NOTEWORTHY This study on chronic intermittent hypoxia (CIH) from pons-medulla provides initial insights into the molecular effects on excitatory neurons, inhibitory neurons, and oligodendrocytes, highlighting our unbiased approach, in comparison with earlier studies focusing on single target genes. Our findings reveal that CIH affects cell classes distinctly, and the dysregulated genes in distinct cell classes are associated with synaptic transmission, ion channels, inflammation, oxidative stress, and intercellular signaling, advancing our understanding of CIH-induced molecular responses.