Contraction Of Muscle Cells Research Articles

Modelling pacemaker oscillations in lymphatic muscle cells: lengthened action potentials by two distinct system effects.

Lymphatic system failures contribute to cardiovascular and various other diseases. A critical function of the lymphatic vascular system is the active pumping of fluid from the interstitium back into the blood circulation by periodic contractions of lymphatic muscle cells (LMCs) in the vessel walls. As in cardiac pacemaking, these periodic contractions can be interpreted as occurring due to linked pacemaker oscillations in the LMC membrane potential (M-clock) and calcium concentration (C-clock). We previously reported a minimal model of synchronized dual-clock-driven oscillations. While this qualitatively replicated the period of oscillations under different conditions, it did not replicate the action potential shape as it varied under those conditions, particularly as regards the extent or lack of a systolic plateau. Here, we modify the model to replicate the plateau behaviour. Using phase-plane analysis we show two qualitatively different dynamical mechanisms that could account for plateau formation, one largely M-clock-driven, the other largely C-clock-driven. The second case occurs with the introduction of a ryanodine receptor; in both cases, we find improved predictions for calcium levels. With enhanced fidelity to the experimental data, the improved model has the potential to help determine opportunities for pharmacological treatment of lymphatic system pumping defects.

Asthma, COPD, the "asthma-COPD" syndrome and severe asthma - relatives or "incidental strangers"?

Objective: Airways obstructive diseases (asthma, COPD, asthma-COPD overlap (ACO) and severe asthma) are different entities characterized by airflow obstruction. They may share common pathogenetic mechanisms allowing new therapeutic options for patients. Methods: A review of the current literature is performed to investigate the common pathogenetic mechanisms among these medical conditions. Results: Different specific cytokones are involved in both asthma and COPD pathogenesis, while ACO shares some of these cytokines placing the condition between the two entities. The cytokines regulate accumulations and contraction of airways smooth muscle cells which leads to different expression of airflow obstruction. A special cytokine, TSLP, is highlighted as playing a key role in the pathogenesis of asthma, COPD, ACO, and severe asthma which opens the opportunity for new treatment options for patients suffering from these conditions. Conclusion: COPD, asthma, ACO and severe asthma share some common elements in their pathogenesis which opens the gate for new therapeutic options for the patients

The ARK2N (C18ORF25) Genetic Variant Is Associated with Muscle Fiber Size and Strength Athlete Status.

Data on the genetic factors contributing to inter-individual variability in muscle fiber size are limited. Recent research has demonstrated that mice lacking the Arkadia (RNF111) N-terminal-like PKA signaling regulator 2N (Ark2n; also known as C18orf25) gene exhibit reduced muscle fiber size, contraction force, and exercise capacity, along with defects in calcium handling within fast-twitch muscle fibers. However, the role of the ARK2N gene in human muscle physiology, and particularly in athletic populations, remains poorly understood. The aim of this study was threefold: (a) to compare ARK2N gene expression between power and endurance athletes; (b) to analyze the relationship between ARK2N gene expression and muscle fiber composition; and (c) to investigate the association between the functional variant of the ARK2N gene, muscle fiber size, and sport-related phenotypes. We found that ARK2N gene expression was significantly higher in power athletes compared to endurance athletes (p = 0.042) and was positively associated with the proportion of oxidative fast-twitch (type IIA) muscle fibers in untrained subjects (p = 0.017, adjusted for age and sex). Additionally, we observed that the ARK2N rs6507691 T allele, which predicts high ARK2N gene expression (p = 3.8 × 10-12), was associated with a greater cross-sectional area of fast-twitch muscle fibers in strength athletes (p = 0.015) and was over-represented in world-class strength athletes (38.6%; OR = 2.2, p = 0.023) and wrestlers (33.8%; OR = 1.8, p = 0.044) compared to controls (22.0%). In conclusion, ARK2N appears to be a gene specific to oxidative fast-twitch myofibers, with its functional variant being associated with muscle fiber size and strength-athlete status.

N-cadherin antagonism is bronchoprotective in severe asthma models.

Severe asthma induces substantial mortality and chronic disability due to intractable airway obstruction, which may become resistant to currently available therapies including corticosteroids and β-adrenergic agonist bronchodilators. A key effector of these changes is exaggerated airway smooth muscle (ASM) cell contraction to spasmogens. No drugs in clinical use effectively prevent ASM hyperresponsiveness in asthma across all severities. We find that N-cadherin, a membrane cell-cell adhesion protein up-regulated in ASM from patients with severe asthma, is required for the development of airway obstruction induced by allergic airway inflammation in mice. Inhibition of N-cadherin by ADH-1 reduced airway hyperresponsiveness independent of allergic inflammation, prevented bronchoconstriction, and actively promoted bronchodilation of airways ex vivo. ADH-1 inhibited ASM contraction by disrupting N-cadherin-δ-catenin interactions, which decreased intracellular actin remodeling. These data provide evidence for an intercellular communication pathway mediating ASM contraction and identify N-cadherin as a potential therapeutic target for inhibiting bronchoconstriction in asthma.

Modelling Skeletal Muscle Motor Unit Recruitment Contributions to Contractile Function: Part 3 - Substrate Oxidation of Phosphagen, Lipid, and Carbohydrate Metabolism

This study aimed to apply and expand a prior model of motor unit recruitment of the vastus lateralis muscle (VL) to explore theoretical motor unit-specific substrate oxidation. The model utilized repeated contractions of varied frequency and fraction of motor unit recruitment, and four different genetic expressions of motor unit proportions. The study applied prior modelled data of the vastus lateralis (VL) motor unit contractile power and turnover of adenosine triphosphate (ATPto) based on non-linear functions of estimated percentage contributions of different energy systems across various muscle fibre types and contraction frequencies. Using LabVIEW™ programming, the model then used the prior data of ATPto and known ATPto coefficients for substrate oxidation for the energy systems of phosphagen, glycolytic, and mitochondrial respiration from fatty acid and carbohydrate to calculate total and fibre type (motor unit) specific creatine phosphate catabolism, glycogenolysis, glycolytic glucose oxidation, fatty acid oxidation in mitochondrial respiration, glucose oxidation in mitochondrial respiration, and lactate production. Results revealed that for the phosphagen system, substrate turnover was far larger than research-based expressions of decreasing concentrations of creatine phosphate and ATP. This is to be expected for modelled research involving temporal summation of metabolism. Creatine phosphate is continually broken down and partially replenished during low intensity exercise, with such partial replenishment sustained during more intense exercise thanks to the creatine kinase shuttle. For carbohydrate oxidation, mitochondrial respiration accounted for greatest substrate oxidation in type I, and I-IIa motor units, where glycolysis accounted for most substrate oxidation in type IIa, IIab and IIb motor units. Fatty acid oxidation was larger for lower motor unit recruitment conditions, and highest for type I-IIa and IIa motor units. This result is logical based on the larger net muscle fibre recruitment for contraction conditions necessitating progression to fast twitch motor units causing higher substrate oxidation. Such findings reinforce the need for more research on fibre type specific substrate oxidation during different exercise intensities and durations.

Acute oral digoxin in healthy adults hastens fatigue and increases plasma K+ during intense exercise, despite preserved skeletal muscle Na+,K+-ATPase.

We investigated acute effects of the Na+,K+-ATPase (NKA) inhibitor, digoxin, on muscle NKA content and isoforms, arterial plasma [K+] ([K+]a) and fatigue with intense exercise. In a randomised, crossover, double-blind design, 10 healthy adults ingested 0.50mg digoxin (DIG) or placebo (CON) 60min before cycling for 1min at 60% then at 95% until fatigue. Pre- and post-exercise muscle biopsies were analysed for [3H]-ouabain binding site content without (OB-Fab) and after incubation in digoxin antibody (OB+Fab) and NKA α1-2 and β1-2 isoform proteins. In DIG, pre-exercise serum [digoxin] reached 3.36 (0.80) nM [mean (SD)] and muscle NKA-digoxin occupancy was 8.2%. Muscle OB-Fab did not differ between trials, whereas OB+Fab was higher in DIG than CON (8.1%, treatment main effect, P=0.001), whilst muscle NKA α1-2 and β1-2 abundances were unchanged by digoxin. Fatigue occurred earlier in DIG than CON [-7.7%, 2.90 (0.77) vs. 3.14 (0.86) min, respectively; P=0.037]. [K+]a increased during exercise until 1min post-exercise (P=0.001), and fell below baseline at 3-10 (P=0.001) and 20min post-exercise (P=0.022, time main effect). In DIG, [K+]a (P=0.035, treatment effect) and [K+]a rise pre-fatigue were greater [1.64 (0.73) vs. 1.55 (0.73), P=0.016], with lesser post-exercise [K+]a decline than CON [-2.55 (0.71) vs. -2.74 (0.62) mM, respectively, P=0.003]. Preserved muscle OB-Fab with digoxin, yet increased OB+Fab with unchanged NKA isoforms, suggests a rapid regulatory assembly of existing NKA α and β subunits exists to preserve muscle NKA capacity. Nonetheless, functional protection against digoxin was incomplete, with earlier fatigue and perturbed [K+]a with exercise. KEY POINTS: Intense exercise causes marked potassium (K+) shifts out of contracting muscle cells, which may contribute to muscle fatigue. Muscle and systemic K+ perturbations with exercise are largely regulated by increased activity of Na+,K+-ATPase in muscle, which can be specifically inhibited by the cardiac glycoside, digoxin. We found that acute oral digoxin in healthy adults reduced time to fatigue during intense exercise, elevated the rise in arterial plasma K+ concentration during exercise and slowed K+ concentration decline post-exercise. Muscle functional Na+,K+-ATPase content was not reduced by acute digoxin, despite an 8.2% digoxin occupancy, and was unchanged at fatigue. Muscle Na+,K+-ATPase isoform protein abundances were unchanged by digoxin or fatigue. These suggest possible rapid assembly of existing subunits into functional pumps. Thus, acute digoxin impaired performance and exacerbated plasma K+ disturbances with intense, fatiguing exercise in healthy participants. These occurred despite the preservation of functional Na+,K+-ATPase in muscle.

Regulation of Vascular Smooth Muscle Cell Contraction during Early Postnatal Ontogenesis

Regulation of Vascular Smooth Muscle Cell Contraction during Early Postnatal Ontogenesis

The evolution of muscle spindles.

Muscle spindles are stretch-sensitive mechanoreceptors found in the skeletal muscles of most four-limbed vertebrates. They are unique amongst sensory receptors in the ability to regulate their sensitivity by contraction of the intrafusal muscle fibres on which the sensory endings lie. Muscle spindles have revealed a remarkable diversity of functions, including reflex action in posture and locomotion, contributing to bodily self awareness, and influencing wound healing. What were the circumstances which gave rise to the evolution of such complex end-organs? We argue that spindles first appeared in early amniotes and only later in frogs and toads. This was considered an example of convergent evolution. Spindles in amphibians and reptiles are characterised by their simple structure, pointing to key features essential for spindle function. Spindle sensitivity in amphibians and reptiles is controlled by intrafusal fibre contractions evoked by branches of motor axons supplying extrafusal muscle. Modern phylogenetic evidence has revised our views on the origin of birds, placing them closer to the dinosaurs than had previously been thought. Birds are the only group, other than mammals, which has a dedicated fusimotor innervation of spindles, another example of convergent evolution, given the widely different origins of the two groups. One factor that may have played a role here was that both groups are endotherms, allowing motor control to develop further in an optimal internal environment. This, as well as other changes within the spindle, has led to the astonishing sophistication of motor control observed especially in many modern mammals.

Mitochondrial-targeted plastoquinone therapy ameliorates early onset muscle weakness that precedes ovarian cancer cachexia in mice.

Cancer cachexia, and the related loss of muscle and strength, worsens quality of life and lowers overall survival. Recently, a novel 'pre-atrophy' muscle weakness was identified during early-stage cancer. While mitochondrial stress responses are associated with early-stage pre-atrophy weakness, a causal relationship has not been established. Using a robust mouse model of metastatic epithelial ovarian cancer (EOC)-induced cachexia, we found the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents pre-atrophy weakness in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. EOC reduced flexor digitorum brevis (FDB) force production and myoplasmic free calcium ([Ca 2+ ] i ) during contraction in single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout EOC. These discoveries identify that muscle weakness can occur independent of atrophy throughout EOC in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force during the early pre-atrophy period and in late-stage EOC once cachexia has become severe.

Regulation of vascular smooth muscle cell contraction during early postnatal ontogenesis

Growth of the body in early postnatal ontogenesis is associated with changes in the functioning of many organ systems, including the cardiovascular system. The circulatory system of newborns is characterized by numerous structural and functional features, which at the systemic level is manifested in a significantly lower level of blood pressure. This review describes the differences in the mechanisms of regulation of vascular smooth muscle cell contraction in early postnatal ontogenesis and in adulthood, including age-related changes in the functioning of ion channels, which activity affects membrane potential level and intracellular concentration of calcium ions, as well as changes in calcium sensitivity of the contractile apparatus. The final section of the review discusses the connection between the mechanisms regulating contraction and differentiation of vascular smooth muscle cells during maturation.

Prenatal exposure to dibutyl phthalate contributes to erectile dysfunction in offspring male rats by activating the RhoA/ROCK signalling pathway

Prenatal exposure to dibutyl phthalate (DBP) has been reported to cause erectile dysfunction (ED) in adult offspring rats. However, its underlying mechanisms are not fully understood. Previously, we found that DBP activates the RhoA/ROCK pathway in the male reproductive system. This study investigated how prenatal exposure to DBP activates the RhoA/ROCK signalling pathway, leading to ED in male rat offspring. Pregnant rats were stratified into DBP-exposed and NC groups, with the exposed group receiving 750 milligrams per kilogram per day (mg/kg/day) of DBP through gavage from days 14–18 of gestation. DBP exposure activated the RhoA/ROCK pathway in the penile corpus cavernosum (CC) of descendants, causing smooth muscle cell contraction, fibrosis, and apoptosis, all of which contribute to ED. In vitro experiments confirmed that DBP induces apoptosis and RhoA/ROCK pathway activation in CC smooth muscle cells. Treatment of DBP-exposed offspring with the ROCK inhibitor Y-27632 for 8 weeks significantly improved smooth muscle cell condition, erectile function, and reduced fibrosis. Thus, prenatal DBP exposure induces ED in offspring through RhoA/ROCK pathway activation, and the ROCK inhibitor Y-27632 shows potential as an effective treatment for DBP-induced ED.

Genetic and functional analysis of Raynaud’s syndrome implicates loci in vasculature and immunity

Raynaud's syndrome is a dysautonomia where exposure to cold causes vasoconstriction and hypoxia, particularly in the extremities. We performed meta-analysis in four cohorts and discovered eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, and RAB6C) where ADRA2A, ACVR2A, NOS3, TMEM51, and IRX1 co-localized with expression quantitative trait loci (eQTLs), particularly in distal arteries. CRISPR gene editing further showed that ADRA2A and NOS3 loci modified gene expression and in situ RNAscope clarified the specificity of ADRA2A in small vessels and IRX1 around small capillaries in the skin. A functional contraction assay in the cold showed lower contraction in ADRA2A-deficient and higher contraction in ADRA2A-overexpressing smooth muscle cells. Overall, our study highlights the power of genome-wide association testing with functional follow-up as a method to understand complex diseases. The results indicate temperature-dependent adrenergic signaling through ADRA2A, effects at the microvasculature by IRX1, endothelial signaling by NOS3, and immune mechanisms by the HLA locus in Raynaud's syndrome.

Pharmacological mechanisms by which baicalin ameliorates cardiovascular disease.

Baicalin is a flavonoid glycoside obtained from the dried root of Scutellaria baicalensis Georgi, which belongs to the Labiatae family. Accumulating evidence indicates that baicalin has favorable therapeutic effects on cardiovascular diseases. Previous studies have revealed the therapeutic effects of baicalin on atherosclerosis, myocardial ischemia/reperfusion injury, hypertension, and heart failure through anti-inflammatory, antioxidant, and lipid metabolism mechanisms. In recent years, some new ideas related to baicalin in ferroptosis, coagulation and fibrinolytic systems have been proposed, and new progress has been made in understanding the mechanism by which baicalin protects cardiomyocytes. However, many relevant underlying mechanisms remain unexplained, and much experimental data is lacking. Therefore, further research is needed to determine these mechanisms. In this review, we summarize the mechanisms of baicalin, which include its anti-inflammatory and antioxidant effects; inhibition of endothelial cell apoptosis; modulation of innate immunity; suppression of vascular smooth muscle cells proliferation, migration, and contraction; regulation of coagulation and fibrinolytic systems; inhibition of myocardial hypertrophy; prevention of myocardial fibrosis; and anti-apoptotic effects on cardiomyocytes.

Effect of different temperature–time combinations on the quality and protein digestive properties of stewed beef tendons

This study investigated the effects of sous vide cooking and traditional high-temperature cooking on the texture, microstructure, protein structure and digestive properties of home made beef tendon using transmission electron microscopy, in vitro digestion and peptidomics. The adverse effects of heating on the muscle fiber structure and protein conformation of beef tendon gradually expanded with increasing temperature. In general, the degree of muscle fiber contraction, protein denaturation, and protein aggregation increases with temperature and time, with a concomitant decrease in protease action. The extent of protein digestion, and the yield of small fragments such as amino acids also decreased with increasing heating temperature and time. However, the solubilization of collagen makes the beef collagen more digestible after heating at 80°C, which indirectly leads to higher digestibility at 80°C. The combined peptide release and bioactive peptide results showed that the beef tendon heated at 60°C for 8 h produced the most peptides after digestion, and also produced four specific bioactive peptides, which were advantageous in terms of the number of digested products and bioactivity. The higher proportion of antioxidant amino acids in the product also gave the tendon heated at 60°C for 8 h a greater potential antioxidant capacity. As a result, beef tendon heated at 60°C for 8 h is more favorable for human digestion. This work may provide guidance for home cooking and dietary health.

Genome-Wide DNA methylation profile analysis identifies differentially methylated loci associated with personal PM2.5 exposure in adults with asthma

Particulate matter with aerodynamic diameters ≤2.5 µm (PM2.5) is a major environmental risk factor for acute asthma exacerbation, and the underlying mechanism is not completely understood. Studies have indicated that DNA methylation is a potential mechanism linking PM2.5 to its health effects. We conducted a panel study involving 24 adult patients with asthma in Beijing,China between 2017 and 2019. PM2.5 and other atmospheric pollutant exposure data were repeatedly measured. Blood samples were collected for genome-wide DNA methylation analysis. A linear mixed-effects (LME) model was conducted to identify differentially methylated probes (DMPs) associated with PM2.5 exposure. After filtering out probes that did not meet the criteria through quality control, 811,001 CpG sites were included in the LME model, and 36 DMPs were strongly associated with personal PM2.5 exposure at false discovery rate (FDR) < 0.05, of which 22 and 14 DMPs negatively and positively correlated with personal PM2.5 exposure, respectively. Functional analysis revealed that DMPs affected smooth muscle cell contraction and development, extracellular matrix synthesis and secretion, T cell activation and differentiation, and inflammatory factor production. This study provides evidence linking personal PM2.5 exposure to genome-wide DNA methylation in adult patients with asthma. Identifying enrichment pathways can provide biological insights into the acute health effects of PM2.5.

Changes of mRNA, miRNA and lncRNA expression contributing to skeletal muscle differences between fetus and adult Mongolian horses

The growth and development of myofibers, as the fundamental units comprising muscle tissue, and their composition type are indeed among the most crucial factors influencing skeletal muscle types. Muscle fiber adaptation is closely associated with alterations in physiological conditions. Muscle fiber types undergo dynamic changes in fetus and adult horses. Our aim is to investigate the mechanisms influencing the differences in muscle fiber types between fetal and adult stages of Mongolian horses. The study investigated the distribution of muscle fiber types within longissimus dorsi muscle of fetus and adult Mongolian horses. A total of 652 differentially expressed genes (DEGs), 476 Differentially expressed lncRNAs (DELs), and 174 Differentially expressed miRNAs (DEMIRs) were identified using deep RNA-seq analysis. The results of functional analysis reveal the transformations in muscle fiber type from the fetal to adult stage in Mongolian horses. The up-regulated DEGs were implicated in the development and differentiation of muscle fibers, while down-regulated DEGs were associated with muscle fiber contraction, transformation, and metabolism. Additionally, connections between non-coding RNA and mRNA landscapes were identified based on their functional alterations, some non-coding RNA target genes may be associated with immunity. These data have broadened our understanding of the specific roles and interrelationships among regulatory molecules involved in Mongolian horse development, this provides new perspectives for selecting and breeding superior individuals and for disease prevention.

Immunomodulatory imide drugs inhibit human detrusor smooth muscle contraction and growth of human detrusor smooth muscle cells, and exhibit vaso-regulatory functions

BackgroundThe immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide and pomalidomide may exhibit therapeutic efficacy in the prostate. In lower urinary tract symptoms (LUTS), voiding and storage disorders may arise from benign prostate hyperplasia, or overactive bladder. While current therapeutic options target smooth muscle contraction or cell proliferation, side effects are mostly cardiovascular. Therefore, we investigated effects of IMiDs on human detrusor and porcine artery smooth muscle contraction, and growth-related functions in detrusor smooth muscle cells (HBdSMC). MethodsCell viability was assessed by CCK8, and apoptosis and cell death by flow cytometry in cultured HBdSMC. Contractions of human detrusor tissues and porcine interlobar and coronary arteries were induced by contractile agonists, or electric field stimulation (EFS) in the presence or absence of an IMID using an organ bath. Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, ResultsDepending on tissue type, IMiDs inhibited cholinergic contractions with varying degree, up to 50 %, while non-cholinergic contractions were inhibited up to 80 % and 60 % for U46619 and endothelin-1, respectively, and EFS-induced contractions up to 75 %. IMiDs reduced viable HBdSM cells in a time-dependent manner. Correspondingly, proliferation was reduced, without showing pro-apoptotic effects. In parallel, IMiDs induced cytoskeletal disorganization. ConclusionsIMiDs exhibit regulatory functions in various smooth muscle-rich tissues, and of cell proliferation in the lower urinary tract. This points to a novel drug class effect for IMiDs, in which the molecular mechanisms of action of IMiDs merit further consideration for the application in LUTS.

Transcriptional landscape of a hypoxia response identifies cell-specific pathways for adaptation.

How the HIF-1 (Hypoxia-Inducible) transcription factor drives and coordinates distinct responses to low oxygen across diverse cell types is poorly understood. We present a multi-tissue single-cell gene-expression atlas of the hypoxia response of the nematode Caenorhabditis elegans . This atlas highlights how cell-type-specific HIF-1 responses overlap and diverge among and within neuronal, intestinal, and muscle tissues. Using the atlas to guide functional analyses of candidate muscle-specific HIF-1 effectors, we discovered that HIF-1 activation drives downregulation of the tspo-1 ( TSPO, Translocator Protein) gene in vulval muscle cells to modulate a hypoxia-driven change in locomotion caused by contraction of body-wall muscle cells. We further showed that in human cardiomyocytes HIF-1 activation decreases levels of TSPO and thereby alters intracellular cholesterol transport and the mitochondrial network. We suggest that TSPO-1 is an evolutionarily conserved mediator of HIF-1-dependent modulation of muscle and conclude that our gene-expression atlas can help reveal how HIF-1 drives cell-specific adaptations to hypoxia.

Gstp1 negatively regulates blood pressure in hypertensive rat via promoting APLNR ubiquitination degradation mediated by Nedd4.

Hypertension is a leading risk factor for disease burden worldwide. Vascular contraction and remodeling contribute to the development of hypertension. Glutathione S-transferase P1 (Gstp1) plays several critical roles in both normal and neoplastic cells. In this study, we investigated the effect of Gstp1 on hypertension as well as on vascular smooth muscle cell (VSMC) contraction and phenotypic switching. We identified the higher level of Gstp1 in arteries and VSMCs from hypertensive rats compared with normotensive rats for the first time. We then developed Adeno-associated virus 9 (AAV9) mediated Gstp1 down-regulation and overexpression in rats and measured rat blood pressure by using the tail-cuff and the carotid catheter method. We found that the blood pressure of spontaneously hypertensive rats (SHR) rose significantly with Gstp1 down-regulation and reduced apparently after Gstp1 overexpression. Similar results were obtained from the observations of 2-kidney-1-clip renovascular (2K1C) hypertensive rats. Gstp1 did not influence blood pressure of normotensive Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats. Further in vitro study indicated that Gstp1 knockdown in SHR-VSMCs promoted cell proliferation, migration, dedifferentiation and contraction, while Gstp1 overexpression showed opposite effects. Results from bioinformatic analysis showed that the Apelin/APLNR system was involved in the effect of Gstp1 on SHR-VSMCs. The rise in blood pressure of SHR induced by Gstp1 knockdown could be reversed by APLNR antagonist F13A. We further found that Gstp1 enhanced the association between APLNR and Nedd4 E3 ubiquitin ligases to induce APLNR ubiquitination degradation. Thus, in the present study, we discovered a novel anti-hypertensive role of Gstp1 in hypertensive rats and provided the experimental basis for designing an effective anti-hypertensive therapeutic strategy.

Diacylglycerol kinase is a keystone regulator of signaling relevant to the pathophysiology of asthma.

Signal transduction by G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immunoreceptors converge at the activation of phospholipase C (PLC) for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). This is a point for second-messenger bifurcation where DAG via protein kinase C (PKC) and IP3 via calcium activate distinct protein targets and regulate cellular functions. IP3 signaling is regulated by multiple calcium influx and efflux proteins involved in calcium homeostasis. A family of lipid kinases belonging to DAG kinases (DGKs) converts DAG to phosphatidic acid (PA), negatively regulating DAG signaling and pathophysiological functions. PA, through a series of biochemical reactions, is recycled to produce new molecules of PIP2. Therefore, DGKs act as a central switch in terminating DAG signaling and resynthesis of membrane phospholipids precursor. Interestingly, calcium and PKC regulate the activation of α and ζ isoforms of DGK that are predominantly expressed in airway and immune cells. Thus, DGK forms a feedback and feedforward control point and plays a crucial role in fine-tuning phospholipid stoichiometry, signaling, and functions. In this review, we discuss the previously underappreciated complex and intriguing DAG/DGK-driven mechanisms in regulating cellular functions associated with asthma, such as contraction and proliferation of airway smooth muscle (ASM) cells and inflammatory activation of immune cells. We highlight the benefits of manipulating DGK activity in mitigating salient features of asthma pathophysiology and shed light on DGK as a molecule of interest for heterogeneous diseases such as asthma.