Ventricle Of Rats Research Articles

TFEB Overexpression, Not mTOR Inhibition, Ameliorates RagCS75Y Cardiomyopathy.

A de novo missense variant in Rag GTPase protein C (RagCS75Y) was recently identified in a syndromic dilated cardiomyopathy (DCM) patient. However, its pathogenicity and the related therapeutic strategy remain unclear. We generated a zebrafish RragcS56Y (corresponding to human RagCS75Y) knock-in (KI) line via TALEN technology. The KI fish manifested cardiomyopathy-like phenotypes and poor survival. Overexpression of RagCS75Y via adenovirus infection also led to increased cell size and fetal gene reprogramming in neonatal rat ventricle cardiomyocytes (NRVCMs), indicating a conserved mechanism. Further characterization identified aberrant mammalian target of rapamycin complex 1 (mTORC1) and transcription factor EB (TFEB) signaling, as well as metabolic abnormalities including dysregulated autophagy. However, mTOR inhibition failed to ameliorate cardiac phenotypes in the RagCS75Y cardiomyopathy models, concomitant with a failure to promote TFEB nuclear translocation. This observation was at least partially explained by increased and mTOR-independent physical interaction between RagCS75Y and TFEB in the cytosol. Importantly, TFEB overexpression resulted in more nuclear TFEB and rescued cardiomyopathy phenotypes. These findings suggest that S75Y is a pathogenic gain-of-function mutation in RagC that leads to cardiomyopathy. A primary pathological step of RagCS75Y cardiomyopathy is defective mTOR–TFEB signaling, which can be corrected by TFEB overexpression, but not mTOR inhibition.

Discordant interventricular differences in the excitation‐contraction coupling explained by the lower levels of troponin and Ca 2+ buffering in the right ventricle of rats

The left and right ventricles have distinctive functional characteristics as well as the anatomical differences. However, precise understanding of interventricular differences in the excitation-contraction (E-C) coupling mechanisms and the Ca2+ homeostasis is still lacking. Here we compared the results from the right and left cardiomyocytes (RVCMs and LVCMs) of rats by using whole-cell patch clamp and IonOptix measuring cytosolic Ca2+ ([Ca2+]i) and contractility. RVCMs showed significantly shorter action potential duration (APD), with higher density of transient outward K+ current (Ito) while similar L-type Ca2+ current. However, the triggered [Ca2+]ichange (Ca2+ transient) was not different while the decaying rate of Ca2+ transient was slower in RVCMs. More perplexingly, the sarcomere shortening amplitude (DSL) was smaller and the relaxation speed was slower in RVCMs than LVCMs. The analysis of SERCA activity in situ revealed approximately 50% lower level in RVCMs. Interestingly, the immunoblot analysis revealed lower expression of cardiac troponin complex (cTnC, cTnI and cTnT) in RVCMs. The lower Ca2+ binding cTnC implied smaller Ca2+ buffering capacity (κS), which could be responsible for the similar amplitude of Ca2+-transient despite the shorter APD in RVCMs. In situ analysis using known concentration of fura-2 revealed lower κS in the RVCMs. Introduction of the 1.9 fold Ito, 0.5 fold SERCA, and 0.7 fold cTn into the mathematical model of rat LVCM reproduced the similar Ca2+ transient and the slower Ca2+ decay along with the shorter APD of RVCM. Taken together, we firstly show the lower expression of cTn proteins in the RVCMs, which gives a clue to explain the inter-ventricular difference in the E-C coupling kinetics.

Cystamine Treatment Fails to Prevent the Development of Pulmonary Hypertension in Chronic Hypoxic Rats

Introduction: Pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary arteries, leading to right ventricular hypertrophy and failure. We have previously found upregulation of transglutaminase 2 (TG2) in the right ventricle of chronic hypoxic rats. The hypothesis of the present study was that treatment with the transglutaminase inhibitor, cystamine, would inhibit the development of pulmonary arterial remodeling, pulmonary hypertension, and right ventricular hypertrophy. Methods: Effect of cystamine on transamidase activity was investigated in tissue homogenates. Wistar rats were exposed to chronic hypoxia and treated with vehicle, cystamine (40 mg/kg/day in mini-osmotic pumps), sildenafil (25 mg/kg/day), or the combination for 2 weeks. Results: Cystamine concentration-dependently inhibited TG2 transamidase activity in liver and lung homogenates. In contrast to cystamine, sildenafil reduced right ventricular systolic pressure and hypertrophy and decreased pulmonary vascular resistance and muscularization in chronic hypoxic rats. Fibrosis in the lung tissue decreased in chronic hypoxic rats treated with cystamine. TG2 expression was similar in the right ventricle and lung tissue of drug and vehicle-treated hypoxic rats. Discussion/Conclusions: Cystamine inhibited TG2 transamidase activity, but cystamine failed to prevent pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial muscularization in the chronic hypoxic rat.

Bioinspired Theranostic Coordination Polymer Nanoparticles for Intranasal Dopamine Replacement in Parkinson's Disease.

Dopamine (DA) is one of the main neurotransmitters found in the central nervous system and has a vital role in the function of dopaminergic (DArgic) neurons. A progressive loss of this specific subset of cells is one of the hallmarks of age-related neurodegenerative disorders such as Parkinson’s disease (PD). Symptomatic therapy for PD has been centered in the precursor l-DOPA administration, an amino acid precursor of DA that crosses the blood–brain barrier (BBB) while DA does not, although this approach presents medium- to long-term side effects. To overcome this limitation, DA-nanoencapsulation therapies are actively being searched as an alternative for DA replacement. However, overcoming the low yield of encapsulation and/or poor biodistribution/bioavailability of DA is still a current challenge. Herein, we report the synthesis of a family of neuromelanin bioinspired polymeric nanoparticles. Our system is based on the encapsulation of DA within nanoparticles through its reversible coordination complexation to iron metal nodes polymerized with a bis-imidazol ligand. Our methodology, in addition to being simple and inexpensive, results in DA loading efficiencies of up to 60%. In vitro, DA nanoscale coordination polymers (DA-NCPs) exhibited lower toxicity, degradation kinetics, and enhanced uptake by BE(2)-M17 DArgic cells compared to free DA. Direct infusion of the particles in the ventricle of rats in vivo showed a rapid distribution within the brain of healthy rats, leading to an increase in striatal DA levels. More importantly, after 4 days of nasal administrations with DA-NCPs equivalent to 200 μg of the free drug per day, the number and duration of apomorphine-induced rotations was significantly lower from that in either vehicle or DA-treated rats performed for comparison purposes. Overall, this study demonstrates the advantages of using nanostructured DA for DA-replacement therapy.

Central administration of sodium-glucose cotransporter-2 inhibitors increases food intake involving adenosine monophosphate-activated protein kinase phosphorylation in the lateral hypothalamus in healthy rats

IntroductionSodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in...

Pharmacological regulation of cytochrome P450 metabolites of arachidonic acid attenuates cardiac injury in diabetic rats

Diabetic cardiomyopathy (DCM) is a well-established complication of type 1 and type 2 diabetes associated with a high rate of morbidity and mortality. DCM is diagnosed at advanced and irreversible stages. Therefore, it is of utmost need to identify novel mechanistic pathways involved at early stages to prevent or reverse the development of DCM. In vivo experiments were performed on type 1 diabetic rats (T1DM). Functional and structural studies of the heart were executed and correlated with mechanistic assessments exploring the role of cytochromes P450 metabolites, the 20-hydroxyeicosatetraenoic acids (20-HETEs) and epoxyeicosatrienoic acids (EETs), and their crosstalk with other homeostatic signaling molecules. Our data displays that hyperglycemia results in CYP4A upregulation and CYP2C11 downregulation in the left ventricles (LV) of T1DM rats, paralleled by a differential alteration in their metabolites 20-HETEs (increased) and EETs (decreased). These changes are concomitant with reductions in cardiac outputs, LV hypertrophy, fibrosis, and increased activation of cardiac fetal and hypertrophic genes. Besides, pro-fibrotic cytokine TGF-ß overexpression and NADPH (Nox4) dependent-ROS overproduction are also correlated with the observed cardiac functional and structural modifications. Of interest, these observations are attenuated when T1DM rats are treated with 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA), which blocks EETs metabolism, or N-hydroxy-N'-(4-butyl-2-methylphenol)Formamidine (HET0016), which inhibits 20-HETEs formation. Taken together, our findings confer pioneering evidence about a potential interplay between CYP450-derived metabolites and Nox4/TGF-β axis leading to DCM. Pharmacologic interventions targeting the inhibition of 20-HETEs synthesis or the activation of EETs synthesis may offer novel therapeutic approaches to treat DCM.

Abnormal Rat Cortical Development Induced by Ventricular Injection of rHMGB1 Mimics the Pathophysiology of Human Cortical Dysplasia.

Cortical dysplasia (CD) is a common cause of drug-resistant epilepsy. Increasing studies have implicated innate immunity in CD with epilepsy. However, it is unclear whether innate immune factors induce epileptogenic CD. Here, we injected recombinant human high mobility group box 1 (rHMGB1) into embryonic rat ventricles to determine whether rHMGB1 can induce epileptogenic CD with pathophysiological characteristics similar to those of human CD. Compared with controls and 0.1 μg rHMGB1-treated rats, the cortical organization was severely disrupted in the 0.2 μg rHMGB1-treated rats, and microgyria and heterotopia also emerged; additionally, disoriented and deformed neurons were observed in the cortical lesions and heterotopias. Subcortical heterotopia appeared in the white matter and the gray–white junction of the 0.2 μg rHMGB1-treated rats. Moreover, there was decreased number of neurons in layer V–VI and an increased number of astrocytes in layer I and V of the cortical lesions. And the HMGB1 antagonist dexmedetomidine alleviated the changes induced by rHMGB1. Further, we found that TLR4 and NF-κB were increased after rHMGB1 administration. In addition, the excitatory receptors, N-methyl-D-aspartate receptor 1 (NR1), 2A (NR2A), and 2B (NR2B) immunoreactivity were increased, and immunoreactivity of excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2) were reduced in 0.2 μg rHMGB1-treated rats compared with controls. While there were no differences in the glutamic acid decarboxylase 65/67 (GAD65/67) immunoreactivity between the two groups. These results indicate that the excitation of cortical lesions was significantly increased. Furthermore, electroencephalogram (EEG) showed a shorter latency of seizure onset and a higher incidence of status epilepticus in the 0.2 μg rHMGB1-treated rats; the frequency and amplitude of EEG were higher in the treated rats than controls. Intriguingly, spontaneous electrographic seizure discharges were detected in the 0.2 μg rHMGB1-treated rats after 5 months of age, and spike-wave discharges of approximately 8 Hz were the most significantly increased synchronous propagated waves throughout the general brain cortex. Taken together, these findings indicate that rHMGB1 exposure during pregnancy could contribute to the development of epileptogenic CD, which mimicked some pathophysiological characteristics of human CD.

Astragaloside IV inhibits adriamycin-induced cardiac ferroptosis by enhancing Nrf2 signaling.

Astragaloside IV (AsIV), an active ingredient isolated from traditional Chinese medicine astragalus membranaceus, is beneficial to cardiovascular health. This study aimed to characterize the functional role of AsIV against adriamycin (ADR)-induced cardiomyopathy. Here, healthy rats were treated with ADR and/or AsIV for 35days. We found that AsIV protected the rats against ADR-induced cardiomyopathy characterized by myocardial fibrosis and cardiac dysfunction. Meanwhile, ADR increased type I and III collagens, TGF-β, NOX2, and NOX4 expression and SMAD2/3 activity in the left ventricles of rats, while those effects were countered by AsIV through suppressing oxidative stress. Moreover, ADR was found to promote cardiac ferroptosis, whereas administration of AsIV attenuated the process via activating Nrf2 signaling pathway and the subsequent GPx4 expression increasing. These results suggest that AsIV might play a protective role against ADR-induced myocardial fibrosis, which may partly attribute to its anti-ferroptotic action by enhancing Nrf2 signaling.

Isolated downregulation of HCN2 in ventricles of rats with streptozotocin-induced diabetic cardiomyopathy

BackgroundIn spite of disrupted repolarization of diabetic heart, some studies report less tendency of diabetic heart to develop ventricular arrhythmias suggesting effective compensatory mechanism. We hypothesized that myocardial alterations in HCN2 and HCN4 channels occur under hyperglycaemia.MethodsDiabetes was induced in rats using a single injection of streptozotocin (STZ; 55 mg/kg body weight, i.p.). Basal ECG was measured. Expression of mRNA for HCN channels, potassium channels and microRNA 1 and 133a were measured in ventricular tissues. Protein expression of HCN2 channel isoform was assessed in five different regions of the heart by western blotting. Differentiated H9c2 cell line was used to examine HCN channels expression under hyperglycaemia in vitro.ResultsSix weeks after STZ administration, heart rate was reduced, QRS complex duration, QT interval and T-wave were prolonged in diabetic rats compared to controls. mRNA and protein expressions of HCN2 decreased exclusively in the ventricles of diabetic rats. HCN2 expression levels in atria of STZ rats and H9c2 cells treated with excess of glucose were not changed. MicroRNA levels were stable in STZ rat hearts. We found significantly decreased mRNA levels of several potassium channels participating in repolarization, namely Kcnd2 (Ito1), Kcnh2 (IKr), Kcnq1 (IKs) and Kcnj11 (IKATP).ConclusionsThis result together with downregulated HCN2 channels suggest that HCN channels might be an integral part of ventricular electric remodelling and might play a role in cardiac repolarization projected in altered arrhythmogenic profile of diabetic heart.

MRI tracking/detection of bone marrow mesenchymal stromal cells transplantation for treatment of ischemic cerebral infarction.

Cerebral stroke is the second leading cause of death with high mortality and morbidity worldwide, currently it lacks effective therapies to improve the prognosis. This study was aimed to explore the role of bone marrow mesenchymal stem cells (BMSCs) transplantation in the recovery of brain structure and function after ischemic cerebral infarction by magnetic resonance imaging (MRI). By applying internal carotid artery embolization, the ischemic cerebral infarction model in rats was established. MRI was performed to detect the imaging changes in the brain tissue after modeling, and the successful modeling was evidenced by the presence of obvious high-signal infarct areas in the brain. BMSCs were then injected into the lateral ventricles of rats, and the recovery of brain tissue and function were quantitatively evaluated by T2-weighted image (T2WI) and voxel-based morphology (VBM) after 28days. The results showed that BMSCs were cell subsets with multiple differentiation potentials. Deficits caused by Ischemic cerebral infarction were relieved by BMSCs transplantation, including increase in damaged cerebral tissue and recovery of cerebral function. In addition, the combined imaging technology of VBM and T2WI quantitatively revealed the effectiveness of BMSCs in repairing damaged brain tissue structure and function. Taken together, the results revealed that the transplantation of BMSCs into the lateral ventricle was beneficial to repair the structure and function of the damaged brain tissue after ischemic cerebral infarction. Moreover, the combination of VBM and T2WI technology can detect the level of brain injury in ischemic cerebral infarction dynamically and noninvasively, and evaluate the recovery of structure and function of damaged brain tissue.

Puerarin pretreatment attenuates cardiomyocyte apoptosis induced by coronary microembolization in rats by activating the PI3K/Akt/GSK-3β signaling pathway.

Coronary microembolization (CME) is associated with cardiomyocyte apoptosis and cardiac dysfunction. Puerarin confers protection against multiple cardiovascular diseases, but its effects and specific mechanisms on CME are not fully known. Hence, our study investigated whether puerarin pretreatment could alleviate cardiomyocyte apoptosis and improve cardiac function following CME. The molecular mechanism associated was also explored. A total of 48 Sprague-Dawley rats were randomly divided into CME, CME + Puerarin (CME + Pue), sham, and sham + Puerarin (sham + Pue) groups (with 12 rats per group). A CME model was established in CME and CME + Pue groups by injecting 42 μm microspheres into the left ventricle of rats. Rats in the CME + Pue and sham + Pue groups were intraperitoneally injected with puerarin at 120 mg/kg daily for 7 days before operation. Cardiac function, myocardial histopathology, and cardiomyocyte apoptosis index were determined via cardiac ultrasound, hematoxylin-eosin (H&E) and hematoxylin-basic fuchsin-picric acid (HBFP) stainings, and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. Western blotting was used to measure protein expression related to the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway. We found that, puerarin significantly ameliorated cardiac dysfunction after CME, attenuated myocardial infarct size, and reduced myocardial apoptotic index. Besides, puerarin inhibited cardiomyocyte apoptosis, as revealed by decreased Bax and cleaved caspase-3, and up-regulated Bcl-2 and PI3K/Akt/GSK-3β pathway related proteins. Collectively, puerarin can inhibit cardiomyocyte apoptosis and thus attenuate myocardial injury caused by CME. Mechanistically, these effects may be achieved through activation of the PI3K/Akt/GSK-3β pathway.

Transcranial ultrasonography as a reliable instrument for the measurement of the cerebral ventricles in rats with experimental hydrocephalus: a pilot study.

Demonstrate that transcranial ultrasonography (TUS) scanning is viable and useful as a diagnostic method in experimental hydrocephalus, as well as to compare measurements of cerebral and ventricular width obtained from TUS scans of hydrocephalic rats with post-mortem anatomical specimens, aiming for the development of accurate criteria to establish ventricular enlargement and progression of hydrocephalus subsequently. Thirty-five male Wistar rats were used. Following hydrocephalus induction, they underwent a transcranial ultrasound scan to measure cerebral and ventricular dimensions, in the fourth and 21 post-induction days. By the end of the experiments, measurements obtained from TUS scans were compared with actual values as seen in the post-mortem specimens of each animal. Ventricular dilation could be clearly visualized in hydrocephalic animals. We performed intraclass correlation coefficient and linear regression analyses that have demonstrated a precise correlation between measurements of TUS scans and post-mortem specimens; we have found a similarity of 0,95 for the cerebral diameter and 0,97 for ventricular width. Transcranial ultrasonography is a useful and reliable diagnostic tool for experimental hydrocephalus; also, it can be used to assess the progression of ventriculomegaly in animal models of hydrocephalus.

Bone Morphogenetic Protein 6 Alleviates Cardiac Fibrosis and Dysfunction in Heart Failure

Cardiac fibrosis, the main pathological process from ventricular remodeling to heart failure, has attracted much more attention in recent years. Transforming growth factor beta-1 (TGF-β1) plays a key role in the pathogenesis of cardiac fibrosis. Bone morphogenetic protein 6 (BMP6), a member of the TGF-β family, is reportedly involved in many fibrosis-related diseases, such as hepatic and renal fibrosis. Nevertheless, there are few reports about the specific role of BMP6 in cardiac fibrosis. Here, we demonstrated the protein levels of BMP6 were lower in patients with heart failure. In addition, BMP6 expression appeared lower in left ventricles of rats in a transverse aortic constriction (TAC) surgery group compared with the sham group. Next, we observed that silencing BMP6 using small interfering RNA remarkably aggravated TGF-β1-induced cardiac fibrosis, while overexpression of BMP6 by Adenovirus largely improved cardiac fibrosis. Moreover, we found that BMP6 played a protective role in cardiac fibrosis via inhibiting the TGF-β1/Smad3 pathway, that partially functioned via interferon regulatory factor 7 (IRF7) suppression. Finally, we introduced Adeno-associated virus-9 (AAV-9) carrying shBMP6 and found that TAC surgery-induced cardiac fibrosis was significantly aggravated, while administration of rh-BMP6 via tail vein injection markedly ameliorated cardiac fibrosis induced by knockdown of BMP6 in vivo. In conclusion, our study demonstrated that BMP6 may serve as a novel biomarker and a therapeutic target in heart failure related to cardiac fibrosis. Funding Statement: This study was supported by the National Natural Science Foundation of China [No. 81770242 to YaChen Zhang] and Natural Science Foundation of Ningbo (No:2019A610388). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: The collection and use of human LV samples were approved by the local human research ethics committee of Shanghai Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine Animal studies were approved by the Animal care and Use Committee of Shanghai Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine.

Efficacy of shear wave elastography for evaluating right ventricular myocardial fibrosis in monocrotaline-induced pulmonary hypertension rats

BackgroundRight ventricular (RV) function is important for outcomes in pulmonary hypertension. Evaluation of RV myocardial characteristics is useful to assess the disease severity. Shear wave elastography (SWE) provides information of shear wave (SW) elasticity, which is related to tissue hardness, and SW dispersion slope, which reflects tissue viscosity. This study aimed to test the hypothesis that SW elasticity is increased and SW dispersion slope is decreased in the right ventricle of monocrotaline (MCT)-induced pulmonary hypertension rats. MethodsRats were divided into MCT-induced pulmonary hypertension group (n = 10) and control group (n = 10). SW elasticity and SW dispersion slope were measured on excised hearts. Myocardial fibrosis was evaluated histologically. ResultsRV hypertrophy was observed in the MCT group. SW elasticity of right ventricle was higher in the MCT group than in the control group (3.5 ± 0.9 kPa vs. 2.5 ± 0.4 kPa, p < 0.01). SW dispersion slope of right ventricle was lower in the MCT group than in the control group (5.3 ± 1.7 m/s/kHz vs. 7.7 ± 1.5 m/s/kHz, p < 0.01). The fibrosis area of right ventricle was increased in MCT group compared with control group (18 ± 5% vs. 8 ± 3%, p < 0.01), and was positively related to SW elasticity and negatively related to SW dispersion slope. ConclusionsHigher SW elasticity and lower SW dispersion slope were observed in the fibrotic myocardium of right ventricle in MCT-induced pulmonary hypertension rats. SWE may have the potential to evaluate RV function by assessing myocardial characteristics.

Breviscapine Pretreatment Inhibits Myocardial Inflammation and Apoptosis in Rats After Coronary Microembolization by Activating the PI3K/Akt/GSK-3β Signaling Pathway.

PurposeCoronary microembolization (CME) can cause myocardial inflammation, apoptosis and progressive cardiac dysfunction. On the other hand, breviscapine exerts a significant cardioprotective effect in many cardiac diseases although its role and the potential mechanisms in CME remain unclear. Therefore, the present study aimed to ascertain whether pretreatment with breviscapine could improve CME-induced myocardial injury by alleviating myocardial inflammation and apoptosis. The possible underlying mechanisms were also explored.MethodsIn this study, 48 Sprague-Dawley (SD) rats were randomly assigned to the CME, CME + breviscapine (CME + BE), CME + breviscapine + LY294002 (CME + BE + LY) and sham groups (12 rats per group). In addition, the CME model was successfully established by injecting 42 μm inert plastic microspheres into the left ventricle of rats. Rats in the CME + BE and CME + BE + LY groups received 40 mg/kg/d of breviscapine for 7 days before inducing CME. Moreover, rats in the CME + BE + LY group were intraperitoneally injected with the phosphoinositide 3-kinase (PI3K) specific inhibitor, LY294002 (10 mg/kg) 30 minutes before CME modeling. 12 h after surgery, the study measured cardiac function, the serum levels of markers of myocardial injury, myocardial inflammation-associated mRNAs and proteins, myocardial apoptosis-associated mRNAs and proteins and conducted myocardial histopathology.ResultsThe findings demonstrated that pretreatment with breviscapine alleviated myocardial injury following CME by improving cardiac dysfunction, decreasing the serum levels of markers of myocardial injury, reducing the size of myocardial microinfarct and lowering the cardiomyocyte apoptotic index. More importantly, pretreatment with breviscapine resulted to a decrease in the levels of inflammatory and pro-apoptotic mRNAs and proteins in myocardial tissues and there was an increase in the levels of anti-apoptotic mRNAs and proteins. However, these protective effects were eliminated when breviscapine was combined with LY294002.ConclusionThe findings from this study indicated that breviscapine may inhibit myocardial inflammation and apoptosis by regulating the PI3K/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway, thereby ameliorating CME-induced cardiac dysfunction and reducing myocardial injury.

Metabolic remodeling in the right ventricle of rats with severe pulmonary arterial hypertension.

It is generally considered that there is an increase in glycolysis in the hypertrophied right ventricle (RV) during pulmonary hypertension (PH), which leads to a decrease in glucose oxidation through the tricarboxylic acid (TCA) cycle. Although recent studies have demonstrated that fatty acid (FA) and glucose accumulated in the RV of patients with PH, the details of this remain to be elucidated. The purpose of the current study was to assess the metabolic remodeling in the RV of rats with PH using a metabolic analysis. Male rats were treated with the vascular endothelial growth factor receptor blocker SU5416 followed by 3weeks of hypoxic conditions and 5weeks of normoxic conditions (Su/Hx rats). Hemodynamic measurements were conducted, and the RV was harvested for the measurement of metabolites. A metabolomics analysis revealed a decreasing trend in the levels of alanine, argininosuccinic acid and downstream TCA cycle intermediates, including fumaric and malic acid and an increasing trend in branched‑chain amino acids (BCAAs) in Su/Hx rats compared with the controls; however, no trends in glycolysis were indicated. The FA metabolomics analysis also revealed a decreasing trend in the levels of long‑chain acylcarnitines, which transport FA from the cytosol to the mitochondria and are essential for beta‑oxidation. The current study demonstrated that the TCA cycle was less activated because of a decreasing trend in the expression of fumaric acid and malic acid, which might be attributable to the expression of adenylosuccinic acid and argininosuccinic acid. These results suggest that dysregulated BCAA metabolism and a decrease in FA oxidation might contribute to the reduction of the TCA cycle reactions.

Differing effects of estrogen deficiency on the contractile function of atrial and ventricular myocardium

Estrogen deficiency has a significant influence on the excitation-contraction coupling in the ventricular myocardium but its impact on the atrial contractile function has not been studied. We have compared the effects of estrogen deficiency on the contractility and cytosolic Ca2+ transient of single cardiomyocytes isolated from the left atrium (LA) and the left ventricle (LV) of rats subjected to ovariectomy (OVX) or sham surgery (Sham). The characteristics of actin-myosin interaction were studied in an in vitro motility assay. We found that OVX decreased the contractility of LV single cardiomyocytes but increased that of LA myocytes. The disturbance of ventricular mechanical function may be explained by the acceleration of Ca2+ transient and reduced Ca2+ sensitivity of the actin-myosin interaction. The augmentation of LA contractility may be explained by accelerated cross-bridge kinetics and increased end-diastolic sarcomere length, which may lead to elevated tension in atrial cells due to the Frank-Starling mechanism.

Sildenafil improves right ventricular remodelling in monocrotaline-induced rats by decreasing myocardial apoptosis and activating peroxisome proliferator-activated receptors.

To assess the effect of sildenafil on monocrotaline-induced right ventricular (RV) remodeling and investigate the possible mechanism. Rats were subcutaneously injected with monocrotaline to establish an RV remodeling model and then administered sildenafil (25 mg/kg) from days 1 to 28. After 28 days of administration, the RV systolic pressure and the RV hypertrophy index (RVHI) were measured. The morphology of the right ventricle was observed by H&E staining. The ultrastructure of the right ventricle was observed using a transmission electron microscope. The myocardial apoptosis of the right ventricle was evaluated by TUNEL staining. The protein expression of apoptosis-related proteins and PPARs were examined by western blotting. The results indicated that sildenafil decreased the RV systolic pressure and RVHI, and improved the microstructure and ultrastructure of the right ventricle in monocrotaline-induced rats. In addition, sildenafil suppressed myocardial apoptosis and promoted the protein expression of PPARs of the right ventricle in monocrotaline-induced rats. Sildenafil inhibits RV remodeling in monocrotaline-induced rats, which might be partially mediated by reducing myocardial apoptosis and activating PPARs.

A single injection of periostin decreases cardiac voltage-gated Na+ channel in rat ventricles.

Changes in electrophysiological properties, such as ion channel expression and activity, are closely related to arrhythmogenesis during heart failure (HF). However, a causative factor for the electrical remodeling in HF has not been determined. Periostin (POSTN), a matricellular protein, is increased in heart tissues of patients with HF. In the present study, we investigated whether a single injection of POSTN affects the electrophysiological properties in rat ventricles. After male Wistar rats were intravenously injected with recombinant rat POSTN (64 µg/kg, 24 hr), electrocardiogram (ECG) was recorded. Whole-cell patch clamp was performed to measure action potential (AP) and Na+ current (INa) in isolated ventricular myocytes. Protein expression of cardiac voltage-gated Na+ channel (NaV1.5) in isolated ventricles was examined by Western blotting. In ECG, POSTN-injection significantly increased RS height. POSTN-injection significantly delayed time to peak in AP and decreased INa in the isolated ventricular myocytes. POSTN-injection decreased NaV1.5 expression in the isolated ventricles. It was confirmed that POSTN (1 µg/ml, 24 hr) decreased INa and NaV1.5 protein expression in neonatal rat ventricular myocytes. This study for the first time demonstrated that a single injection of POSTN in rats decreased INa by suppressing NaV1.5 expression in the ventricular myocytes, which was accompanied by a prolongation of time to peak in AP and an increase of RS height in ECG.

Cardiovascular Properties of the Androgen-Induced PCOS Model in Rats: The Role of Oxidative Stress.

Polycystic ovary syndrome (PCOS) is a multifaced reproductive endocrinopathy affecting 6-20% of women of childbearing age. It was previously shown that women with PCOS have an increased risk of cardiovascular (CV) diseases. The aim of this study was to evaluate the cardiodynamic parameters of isolated rats' hearts, blood pressure levels, and histomorphological changes in the heart tissue following the androgen-induced PCOS model in rats and the role of oxidative stress in the development of these CV properties of PCOS. 21-day-old female rats (n = 12) were divided into control and PCOS groups. PCOS was induced by administration of testosterone enanthate (1 mg/kg BW, daily) during 35 days. During the autoregulation protocol (40-120 mmHg) on the Langendorff apparatus, ex vivo cardiodynamic parameters of retrogradely perfused hearts showed enhanced contractile function and increased lusitropic effects in the left ventricle (LV) in PCOS rats. Systolic and diastolic pressures in LV were elevated at all perfusion pressure values. Systemic arterial systolic blood pressure showed borderline elevation, while mean arterial blood pressure was significantly higher in PCOS rats. Histological evaluation of heart tissue depicted hypertrophic (8.3%) alterations in LV cardiomyocytes and increase (7.3%) in LV wall thickness. Oxidative stress parameters were altered in systemic circulation, coronary venous effluent (CVE), and heart tissue. Levels of superoxide dismutase and reduced glutathione were decreased in blood and heart tissue, while catalase activity was not altered. Degree of lipid peroxidation was increased in circulation as well as heart tissue. Increased levels of O2− in CVE indicated the cardiotoxic effects in the rat PCOS model. The mentioned alterations of oxidative stress parameters in the blood, CVE, and heart could be recommended as potential contributors underlying the development of CV risk in PCOS women.