scholarly journals In vivo genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial-centered pathway activated in ischemic heart failure

2008 ◽  
Vol 294 (1) ◽  
pp. H88-H98 ◽  
Author(s):  
Ahmad Y. Sheikh ◽  
Hyung J. Chun ◽  
Alexander J. Glassford ◽  
Ramendera K. Kundu ◽  
Ingo Kutschka ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Cardiac Failure ◽  
Cellular Localization ◽  
Hypoxic Exposure ◽  
Peptide Ligand ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Signaling by the peptide ligand apelin and its cognate G protein-coupled receptor APJ has a potent inotropic effect on cardiac contractility and modulates systemic vascular resistance through nitric oxide-dependent signaling. In addition, there is evidence for counterregulation of the angiotensin and vasopressin pathways. Regulatory stimuli of the apelin-APJ pathway are of obvious importance but remain to be elucidated. To better understand the physiological response of apelin-APJ to disease states such as heart failure and to elucidate the mechanism by which such a response might occur, we have used the murine model of left anterior descending coronary artery ligation-induced ischemic cardiac failure. To identify the key cells responsible for modulation and production of apelin in vivo, we have created a novel apelin-lacZ reporter mouse. Data from these studies demonstrate that apelin and APJ are upregulated in the heart and skeletal muscle following myocardial injury and suggest that apelin expression remains restricted to the endothelium. In cardiac failure, endothelial apelin expression correlates with other hypoxia-responsive genes, and in healthy animals both apelin and APJ are markedly upregulated in various tissues following systemic hypoxic exposure. Experiments with cultured endothelial cells in vitro show apelin mRNA and protein levels to be increased by hypoxia, through a hypoxia-inducible factor-mediated pathway. These studies suggest that apelin-expressing endothelial cells respond to conditions associated with heart failure, possibly including local tissue hypoxia, and modulate apelin-APJ expression to regulate cardiovascular homeostasis. The apelin-APJ pathway may thus provide a mechanism for systemic endothelial monitoring of tissue perfusion and adaptive regulation of cardiovascular function.

Regulation of K+ and Ca2+ channels in experimental cardiac failure

1991 ◽  
Vol 261 (6) ◽  
pp. H1979-H1987 ◽  
Author(s):  
M. Gopalakrishnan ◽  
D. J. Triggle ◽  
A. Rutledge ◽  
Y. W. Kwon ◽  
J. A. Bauer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Right Ventricle ◽  
Cardiac Failure ◽  
Radioligand Binding ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
The Right

To examine the status of ATP-sensitive K+ (K+ATP) channels and 1,4-dihydropyridine-sensitive Ca2+ (Ca2+DHP) channels during experimental cardiac failure, we have measured the radioligand binding properties of [3H]glyburide and [3H]PN 200 110, respectively, in tissue homogenates from the rat cardiac left ventricle, right ventricle, and brain 4 wk after myocardial infarction induced by left coronary artery ligation. The maximal values (Bmax) for [3H]glyburide and [3H]PN 200 110 binding were reduced by 39 and 40%, respectively, in the left ventricle, and these reductions showed a good correlation with the right ventricle-to-body weight ratio in heart-failure rats. The ligand binding affinities were not altered. In the hypertrophied right ventricle, Bmax values for both the ligands were not significantly different when data were normalized to DNA content or right ventricle weights but showed an apparent reduction when normalized to unit protein or tissue weight. Moderate reductions in channel densities were observed also in whole brain homogenates from heart failure rats. Assessment of muscarinic receptors, beta-adrenoceptors and alpha 1-adrenoceptors by [3H]quinuclidinyl benzilate, [3H]dihydroalprenolol, and [3H]prazosin showed reductions in left ventricular muscarinic and beta-adrenoceptor densities but not in alpha 1-adrenoceptor densities, consistent with earlier observations. It is suggested that these changes may in part contribute to the pathology of cardiac failure.

scholarly journals Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure

2020 ◽  
Author(s):  
Dongze Zhang ◽  
Huiyin Tu ◽  
Chaojun Wang ◽  
Liang Cao ◽  
Wenfeng Hu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Coronary Artery ◽  
Ventricular Arrhythmias ◽  
Sympathetic Neurons ◽  
Coronary Artery Ligation ◽  
Channel Blockers ◽  
Artery Ligation ◽  
Cell Excitability ◽  
Ventricular Arrhythmogenesis

Abstract Aims Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Methods and results Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats. Conclusions Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.

An antibody to leukocyte integrins attenuates coronary vascular injury due to ischemia and reperfusion in dogs

1997 ◽  
Vol 272 (2) ◽  
pp. H618-H624 ◽  
Author(s):  
L. D. Horwitz ◽  
D. Kaufman ◽  
Y. Kong
Keyword(s):  
Coronary Artery ◽  
Leukocyte Adhesion ◽  
Microvascular Permeability ◽  
Coronary Artery Ligation ◽  
Ischemia And Reperfusion ◽  
Artery Ligation ◽  
Isotope Technique ◽  
Coronary Ischemia

Ischemia and reperfusion cause coronary vascular and myocardial injury, which may be due to leukocyte-mediated processes. Antileukocyte measures have reduced injury after brief reperfusion periods of 1-3 h, but there has been little information on whether benefits are apparent after longer periods of reperfusion. We examined the effect of pretreatment with a monoclonal antibody (R15.7) to the CD18 family of leukocyte adhesion molecules (beta2-integrins) in dogs exposed to regional coronary ischemia for 1 h of left anterior descending coronary artery ligation and then reperfused for 48 h. Coronary microvascular permeability was assessed in vivo by measurement of protein leak index (PLI), using a double-isotope technique with autologous radiolabeled transferrin and erythrocytes. Vasorelaxation was measured in vitro with preconstricted epicardial coronary artery rings subjected to increasing concentrations of the endothelium-dependent vasodilators bradykinin (BK) and ADP and the endothelium-independent vasodilator nitroprusside. At 48 h of reperfusion in untreated dogs there were substantial increases in PLI in the previously ischemic regions, indicative of increased extravascular transferrin. These abnormalities were decreased, but not abolished, in the dogs treated with R15.7. Relaxation of rings from the ischemic/reperfused artery to BK and ADP were blunted in the untreated dogs. R15.7 resulted in improvement in some, but not all, indexes of relaxation in response to BK and ADP. Relaxation to nitroprusside was normal in ischemic/reperfused coronary rings from both treated and untreated dogs. Therefore, after 1 h of regional coronary ischemia and 48 h of reperfusion, coronary endothelial injury, which was manifested by increased coronary microvascular permeability and abnormalities in coronary endothelium-dependent relaxation, was reduced by pretreatment with the anti-CD18 integrin antibody R15.7.

scholarly journals Integrative System Biology Analyses Identify Seven MicroRNAs to Predict Heart Failure

2019 ◽  
Vol 5 (1) ◽  
pp. 22 ◽  
Author(s):  
Henri Charrier ◽  
Marie Cuvelliez ◽  
Emilie Dubois-Deruy ◽  
Paul Mulder ◽  
Vincent Richard ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systems Biology ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mirna Signature ◽  
Artery Ligation ◽  
Proteomic Data

Heart failure (HF) has several etiologies including myocardial infarction (MI) and left ventricular remodeling (LVR), but its progression remains difficult to predict in clinical practice. Systems biology analyses of LVR after MI provide molecular insights into this event such as modulation of microRNA (miRNA) that could be used as a signature of HF progression. To define a miRNA signature of LVR after MI, we use 2 systems biology approaches, integrating either proteomic data generated from LV of post-MI rat induced by left coronary artery ligation or multi-omics data (proteins and non-coding RNAs) generated from plasma of post-MI patients from the REVE-2 study. The first approach predicted that 13 miRNAs and 3 of these miRNAs would be validated to be associated with LVR in vivo: miR-21-5p, miR-23a-3p and miR-222-3p. The second approach predicted that 24 miRNAs among 1310 molecules and 6 of these miRNAs would be selected to be associated with LVR in silico: miR-17-5p, miR-21-5p, miR-26b-5p, miR-222-3p, miR-335-5p and miR-375. We identified a signature of 7 microRNAs associated with LVR after MI that support the interest of integrative systems biology analyses to define a miRNA signature of HF progression.

scholarly journals Changes in myofilament proteins, but not Ca2+ regulation, are associated with a high-fat diet-induced improvement in contractile function in heart failure

2011 ◽  
Vol 301 (4) ◽  
pp. H1438-H1446 ◽  
Author(s):  
Y. Cheng ◽  
W. Li ◽  
T. A. McElfresh ◽  
X. Chen ◽  
J. M. Berthiaume ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Expression ◽  
Contractile Function ◽  
Left Ventricular ◽  
Contractile Properties ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cell Shortening ◽  
Regulatory Properties

Pathological conditions such as diabetes, insulin resistance, and obesity are characterized by elevated plasma and myocardial lipid levels and have been reported to exacerbate the progression of heart failure (HF). Alterations in cardiomyocyte Ca2+ regulatory properties and myofilament proteins have also been implicated in contractile dysfunction in HF. However, our prior studies reported that high saturated fat (SAT) feeding improves in vivo myocardial contractile function, thereby exerting a cardioprotective effect in HF. Therefore, we hypothesized that SAT feeding improves contractile function by altering Ca2+ regulatory properties and myofilament protein expression in HF. Male Wistar rats underwent coronary artery ligation (HF) or sham surgery (SH) and were fed normal chow (SHNC and HFNC groups) or a SAT diet (SHSAT and HFSAT groups) for 8 wk. Contractile properties were measured in vivo [echocardiography and left ventricular (LV) cannulation] and in isolated LV cardiomyocytes. In vivo measures of contractility (peak LV +dP/d t and −dP/d t) were depressed in the HFNC versus SHNC group but improved in the HFSAT group. Isolated cardiomyocytes from both HF groups were hypertrophied and had decreased percent cell shortening and a prolonged time to half-decay of the Ca2+ transient versus the SH group; however, SAT feeding reduced in vivo myocyte hypertrophy in the HFSAT group only. The peak velocity of cell shortening was reduced in the HFNC group but not the HFSAT group and was positively correlated with in vivo contractile function (peak LV +dP/d t). The HFNC group demonstrated a myosin heavy chain (MHC) isoform switch from fast MHC-α to slow MHC-β, which was prevented in the HFSAT group. Alterations in Ca2+ transients, L-type Ca2+ currents, and protein expression of sarco(endo)plasmic reticulum Ca2+-ATPase and phosphorylated phospholamban could not account for the changes in the in vivo contractile properties. In conclusion, the cardioprotective effects associated with SAT feeding in HF may occur at the level of the isolated cardiomyocyte, specifically involving changes in myofilament function but not sarcoplasmic reticulum Ca2+ regulatory properties.

Cellular basis for contractile dysfunction in the diaphragm from a rabbit infarct model of heart failure

2000 ◽  
Vol 278 (4) ◽  
pp. C739-C746 ◽  
Author(s):  
Niall G. MacFarlane ◽  
G. Murray Darnley ◽  
Godfrey L. Smith
Keyword(s):  
Heart Failure ◽  
Cyclopiazonic Acid ◽  
Progressive Increase ◽  
Stimulation Frequency ◽  
Exercise Intolerance ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Intracellular Ca ◽  
Rabbit Coronary Artery

Abnormal respiratory muscle function is thought to contribute to breathlessness and exercise intolerance in heart failure but little is known about possible alterations in the function of such muscle. We have measured tetanic force and intracellular Ca2+ concentration ([Ca2+]i) in isolated, arterially perfused hemidiaphragm preparations from a rabbit coronary artery ligation model of heart failure. Increasing stimulation frequency (10–100 Hz) caused a progressive increase of force and [Ca2+]i in control preparations, whereas force and [Ca2+]i only increased between 10 and 25 Hz stimulation (decreasing at higher frequencies) in preparations from ligated animals. Cyclopiazonic acid produced a dose-dependent shift in the relationship between stimulation frequency and [Ca2+]i in control preparations that was similar to the shift observed in the diaphragm of coronary-ligated animals. These data indicate that the in vitro contractile characteristics of the diaphragm are significantly altered in our model and that altered [Ca2+]i regulation contributes to the reduced diaphragm strength observed in heart failure.

Abstract 18592: Anti-arrhythmic Effect of a Novel Rycal, S44121 / Arm036, in a Post-myocardial Infarction Mouse Model of Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jerome Thireau ◽  
Charlotte Farah ◽  
Muriel Bouly ◽  
Jerome Roussel ◽  
Alain Lacampagne ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Mouse Model ◽  
Ryanodine Receptors ◽  
Left Ventricular ◽  
Cardiac Contraction ◽  
Post Myocardial Infarction ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Introduction: Targeting leaky cardiac ryanodine receptors (RyR2) to prevent diastolic Ca2+ release from the sarcoplasmic reticulum (SR) is a promising pharmacological approach, to rescue the impaired cardiac contraction and prevent Ca2+-dependent arrhythmias in heart failure (HF) and disease. Hypothesis: Based on prior work from the Marks group, the Rycal S44121 (also known as ARM036) is an experimental small molecule stabilizer of RyR. We investigated the effects of S44121 in a post-myocardial infarction (PMI) mouse model of HF. Methods and results: Mice were randomly assigned to 3 groups: Sham, PMI (subjected to left coronary artery ligation), and PMI-S (treated for 3 weeks with S44121 by subcutaneous osmotic pumps on day 7 post-MI, 10 mg/kg/day). Intracellular Ca2+ was measured on single left ventricular myocytes. PMI mice exhibited a 4-fold increase in the frequency of spontaneous Ca2+ release events, Ca2+ sparks, as measured in quiescent cells using the fluorescent Ca2+ indicator Fluo-4. PMI mice also exhibited higher global diastolic Ca2+, measured with the ratiometric fluorescent probe, Indo-1 AM, and increased the occurrence of ectopic diastolic Ca2+ waves. Acute application of S44121 (10 μM for 15 min) reduced Ca2+ sparks frequency. Chronic treatment of mice with S44121 also normalized the frequency of Ca2+ sparks and of ectopic Ca2+ waves, and corrected diastolic cellular Ca2+ overload. Effects were maximal at 20 mg/kg/day. Furthermore, treatment with S44121 abolished Ca2+ waves promoted by β-adrenergic challenge (acute application of isoproterenol, 10 nM). The potential anti-arrhythmic benefit of S44121 was assessed in vivo using telemetric surface electrocardiograms. S44121 had no effect on ECG intervals and did not alter the heart rate. However, anti-arrhythmic effects were confirmed by observation of a dose-dependent reduction of spontaneous ventricular extrasystoles and ventricular tachycardia. Near maximum benefits were observed at 10 mg/kg/day, both in basal conditions or following a challenge with acute treatment of isoproterenol (0.5 mg/kg, dosed ip). Conclusion: In mice with post-ischemic HF, treatment with S44121 prevented the abnormal diastolic SR Ca2+ leak and ectopic Ca2+ waves, and reduced ventricular arrhythmias.

Abstract 464: Membrane Microparticles From Ischemic Muscle Induce In Vitro Progenitor Cells Differentiation And In Vivo Neovascularization.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Aurelie S Leroyer ◽  
Teni G Ebrahimian ◽  
Jose Vilar ◽  
Bernard I Levy ◽  
Alain Tedgui ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Progenitor Cells ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Artery Ligation ◽  
Control Muscle ◽  
Tissue Ischemia ◽  
Subunit Expression

Postischemic neovascularization is mediated, at least in part, by the homing of progenitor cells to sites of injury and their differentiation into endothelial cells (EC). However, the mechanisms of in situ progenitor differentiation remain for the most part unknown. We hypothesized that miproparticles (MPs) released following ischemia-induced cell activation or apoptosis are the endogenous signal of postischemic vasculogenesis. MPs were detected by electron microscopy as vesicles of 0.1 to 1 μm in diameter in mice ischemic hindlimb muscle, 48hrs after unilateral femoral artery ligation. After isolation by sequential centrifugations, flow cytometry analyses showed that AnnexinV+ MPs concentration in ischemic calf was 3.5-fold higher than in control muscle (1392±406 vs. 394±180 AnnV+MPs/mg, p<0.005) and mainly originated from endothelial cells (47% of MPs are CD144+). MPs isolated from ischemic muscles induced a more potent in vitro bone marrow-mononuclear cells (BM-MNC) differentiation into EPC, than those isolated from control muscle (6.1±1.0% vs. 3.5±0.7% Dil-LDL/BS1lectin+ cells/field, p<0.05). Moreover, MPs isolated from GFP+ ischemic muscles colocalized with differentiated BM-MNC. MPs isolated from atherosclerotic plaque were uneffective whereas those isolated from apoptotic or IL-1 activated EC also promoted BM-MNC differentiation. Interestingly, MPs from ischemic muscles produced more reactive oxygen species and expressed significantly higher levels of NADPH oxidase p47 (6 fold ; p<0.05) and p67 subunits (16 fold ; p<0.005) than those from control, whereas gp91 subunit expression was unchanged. The MPs-induced BM-MNC differentiation was reduced by two fold with MPs isolated from gp91-deficient mice (p<0.05). MPs effect on post-ischemic vasculogenesis and revascularization was examined in the ischemic hindlimb model. MPs isolated from ischemic muscles were injected into ischemic legs in parallel with venous injection of BM-MNC. MPs increased the pro-angiogenic effect of BM-MNC transplantation and this effect was blunted with MPs from gp91−/− mice. These results demonstrate that MPs produced after tissue ischemia stimulate progenitor cell differentiation and subsequently promote postnatal neovascularization.

scholarly journals Effects of Dantrolene on Arrhythmogenicity in Isolated Regional Ischemia-Reperfusion Rabbit Hearts with or without Pacing-Induced Heart Failure

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Chung-Chuan Chou ◽  
Hui-Ling Lee ◽  
Po-Cheng Chang ◽  
Hung-Ta Wo ◽  
Ming-Shien Wen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ischemia Reperfusion ◽  
Rabbit Model ◽  
Control Group ◽  
Ventricular Premature Beat ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Regional Ischemia ◽  
Intracellular Ca

Dantrolene was reported to suppress ventricular fibrillation (VF) in failing hearts with acute myocardial infarction, but its antiarrhythmic efficacy in regional ischemia-reperfusion (IR) hearts remains debatable. Heart failure (HF) was induced by right ventricular pacing. The IR rabbit model was created by coronary artery ligation for 30 min, followed by reperfusion for 15 min in vivo in both HF and non-HF groups (n= 9 in each group). Simultaneous voltage and intracellular Ca2+(Cai) optical mapping was then performed in isolated Langendorff-perfused hearts. Electrophysiological studies were conducted and VF inducibility was evaluated by dynamic pacing. Dantrolene (10 μM) was administered after baseline studies. The HF group had a higher VF inducibility than the control group. Dantrolene had both antiarrhythmic (prolonged action potential duration (APD) and effective refractory period) and proarrhythmic effects (slowed conduction velocity, steepened APD restitution slope, and enhanced arrhythmogenic alternans induction) but had no significant effects on ventricular premature beat (VPB) suppression and VF inducibility in both groups. A higher VF conversion rate in the non-HF group was likely due to greater APD prolonging effects in smaller hearts compared to the HF group. The lack of significant effects on VPB suppression by dantrolene suggests that triggered activity might not be the dominant mechanism responsible for VPB induction in the IR model.

scholarly journals Protective Effects of Rhodiola Crenulata Extract on Hypoxia-Induced Endothelial Damage via Regulation of AMPK and ERK Pathways

2018 ◽  
Vol 19 (8) ◽  
pp. 2286 ◽  
Author(s):  
Pi-Kai Chang ◽  
I-Chuan Yen ◽  
Wei-Cheng Tsai ◽  
Tsu-Chung Chang ◽  
Shih-Yu Lee
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Umbilical Vein ◽  
Hypoxic Exposure ◽  
No Production ◽  
Root Extract ◽  
Protective Effects ◽  
Rhodiola Crenulata

Rhodiola crenulata root extract (RCE) has been shown to possess protective activities against hypoxia both in vitro and in vivo. However, the effects of RCE on response to hypoxia in the endothelium remain unclear. In this study, we aimed to examine the effects of RCE in endothelial cells challenged with hypoxic exposure and to elucidate the underlying mechanisms. Human umbilical vein endothelial cells were pretreated with or without RCE and then exposed to hypoxia (1% O2) for 24 h. Cell viability, nitric oxide (NO) production, oxidative stress markers, as well as mechanistic readouts were studied. We found that hypoxia-induced cell death, impaired NO production, and oxidative stress. These responses were significantly attenuated by RCE treatment and were associated with the activation of AMP-activated kinase and extracellular signal-regulated kinase 1/2 signaling pathways. In summary, we showed that RCE protected endothelial cells from hypoxic insult and suggested that R. crenulata might be useful for the prevention of hypoxia-associated vascular dysfunction.

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