Editorial Board
Tuesday, January 17th, 2012Publication year: 2012
Source: Journal of Molecular and Cellular Cardiology, Volume 52, Issue 1, January 2012, Pages i
[No author name available]
Archive for the ‘Health news’ Category
Carbonic Anhydrase XIV in the Normal and Hypertrophic Myocardium
Tuesday, January 17th, 2012Publication year: 2011
Source: Journal of Molecular and Cellular Cardiology, Available online 22 December 2011
Lorena A. Vargas, Bernardo V. Alvarez
Two AE3 transcripts, full-length (AE3fl) and cardiac (AE3c) are expressed in the heart. AE3 catalyzes electroneutral Cl/HCO3exchange across cardiomyocyte sarcolemma. AE proteins associate with carbonic anhydrases (CA), including CAII and CAIV, forming a HCO3transport metabolon (BTM),increasingHCO3fluxes and regulating cardiomyocytes pH. CAXIV, which is also expressed in the heart’s sarcolemma, is a transmembrane enzyme with an extracellular catalytic domain. Herein, AE3/CAXIV physical association was examined by coimmunoprecipitation using rodent heart lysates. CAXIV immunoprecipitated with anti-AE3 antibody and both AE3fl and AE3c were reciprocally immunoprecipitated using anti-CAXIV antibody, indicating AE3fl-AE3c/CAXIV interaction in the myocardium. Coimmunoprecipitation experiments on heart lysates from a mouse with targeted disruption of theae3gene, failed to pull down AE3 with the CAXIV antibody. Confocal images demonstrated colocalization of CAXIV and AE3 in mouse ventricularmyocytes. Functional association of AE3fl and CAXIV was examined in isolated hypertrophic rat cardiomyocytes, using fluorescence measurements of BCECF to monitor cytosolic pH. Hypertrophic cardiomyocytes of spontaneously hypertensive rats (SHR) presented elevated myocardial AE-mediated Cl/HCO3exchange activity (JHCO3-mM.min) compared to normal (Wistar) rats (7.5 ± 1.3, n = 4versus2.9 ± 0.1, n = 6, respectively).AE3fl, AE3c,CAII, CAIV, and CAIX protein expression were similar in SHR and Wistar rat heart. However, immunoblots revealed a twofold increase of CAXIV protein expression in the SHR myocardium compared to normal hearts (n = 11). Furthermore, the CA-inhibitor, benzolamide, neutralized the stimulatory effect of extracellular CA on AE3 transport activity (3.7 ± 1.5, n = 3), normalizing AE3-dependent HCO3fluxes in SHR. CAXIV/AE3 interaction constitutes an extracellular component of a BTM which potentiates AE3-mediated HCO3transport in the heart. Increased CAXIV expression and consequent AE3/CAXIV complex formation would render AE3 hyperactive in the SHR heart.
Highlights
► AE3 Cl/HCO3exchanger interacts with the CAXIV enzyme in the heart. ► CAXIV bound to and enhanced AE3 transport, establishing a physical/functional coupling. ► Hypertrophic rat hearts showed elevated CAXIV protein expression. ► AE-mediated HCO3fluxes increased in the hypertrophic myocardium compared to normal. ► AE3/CAXIV complex formation would render AE3 hyperactive in the hypertrophic heart.
Stimulation of the AT2 receptor reduced atherogenesis in ApoE/AT1Adouble knock out mice
Tuesday, January 17th, 2012Publication year: 2011
Source: Journal of Molecular and Cellular Cardiology, Available online 22 December 2011
Vedat Tiyerili, Cornelius F.H. Mueller, Ulrich M. Becher, Thomas Czech, Martin van Eickels, …
AT1 receptor blockers (ARB) and in part ACE inhibitors (ACI) potentially exert beneficial effects on atherogenesis independent of AT1 receptor inhibition. These pleiotropic effects might be related to angiotensin II mediated activation of the AT2 receptor. To analyze this hypothesis we investigated the development of atherosclerosis and the role of ACIs and ARBs in Apolipoprotein E-deficient (ApoE) mice and in ApoE/AT1A receptor double knockout mice (ApoE/AT1A). ApoEmice and ApoE/AT1Amice were fed cholesterol-rich diet for 7 weeks. Vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation were evident in ApoEmice, but were markedly reduced in ApoE/AT1Amice. Concomitant treatment of ApoE/AT1Amice with either telmisartan or ramipril had no additional effect on blood pressure, vascular oxidative stress, AT2 receptor expression, and endothelial function. Remarkably, atherosclerotic lesion formation was increased in ramipril treated ApoE/AT1Amice compared to untreated ApoE/AT1Amice whereas pharmacological AT1 receptor inhibition with Telmisartan had no additional effect on atherogenesis. Moreover, chronic AT2 receptor inhibition with PD123,319 significantly increased plaque development in ApoE/AT1Amice. In additional experiments, direct AT2 receptor stimulation reduced atherogenesis in ApoE/AT1Amice. Taken together, our data demonstrate a relevant antiatherosclerotic role of the AT2 receptor in atherosclerotic mice and provide novel insight in RAS-physiology.
Highlights
► Atherogenesis was increased in ramipril treated ApoE−/−/AT1A−/− mice. ► PD123,319 increased plaque development in ApoE−/−/AT1A−/− mice. ► AT2 receptor confers atheroprotective effects when AT1 receptor action is inhibited. ► Relevant antiatherosclerotic role of the AT2 receptor in atherosclerotic mice.
Homocysteine Induces Cardiomyocyte Dysfunction and Apoptosis through p38 MAPK-Mediated Increase in Oxidant Stress
Tuesday, January 17th, 2012Publication year: 2011
Source: Journal of Molecular and Cellular Cardiology, Available online 29 December 2011
Xu Wang, Lei Cui, Jacob Joseph, Bingbing Jiang, David Pimentel, …
Elevated plasma homocysteine (Hcy) is a risk factor for cardiovascular disease. While Hcy has been shown to promote endothelial dysfunction by decreasing the bioavailability of nitric oxide and increasing oxidative stress in the vasculature, the effects of Hcy on cardiomyocytes remain less understood. In this study we explored the effects of hyperhomocysteinemia (HHcy) on myocardial functionex vivoand examined the direct effects of Hcy on cardiomyocyte function and survivalin vitro. Studies with isolated hearts from wild type and HHcy mice (heterozygous cystathionine-beta synthase deficient mice) demonstrated that HHcy mouse hearts had more severely impaired cardiac relaxation and contractile function and increased cell death following ischemia reperfusion (I/R). In isolated cultured adult rat ventricular myocytes, exposure to Hcy for 24 hours impaired cardiomyocyte contractility in a concentration-dependent manner, and promoted apoptosis as revealed by terminal dUTP nick-end labeling and cleaved caspase-3 immunoblotting. These effects were associated with activation of p38 MAPK, decreased expression of thioredoxin (TRX) protein, and increased production of reactive oxygen species (ROS). Inhibition of p38 MAPK by the selective inhibitor SB203580 (5 μM) prevented all of these Hcy-induced changes. Furthermore, adenovirus-mediated overexpression of TRX in cardiomyocytes significantly attenuated Hcy-induced ROS generation, apoptosis, and impairment of myocyte contractility. Thus, Hcy may increase the risk for CVD not only by causing endothelial dysfunction, but also by directly exerting detrimental effects on cardiomyocytes.
Highlights
► Effects of hyperhomocysteinemia on myocardium are not well understood. ► Ischemia-reperfusion caused worse injury in hyperhomocysteinemic mice. ► Homocysteine impaired contractility and promoted apoptosis in cardiomyocytes. ► Mechanism is via activation of p38MAPK and increase in oxidant stress. ► Overexpression of thioredoxin decreased oxidant stress and rescued cardiomyocytes.
Sexual Dimorphism in Cardiac Triacylglyceride Dynamics in Mice on Long Term Caloric Restriction
Tuesday, January 17th, 2012Publication year: 2011
Source: Journal of Molecular and Cellular Cardiology, Available online 2 December 2011
Natasha H. Banke, Lin Yan, Kayla M. Pound, Sunil Dhar, Heather Reinhardt, …
Human studies indicate augmented myocardial lipid metabolism in females, and that sex and obesity interact to predict myocardial fatty acid oxidation and storage. Altered lipid dynamics precede cardiomyopathies, and many studies now address high fat diets. Conversely, caloric restriction (CR), is the most studied model for longevity and stress resistance, including protection against myocardial ischemia. However, no information exists on the effects of long-term caloric restriction (CR) on triacylglyceride (TAG) content and dynamics in the heart. This study explored the effects of CR, sex and age on TAG dynamics in mouse hearts. Male and female SVJ129 mice were fed either normal (ND) or CR diet for 3 or 10 months. In 5-month-old mice, CR similarly decreased cardiac TAG in males (ND: 25.5 +/− 4.5 nanomoles/mg protein; CR: 12.6 +/− 2.7, P < 0.05) and females (ND: 30.1 +/− 4.4; CR: 13.7 +/− 1.2) (no significant differences in TAG content were seen between sexes). CR reduced the contribution of exogenous palmitate to oxidative metabolism in males and females, by 15% and 11% respectively, versus ND, without affecting cardiac workload. CR also induced a larger reduction in TAG turnover in male (68%) than female hearts (38%). Interestingly, in 5 month old male mice, CR reproduced the lower TAG turnover rates of middle-aged males (ND 13-month-old male = 423 +/−76 nanomoles/mg protein/min). Thus, long term CR reduces TAG pool dynamics. Despite reduced content, hearts of female mice subjected to CR retained a more dynamic TAG pool than males, while males respond with greater metabolic remodeling of cardiac lipid dynamics.
Highlights
► The current manuscript compares the effects of gender and age on TAG dynamics in the myocardium after long-term caloric restriction. ► Long-term CR results in a reduction of endogenous lipid stores and a significant decrease in TAG turnover. ► In female myocardium, TAG turnover does not decrease to the same extent as in male myocardium. ► The female myocardium preserves TAG involvement in lipid metabolism.
Soluble epoxide hydrolase inhibition improves myocardial perfusion and function in experimental heart failure
Tuesday, January 17th, 2012Publication year: 2011
Source: Journal of Molecular and Cellular Cardiology, Available online 6 December 2011
Nassiba Merabet, Jeremy Bellien, Etienne Glevarec, Lionel Nicol, Daniele Lucas, …
ObjectivesThe study addressed the hypothesis that soluble epoxide hydrolase (sEH) inhibition, which increases cardiovascular protective epoxyeicosatrienoic acids (EETs), exerts beneficial effects in an established chronic heart failure (CHF) model.MethodsIn CHF rats, left ventricular (LV) function, perfusion and remodeling were assessed using MRI and invasive hemodynamics after 42-days (starting 8 days after coronary ligation) and delayed 3-days (starting 47 days after coronary ligation) treatment with the sEH inhibitor AUDA (twice 0.25 mg/day).ResultsDelayed 3-days and 42-days AUDA increased plasma EETs demonstrating the effective inhibition of sEH. Delayed 3-days and 42-days AUDA enhanced cardiac output without change in arterial pressure, thus reducing total peripheral resistance. Both treatment periods increased the slope of the LV end-systolic pressure-volume relation, but only 42-days AUDA decreased LV end-diastolic pressure, relaxation constant Tau and the slope of the LV end-diastolic pressure-volume relation, associated with a reduced LV diastolic volume and collagen density. Delayed 3-days and, to a larger extent, 42-days AUDA increased LV perfusion associated with a decreased LV hypoxia-inducible factor-1alpha. Both treatment periods decreased reactive oxygen species level and increased reduced-oxidized glutathione ratio. Finally, MSPPOH, an inhibitor of the EETs-synthesizing enzyme cytochrome epoxygenases, abolished the beneficial effects of 3-days AUDA on LV function and perfusion.ConclusionsAugmentation of EETs availability by pharmacological inhibition of sEH increases LV diastolic and systolic function in established CHF. This notably results from short-term processes,i.e.increased LV perfusion, reduced LV oxidative stress and peripheral vasodilatation, but also from long-term effects,i.e.reduced LV remodeling.
Highlights
► We studied the effects of a soluble epoxide hydrolase inhibitor in heart failure rats ► The inhibitor induced an increase in epoxyeicosatrienoic acids bioavailability ► This was associated with an improvement in systolic and diastolic cardiac function ► Enhanced cardiac perfusion and reduced oxidative stress contributed to this effect ► This pharmacological strategy represents a promising approach to treat heart failure
The cardiac sympathetic co-transmitter galanin reduces acetylcholine release and vagal bradycardia: Implications for neural control of cardiac excitability
Tuesday, January 17th, 2012Publication year: 2011
Source: Journal of Molecular and Cellular Cardiology, Available online 7 December 2011
Neil Herring, James Cranley, Michael N. Lokale, Dan Li, Julia Shanks, …
The autonomic phenotype of congestive cardiac failure is characterised by high sympathetic drive and impaired vagal tone, which are independent predictors of mortality. We hypothesize that impaired bradycardia to peripheral vagal stimulation following high-level sympathetic drive is due to sympatho-vagal crosstalk by the adrenergic co-transmitters galanin and neuropeptide-Y (NPY). Moreover we hypothesize that galanin acts similarly to NPY by reducing vagal acetylcholine release via a receptor mediated, protein kinase-dependent pathway. Prolonged right stellate ganglion stimulation (10 Hz, 2 minutes, in the presence of 10 μM metoprolol) in an isolated guinea pig atrial preparation with dual autonomic innervation leads to a significant (p < 0.05) reduction in the magnitude of vagal bradycardia (5 Hz) maintained over the subsequent 20 minutes (n = 6). Immunohistochemistry demonstrated the presence of galanin in a small number of tyrosine hydroxylase positive neurons from freshly dissected stellate ganglion tissue sections. Following 3 days of tissue culture however, all stellate neurons expressed galanin. Stellate stimulation caused the release of low levels of galanin and significantly higher levels of NPY into the surrounding perfusate (n = 6, using ELISA). The reduction in vagal bradycardia post sympathetic stimulation was partially reversed by the galanin receptor antagonist M40 after 10 minutes (1 μM, n = 5), and completely reversed with the NPY Y2receptor antagonist BIIE 0246 at all time points (1 μM, n = 6). Exogenous galanin (n = 6, 50–500 nM) also reduced the heart rate response to vagal stimulation but had no effect on the response to carbamylcholine that produced similar degrees of bradycardia (n = 6). Galanin (500 nM) also significantly attenuated the release ofH-acetylcholine from isolated atria during field stimulation (5 Hz, n = 5). The effect of galanin on vagal bradycardia could be abolished by the galanin receptor antagonist M40 (n = 5). Importantly the GalR1receptor was immunofluorescently co-localized with choline acetyl-transferase containing neurons at the sinoatrial node. The protein kinase C inhibitor calphostin (100 nM, n = 6) abolished the effect of galanin on vagal bradycardia whilst the protein kinase A inhibition H89 (500 nM, n = 6) had no effect. These results demonstrate that prolonged sympathetic activation releases the slowly diffusing adrenergic co-transmitter galanin in addition to NPY, and that this contributes to the attenuation in vagal bradycardia via a reduction in acetylcholine release. This effect is mediated by GalR1receptors on vagal neurons coupled to protein kinase C dependent signaling pathways. The role of galanin may become more important following an acute injury response where galanin expression is increased.
Highlights
► Galanin is found in guinea pig stellate neurons and GalR1 on cardiac vagal neurons ► Stellate galanin expression increases following 3 days of cell culture ► High level sympathetic stimulation releases galanin which reduces vagal bradycardia ► Galanin reduces acetylcholine release and bradycardia via a GalR1dependent pathway ► Galanin signals via protein kinase C rather than protein kinase A dependent pathways.
MicroRNA-20a inhibits stress-induced cardiomyocyte apoptosis involving its novel target Egln3/PHD3
Tuesday, January 17th, 2012Publication year: 2011
Source: Journal of Molecular and Cellular Cardiology, Available online 11 December 2011
Derk Frank, Johanne Gantenberg, Inka Boomgaarden, Christian Kuhn, Rainer Will, …
Excessive stress, e.g. due to biomechanical overload or ischemia/reperfusion is a potent inductor of cardiomyocyte apoptosis, which contributes to maladaptive remodeling. Despite substantial progress in the understanding of the molecular pathophysiology, many components of the signaling pathways underlying remodeling in general and apoptosis in particular still remain unknown. Recent evidence suggests that microRNAs (miRs) play an important role in the heart´s response to increased cardiac stress.To identify novel modulators of stress-dependent remodeling, we conducted a genome-wide miR-screen of mechanically stretched neonatal rat cardiomyocytes (NRCM). Out of 351 miRs, eight were significantly regulated by biomechanical stress, including microRNA-20a, which is part of the miR17 ~ 92 cluster. Interestingly, further expression analyses also revealed upregulation of microRNA-20a in anin vitrohypoxia/”reperfusion” model. Given the potential apoptosis-modulating properties of the miR17 ~ 92 cluster, we subjected NRCM to hypoxia and subsequent reoxygenation. AdmiR-20a significantly inhibited hypoxia-mediated apoptosis in a dose-dependent fashion, while targeted knockdown of miR-20a in NRCM induced cardiomyocyte apoptosis. Mechanistically, the antiapoptotic effect of miR-20a appears to be mediated through direct targeting and subsequent downregulation of the proapoptotic factor Egln3.Thus, miR-20a is upregulated in acute biomechanical stress as well as hypoxia and inhibits apoptosis in cardiomyocytes. These properties reveal miR-20a as a cardioprotective micro-RNA and a potential target for novel therapeutic strategies to prevent cardiac remodeling.
Highlights
► Excessive stress, such as ischemia, is a potent inductor of cardiomyocyte apoptosis. ► In a genome-wide screen for differentially regulated microRNAs in stressed cardiomyocytes we identified miR-20a ► MiR-20a inhibited hypoxia-mediated apoptosis, while knockdown of miR-20a induced cardiomyocyte apoptosis. ► The antiapoptotic effect of miR-20a appears to be mediated through direct targeting of the proapoptotic factor Egln3.
Transcription coactivator Eya2 is a critical regulator of physiological hypertrophy
Tuesday, January 17th, 2012Publication year: 2011
Source: Journal of Molecular and Cellular Cardiology, Available online 14 December 2011
Seung Hee Lee, Jooyeon Kim, Joo Young Ryu, Suho Lee, Dong Kwon Yang, …
Despite its significant clinical implications, physiological hypertrophy remains poorly understood. In this study, the transcription coactivator Eya2 was shown to be up-regulated during physiological hypertrophy. Transgene- or adenovirus-mediated overexpression of Eya2 led to up-regulation of mTOR, a critical mediator of physiological hypertrophy. Luciferase reporter and chromatin immunoprecipitation assays revealed that Eya2 directly binds to and activates mTOR expression. The phosphorylation of mTOR downstream molecules was significantly enhanced in Eya2 transgenic (TG) hearts, implying that the Eya2-mediated induction of mTOR expression leads to an elevated mTOR activity. The transcription factor Six1 was also up-regulated during physiological hypertrophy and formed a complex with Eya2. Luciferase reporter and electrophoretic mobility shift assays revealed that the Eya2-Six1 complex binds to and enhances the expression of mTOR in a synergistic manner. Under pressure overload, Eya2 transgenic hearts developed hypertrophy which exhibited important molecular signatures of physiological hypertrophy, as assessed by gene expression profiling and measurements of expression levels of physiological hypertrophy-related genes by quantitative (q) RT-PCR. Examination of heart sections under electron microscopy revealed that the mitochondrial integrity remained largely intact in Eya2 transgenic mice, but not in wild-type littermates, under pressure overload. This finding was confirmed by measurements of mitochondrial DNA contents and the expression levels of mitochondrial function-related genes by qRT-PCR. These data suggest that Eya2 in a physical complex with Six1 plays a critical role in physiological hypertrophy. The cardioprotective effect of Eya2 appears to be due, at least in part, to its preservation of mitochondrial integrity upon pressure overload.
Highlights
► Eya2 directly regulates the expression of mTOR during physiological hypertrophy. ► Eya2 and Six1 synergistically up-regulate mTOR expression. ► Eya2 TG exhibits characteristics of physiological cardiac hypertrophy. ► Mitochondrial integrity is preserved in Eya2 TG hearts under pressure overload. ► Activation of Eya2 and Six1 transcriptional complex is cardioprotective.
Pathophysiology of the cardiac late Na Current and its potential as a drug target
Tuesday, January 17th, 2012Publication year: 2011
Source: Journal of Molecular and Cellular Cardiology, Available online 16 December 2011
Jonathan D. Moreno, Colleen E. Clancy
A pathological increase in the late component of the cardiac Nacurrent, INaL, has been linked to disease manifestation in inherited and acquired cardiac diseases including the long QT variant 3 (LQT3) syndrome and heart failure. Disruption in INaLleads to action potential prolongation, disruption of normal cellular repolarization, development of arrhythmia triggers, and propensity to ventricular arrhythmia. Attempts to treat arrhythmogenic sequelae from inherited and acquired syndromes pharmacologically with common Nachannel blockers (e.g. flecainide, lidocaine, and amiodarone) have been largely unsuccessful. This is due to drug toxicity and the failure of most current drugs to discriminate between the peak current component, chiefly responsible for single cell excitability and propagation in coupled tissue, and the late component (INaL) of the Nacurrent. Although small in magnitude as compared to the peak Nacurrent (~ 1 – 3%), INaLalters action potential properties and increases Naloading in cardiac cells. With the increasing recognition that multiple cardiac pathological conditions share phenotypic manifestations of INaLupregulation, there has been renewed interest in specific pharmacological inhibition of INa.The novel antianginal agent ranolazine, which shows a marked selectivity for late versus peak Nacurrent, may represent a novel drug archetype for targeted reduction of INaL. This article aims to review common pathophysiological mechanisms leading to enhanced INaLin LQT3 and heart failure as prototypical disease conditions. Also reviewed are promising therapeutic strategies tailored to alter the molecular mechanisms underlying INamediated arrhythmia triggers.
Highlights
► INaLcan disrupt cellular repolarization and increase propensity to ventricular arrhythmia. ► Although small compared to peak Nacurrent, INaLincreases Naloading in cardiac cells. ► Multiple cardiac pathological conditions share phenotypic manifestations of INaLupregulation. ► Specific pharmacological inhibition of INais desired