共查询到20条相似文献,搜索用时 15 毫秒
1.
Mei-pian Chen Z. Ioav Cabantchik Shing Chan Godfrey Chi-fung Chan Yiu-fai Cheung 《PloS one》2014,9(11)
Background
Iron overload cardiomyopathy that prevails in some forms of hemosiderosis is caused by excessive deposition of iron into the heart tissue and ensuing damage caused by a raise in labile cell iron. The underlying mechanisms of iron uptake into cardiomyocytes in iron overload condition are still under investigation. Both L-type calcium channels (LTCC) and T-type calcium channels (TTCC) have been proposed to be the main portals of non-transferrinic iron into heart cells, but controversies remain. Here, we investigated the roles of LTCC and TTCC as mediators of cardiac iron overload and cellular damage by using specific Calcium channel blockers as potential suppressors of labile Fe(II) and Fe(III) ingress in cultured cardiomyocytes and ensuing apoptosis.Methods
Fe(II) and Fe(III) uptake was assessed by exposing HL-1 cardiomyocytes to iron sources and quantitative real-time fluorescence imaging of cytosolic labile iron with the fluorescent iron sensor calcein while iron-induced apoptosis was quantitatively measured by flow cytometry analysis with Annexin V. The role of calcium channels as routes of iron uptake was assessed by cell pretreatment with specific blockers of LTCC and TTCC.Results
Iron entered HL-1 cardiomyocytes in a time- and dose-dependent manner and induced cardiac apoptosis via mitochondria-mediated caspase-3 dependent pathways. Blockade of LTCC but not of TTCC demonstrably inhibited the uptake of ferric but not of ferrous iron. However, neither channel blocker conferred cardiomyocytes with protection from iron-induced apoptosis.Conclusion
Our study implicates LTCC as major mediators of Fe(III) uptake into cardiomyocytes exposed to ferric salts but not necessarily as contributors to ensuing apoptosis. Thus, to the extent that apoptosis can be considered a biological indicator of damage, the etiopathology of cardiosiderotic damage that accompanies some forms of hemosiderosis would seem to be unrelated to LTCC or TTCC, but rather to other routes of iron ingress present in heart cells. 相似文献2.
Background
Cancer has continually been the leading cause of death worldwide for decades. Thus, scientists have actively devoted themselves to studying cancer therapeutics. Doxorubicin is an efficient drug used in cancer therapy, but also produces reactive oxygen species (ROS) that induce severe cytotoxicity against heart cells. Quercetin, a plant-derived flavonoid, has been proven to contain potent antioxidant and anti-inflammatory properties. Thus, this in vitro study investigated whether quercetin can decrease doxorubicin-induced cytotoxicity and promote cell repair systems in cardiomyocyte H9C2 cells.Results
Proteomic analysis and a cell biology assay were performed to investigate the quercetin-induced responses. Our data demonstrated that quercetin treatment protects the cardiomyocytes in a doxorubicin-induced heart damage model. Quercetin significantly facilitated cell survival by inhibiting cell apoptosis and maintaining cell morphology by rearranging the cytoskeleton. Additionally, 2D-DIGE combined with MALDI-TOF MS analysis indicated that quercetin might stimulate cardiomyocytes to repair damage after treating doxorubicin by modulating metabolic activation, protein folding and cytoskeleton rearrangement.Conclusion
Based on a review of the literature, this study is the first to report detailed protective mechanisms for the action of quercetin against doxorubicin-induced cardiomyocyte toxicity based on in-depth cell biology and proteomic analysis. 相似文献3.
4.
Yuan-Wu Chen Hsu-Shan Huang Yi-Shing Shieh Kuo-Hsing Ma Shing-Hwa Huang Dueng-Yuan Hueng Huey-Kang Sytwu Gu-Jiun Lin 《PloS one》2014,9(8)
Objective
Oral squamous cell carcinoma (OSCC) is a prevalent cancer, especially in developing countries. Anthracyclines and their anthraquinone derivatives, such as doxorubicin, exhibit a cell growth inhibitory effect and have been used as anti-cancer drugs for many years. However, the cardiotoxicity of anthracycline antibiotics is a major concern in their clinical application. NSC745885 is a novel compound synthesized from 1,2-diaminoanthraquinone, which subsequently reacts with thionyl chloride and triethylamine. The present study aimed to investigate the anti-oral cancer potential and the safety of NSC745885.Methods
We investigated the anti-cancer potential of NSC745885 in oral squamous carcinoma cell lines and in an in vivo oral cancer xenograft mouse model. The expression of apoptotic related genes were evaluated by real-time RT-PCR and western bloting, and the in vivo assessment of apoptotic marker were measured by immunohistochemical staining. The anti-tumor efficiency and safety between doxorubicin and NSC745885 were also compared.Results
Our results demonstrated that NSC745885 exhibits anti-oral cancer activity through the induction of apoptosis in cancer cells and in tumor-bearing mice, and this treatment did not induce marked toxicity in experimental mice. This compound also exhibits a comparable anti-tumor efficiency and a higher safety in experimental mice when compared to doxorubicin.Conclusions
The data of this study provide evidence for NSC745885 as a potential novel therapeutic drug for the treatment of human OSCC. 相似文献5.
Rehana Qureshi Onur Yildirim Adeline Gasser Christine Basmadjian Qian Zhao Jean-Philippe Wilmet Laurent Désaubry Canan G. Nebigil 《PloS one》2015,10(11)
Aims
The clinical use of doxorubicin for the treatment of cancer is limited by its cardiotoxicity. Flavaglines are natural products that have both potent anticancer and cardioprotective properties. A synthetic analog of flavaglines, FL3, efficiently protects mice from the cardiotoxicity of doxorubicin. The mechanism underlying this cardioprotective effect has yet to be elucidated.Methods and Results
Here, we show that FL3 binds to the scaffold proteins prohibitins (PHBs) and thus promotes their translocation to mitochondria in the H9c2 cardiomyocytes. FL3 induces heterodimerization of PHB1 with STAT3, thereby ensuring cardioprotection from doxorubicin toxicity. This interaction is associated with phosphorylation of STAT3. A JAK2 inhibitor, WP1066, suppresses both the phosphorylation of STAT3 and the protective effect of FL3 in cardiomyocytes. The involvement of PHBs in the FL3-mediated cardioprotection was confirmed by means of small interfering RNAs (siRNAs) targeting PHB1 and PHB2. The siRNA knockdown of PHBs inhibits both phosphorylation of STAT3 and the cardioprotective effect of FL3.Conclusion
Activation of mitochondrial STAT3/PHB1 complex by PHB ligands may be a new strategy against doxorubicin-induced cardiotoxicity and possibly other cardiac problems. 相似文献6.
Long Wu Jun Xu Weiqi Yuan Baojian Wu Hao Wang Guangquan Liu Xiaoxiong Wang Jun Du Shaohui Cai 《PloS one》2014,9(11)
Purpose
P-glycoprotein mediated efflux is one of the main mechanisms for multidrug resistance in cancers, and 3-Bromopyruvate acts as a promising multidrug resistance reversal compound in our study. To test the ability of 3-Bromopyruvate to overcome P-glycoprotein-mediated multidrug resistance and to explore its mechanisms of multidrug resistance reversal in MCF-7/ADR cells, we evaluate the in vitro and in vivo modulatory activity of this compound.Methods
The in vitro and in vivo activity was determined using the MTT assay and human breast cancer xenograft models. The gene and protein expression of P-glycoprotein were determined using real-time polymerase chain reaction and the Western blotting technique, respectively. ABCB-1 bioactivity was tested by fluorescence microscopy, multi-mode microplate reader, and flow cytometry. The intracellular levels of ATP, HK-II, and ATPase activity were based on an assay kit according to the manufacturer’s instructions.Results
3-Bromopyruvate treatment led to marked decreases in the IC50 values of selected chemotherapeutic drugs [e.g., doxorubicin (283 folds), paclitaxel (85 folds), daunorubicin (201 folds), and epirubicin (171 folds)] in MCF-7/ADR cells. 3-Bromopyruvate was found also to potentiate significantly the antitumor activity of epirubicin against MCF-7/ADR xenografts. The intracellular level of ATP decreased 44%, 46% in the presence of 12.5.25 µM 3-Bromopyruvate, whereas the accumulation of rhodamine 123 and epirubicin (two typical P-glycoprotein substrates) in cells was significantly increased. Furthermore, we found that the mRNA and the total protein level of P-glycoprotein were slightly altered by 3-Bromopyruvate. Moreover, the ATPase activity was significantly inhibited when 3-Bromopyruvate was applied.Conclusion
We demonstrated that 3-Bromopyruvate can reverse P-glycoprotein-mediated efflux in MCF-7/ADR cells. Multidrug resistance reversal by 3-Bromopyruvate occurred through at least three approaches, namely, a decrease in the intracellular level of ATP and HK-II bioactivity, the inhibition of ATPase activity, and the slight decrease in P-glycoprotein expression in MCF-7/ADR cells. 相似文献7.
Menglei Huan Bangle Zhang Zenghui Teng Han Cui Jieping Wang Xinyou Liu Hui Xia Siyuan Zhou Qibing Mei 《PloS one》2012,7(9)
Background
Conventional chemotherapy agent such as doxorubicin (DOX) is of limited clinical use because of its inherently low selectivity, which can lead to systemic toxicity in normal healthy tissue.Methods
A pH stimuli-sensitive conjugate based on polyethylene glycol (PEG) with covalently attachment doxorubicin via hydrazone bond (PEG-hyd-DOX) was prepared for tumor targeting delivery system. While PEG-DOX conjugates via amid bond (PEG-ami-DOX) was synthesized as control.Results
The synthetic conjugates were confirmed by proton nuclear magnetic resonance (NMR) spectroscopy, the release profile of DOX from PEG-hyd-DOX was acid-liable for the hydrazone linkage between DOX and PEG, led to different intracellular uptake route; intracellular accumulation of PEG-hyd-DOX was higher than PEG-ami-DOX due to its pH-triggered profile, and thereby more cytotoxicity against MCF-7, MDA-MB-231 (breast cancer models) and HepG2 (hepatocellular carcinoma model) cell lines. Following the in vitro results, we xenografted MDA-MB-231 cell onto SCID mice, PEG-hyd-DOX showed stronger antitumor efficacy than free DOX and was tumor-targeting.Conclusions
Results from these in vivo experiments were consistent with our in vitro results; suggested this pH-triggered PEG-hyd-DOX conjugate could target DOX to tumor tissues and release free drugs by acidic tumor environment, which would be potent in antitumor drug delivery. 相似文献8.
Stephanie Morgan Federica Lopes Charlie Gourley Richard A. Anderson Norah Spears 《PloS one》2013,8(7)
Purpose
Chemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin) were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined.Experimental design
Newborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect.Results
Histological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001) and doxorubicin (3 fold, p<0.01). TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01) but not against doxorubicin treatment.Conclusion
Cisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s) the patient is exposed to. 相似文献9.
Shih-Yi Lee Hui-Chun Ku Yueh-Hsiung Kuo Kai-Chien Yang Ping-Chen Tu His-Lin Chiu Ming-Jai Su 《Journal of biomedical science》2015,22(1)
Background
Cardiac oxidative stress, bioenergetics and catecholamine play major roles in heart failure progression. However, the relationships between these three dominant heart failure factors are not fully elucidated. Caffeic acid ethanolamide (CAEA), a synthesized derivative from caffeic acid that exerted antioxidative properties, was thus applied in this study to explore its effects on the pathogenesis of heart failure.Results
In vitro studies in HL-1 cells exposed to isoproterenol showed an increase in cellular and mitochondria oxidative stress. Two-week isoproterenol injections into mice resulted in ventricular hypertrophy, myocardial fibrosis, elevated lipid peroxidation, cardiac adenosine triphosphate and left ventricular ejection fraction decline, suggesting oxidative stress and bioenergetics changes in catecholamine-induced heart failure. CAEA restored oxygen consumption rates and adenosine triphosphate contents. In addition, CAEA alleviated isoproterenol-induced cardiac remodeling, cardiac oxidative stress, cardiac bioenergetics and function insufficiency in mice. CAEA treatment recovered sirtuin 1 and sirtuin 3 activity, and attenuated the changes of proteins, including manganese superoxide dismutase and hypoxia-inducible factor 1-α, which are the most likely mechanisms responsible for the alleviation of isoproterenol-caused cardiac injuryConclusion
CAEA prevents catecholamine-induced cardiac damage and is therefore a possible new therapeutic approach for preventing heart failure progression. 相似文献10.
Sabrina Greulich Weena J. Y. Chen Bujar Maxhera Luuk J. Rijzewijk Rutger W. van der Meer Jacqueline T. Jonker Heidi Mueller Daniella Herzfeld de Wiza Ralf-Ruediger Floerke Konstantinos Smiris Hildo J. Lamb Albert de Roos Jeroen J. Bax Johannes A. Romijn Jan W. A. Smit Payam Akhyari Artur Lichtenberg Juergen Eckel Michaela Diamant D. Margriet Ouwens 《PloS one》2013,8(3)
Context
Adipokines are linked to the development of cardiovascular dysfunction in type 2 diabetes (DM2). In DM2-patients, circulating levels of omentin-1, an adipokine preferentially expressed in epicardial adipose tissue, are decreased. This study investigated whether omentin-1 has a cardioprotective function.Methods
Omentin-1 levels in plasma and cardiac fat depots were determined in DM2-patients versus controls. Moreover, the relation between omentin-1 levels and cardiac function was examined in men with uncomplicated DM2. Finally, we determined whether omentin-1 could reverse the induction of cardiomyocyte dysfunction by conditioned media derived from epicardial adipose tissue from patients with DM2.Results
Omentin-1 was highly expressed and secreted by epicardial adipose tissue, and reduced in DM2. Circulating omentin-1 levels were lower in DM2 versus controls, and positively correlated with the diastolic parameters early peak filling rate, early deceleration peak and early deceleration mean (all P<0.05). The improved diastolic function following pioglitazone treatment associated with increases in omentin-1 levels (P<0.05). In vitro, exposure of cardiomyocytes to conditioned media derived from epicardial adipose tissue from patients with DM2 induced contractile dysfunction and insulin resistance, which was prevented by the addition of recombinant omentin.Conclusion
These data identify omentin-1 as a cardioprotective adipokine, and indicate that decreases in omentin-1 levels could contribute to the induction of cardiovascular dysfunction in DM2. 相似文献11.
12.
Hellman U Malm L Ma LP Larsson G Mörner S Fu M Engström-Laurent A Waldenström A 《PloS one》2010,5(12):e14393
Background
Hyaluronan (HA) is a glycosaminoglycan located in the interstitial space which is essential for both structural and cell regulatory functions in connective tissue. We have previously shown that HA synthesis is up-regulated in a rat model of experimental cardiac hypertrophy and that cardiac tissue utilizes two different HA synthases in the hypertrophic process. Cardiomyocytes and fibroblasts are two major cell types in heart tissue. The fibroblasts are known to produce HA, but it has been unclear if cardiomyocytes share the same feature, and whether or not the different HA synthases are activated in the different cell types.Methodology/Principal Findings
This study shows, for the first time that cardiomyocytes can produce HA. Cardiomyocytes (HL-1) and fibroblasts (NIH 3T3) were cultivated in absence or presence of the growth factors FGF2, PDGF-BB and TGFB2. HA concentration was quantified by ELISA, and the size of HA was estimated using dynamic light scattering. Cardiomyocytes synthesized HA but only when stimulated by PDGF-BB, whereas fibroblasts synthesized HA without addition of growth factors as well as when stimulated by any of the three growth factors. When fibroblasts were stimulated by the growth factors, reverse dose dependence was observed, where the highest dose induced the least amount of HA. With the exception of TGFB2, a trend of reverse dose dependence of HA size was also observed.Conclusions/Significance
Co-cultivation of cardiomyocytes and fibroblasts (80%/20%) increased HA concentration far more that can be explained by HA synthesis by the two cell types separately, revealing a crosstalk between cardiomyocytes and fibroblasts that induces HA synthesis. We conclude that dynamic changes of the myocardium, such as in cardiac hypertrophy, do not depend on the cardiomyocyte alone, but are achieved when both cardiomyocytes and fibroblasts are present. 相似文献13.
Hong-zhu Li Jin Guo Jun Gao Li-ping Han Chun-ming Jiang Hong-xia Li Shu-zhi Bai Wei-hua Zhang Guang-wei Li Li-na Wang Hong Li Ya-jun Zhao Yan Lin Ye Tian Guang-dong Yang Rui Wang Ling-yun Wu Bao-feng Yang Chang-qing Xu 《Journal of biomedical science》2011,18(1):18
Background
Myocardial ischemia/reperfusion injury is the major cause of morbidity and mortality for cardiovascular diseases. Dopamine D2 receptors are expressed in cardiac tissues. However, the roles of dopamine D2 receptors in myocardial ischemia/reperfusion injury and cardiomyocyte apoptosis are unclear. Here we investigated the effects of both dopamine D2 receptors agonist (bromocriptine) and antagonist (haloperidol) on apoptosis of cultured neonatal rat ventricular myocytes induced by ischemia/reperfusion injury.Methods
Myocardial ischemia/reperfusion injury was simulated by incubating primarily cultured neonatal rat cardiomyocytes in ischemic (hypoxic) buffer solution for 2 h. Thereafter, these cells were incubated for 24 h in normal culture medium.Results
Treatment of the cardiomyocytes with 10 μM bromocriptine significantly decreased lactate dehydrogenase activity, increased superoxide dismutase activity, and decreased malondialdehyde content in the culture medium. Bromocriptine significantly inhibited the release of cytochrome c, accumulation of [Ca2+]i, and apoptosis induced by ischemia/reperfusion injury. Bromocriptine also down-regulated the expression of caspase-3 and -9, Fas and Fas ligand, and up-regulated Bcl-2 expression. In contrast, haloperidol (10 μM) had no significant effects on the apoptosis of cultured cardiomyocytes under the aforementioned conditions.Conclusions
These data suggest that activation of dopamine D2 receptors can inhibit apoptosis of cardiomyocytes encountered during ischemia/reperfusion damage through various pathways. 相似文献14.
Aims
Integrin-linked kinase (ILK) is a multifunctional kinase linking the extracellular matrix to intracellular signaling pathways, whose activation in the heart gives rise to a number of functional consequences. The aim of this study is to demonstrate the therapeutic and survival benefit of cardiac ILK overexpression in a rat model of dilated cardiomyopathy.Methods and Results
The dilated cardiomyopathy model was generated in rats by intraperitoneal administration of six equal doses of doxorubicin over a 2 week period. Five weeks after the first injection, echocardiographic analysis demonstrated impaired cardiac function and, at that point, recombinant adenoviral vector harboring ILK cDNA or vehicle was injected into the myocardium, and the rats re-studied 4 weeks later. Compared with vehicle injection, ILK treatment ameliorated inflammatory cell infiltration and cardiomyocyte degeneration, as well as left ventricular dilation and dysfunction. ILK treatment was also associated with a reduction in apoptosis and an increase in proliferation of cardiomyocytes, as well as decreased oxidative stress and autophagic vacuole accumulation. Importantly, mortality was lower in rats following ILK treatment than in those following vehicle injection. In cultured neonatal rat cardiomyocytes, we also found that ILK overexpression protected against doxorubicin-induced apoptosis, giving rise to an increase in their proliferation.Conclusions
These data demonstrate for the first time that ILK gene therapy improves cardiac function and survival in a model of dilated cardiomyopathy, and this may be mediated through suppression of inflammation, prevention of ventricular remodeling, inhibition of cardiomyocyte apoptosis and autophagy, and stimulation of cardiomyocyte proliferation. 相似文献15.
Miteva K Haag M Peng J Savvatis K Becher PM Seifert M Warstat K Westermann D Ringe J Sittinger M Schultheiss HP Tschöpe C Van Linthout S 《PloS one》2011,6(12):e28513
Background
Under conventional heart failure therapy, inflammatory cardiomyopathy typically has a progressive course, indicating a need for alternative therapeutic strategies to improve long-term outcomes. We recently isolated and identified novel cardiac-derived cells from human cardiac biopsies: cardiac-derived adherent proliferating cells (CAPs). They have similarities with mesenchymal stromal cells, which are known for their anti-apoptotic and immunomodulatory properties. We explored whether CAPs application could be a novel strategy to improve acute Coxsackievirus B3 (CVB3)-induced myocarditis.Methodology/Principal Findings
To evaluate the safety of our approach, we first analyzed the expression of the coxsackie- and adenovirus receptor (CAR) and the co-receptor CD55 on CAPs, which are both required for effective CVB3 infectivity. We could demonstrate that CAPs only minimally express both receptors, which translates to minimal CVB3 copy numbers, and without viral particle release after CVB3 infection. Co-culture of CAPs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis and viral progeny release. In addition, CAPs reduced CD4 and CD8 T cell proliferation. All CAPs-mediated protective effects were nitric oxide- and interleukin-10-dependent and required interferon-γ. In an acute murine model of CVB3-induced myocarditis, application of CAPs led to a decrease of cardiac apoptosis, cardiac CVB3 viral load and improved left ventricular contractility parameters. This was associated with a decline in cardiac mononuclear cell activity, an increase in T regulatory cells and T cell apoptosis, and an increase in left ventricular interleukin-10 and interferon-γ mRNA expression.Conclusions
We conclude that CAPs are a unique type of cardiac-derived cells and promising tools to improve acute CVB3-induced myocarditis. 相似文献16.
Enkui Hao Fangfang Lang Yong Chen Huilin Zhang Xiao Cong Xiaoqian Shen Guohai Su 《PloS one》2013,8(7)
Background/Aims
Septic cardiomyopathy is a severe condition that remains a challenge for clinical management. This study investigated whether the natural polyphenolic compound resveratrol could be used as a prophylactic treatment to alleviate sepsis-related myocardial injury; the underlying molecular mechanisms were deciphered by both in vitro and in vivo experiments.Methods
A mouse model of endotoxin-induced cardiomyopathy was developed by intraperitoneal injection of LPS, and resveratrol was administered prophylatically to the animals. Serum LDH and CK activities were measured to detect myocardial injury, and echocardiography was performed to monitor cardiac structure and function. Various cytokines/chemokines and the Nrf2 antioxidant defense system were examined in the heart tissue. The effects of resveratrol on LPS-induced Nrf2 activation, ROS generation, and apoptotic cell death were further investigated in cultured primary human cardiomyocytes. An Nrf2 specific siRNA was used to define its role in resveratrol-mediated cardiomyocyte protective effect.Results
Resveratrol pretreatment significantly attenuated LPS-induced myocardial injury in mice, which was associated with suppressed proinflammatory cytokine production and enhanced Nrf2 activation in the heart. In cultured primary human cardiomyocytes, resveratrol activated Nrf2, inhibited LPS-induced ROS generation, and effectively protected the cells from LPS-induced apoptotic cell death. Knockdown of Nrf2 abrogated resveratrol-mediated protection of the cells from LPS-induced cell death.Conclusion
Resveratrol effectively alleviates endotoxin-induced cardiac toxicity through mechanisms that involve the Nrf2 antioxidant defense pathway. Our data suggest that resveratrol might be developed as a useful prophylactic management for septic cardiomyopathy. 相似文献17.
Koenig X Dysek S Kimbacher S Mike AK Cervenka R Lukacs P Nagl K Dang XB Todt H Bittner RE Hilber K 《PloS one》2011,6(5):e20300
Background
Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is associated with severe cardiac complications including cardiomyopathy and cardiac arrhythmias. Recent research suggests that impaired voltage-gated ion channels in dystrophic cardiomyocytes accompany cardiac pathology. It is, however, unknown if the ion channel defects are primary effects of dystrophic gene mutations, or secondary effects of the developing cardiac pathology.Methodology/Principal Findings
To address this question, we first investigated sodium channel impairments in cardiomyocytes derived from dystrophic neonatal mice prior to cardiomyopahty development, by using the whole cell patch clamp technique. Besides the most common model for DMD, the dystrophin-deficient mdx mouse, we also used mice additionally carrying an utrophin mutation. In neonatal cardiomyocytes, dystrophin-deficiency generated a 25% reduction in sodium current density. In addition, extra utrophin-deficiency significantly altered sodium channel gating parameters. Moreover, also calcium channel inactivation was considerably reduced in dystrophic neonatal cardiomyocytes, suggesting that ion channel abnormalities are universal primary effects of dystrophic gene mutations. To assess developmental changes, we also studied sodium channel impairments in cardiomyocytes derived from dystrophic adult mice, and compared them with the respective abnormalities in dystrophic neonatal cells. Here, we found a much stronger sodium current reduction in adult cardiomyocytes. The described sodium channel impairments slowed the upstroke of the action potential in adult cardiomyocytes, and only in dystrophic adult mice, the QRS interval of the electrocardiogram was prolonged.Conclusions/Significance
Ion channel impairments precede pathology development in the dystrophic heart, and may thus be considered potential cardiomyopathy triggers. 相似文献18.
19.
S. de Haan K. de Boer J. Commandeur A. M. Beek A. C. van Rossum C. P. Allaart 《Netherlands heart journal》2014,22(10):449-455
Objective
Implantable cardioverter defibrillators (ICD) and cardiac resynchronisation therapy (CRT) have substantially improved the survival of patients with cardiomyopathy. Eligibility for this therapy requires a left ventricular ejection fraction (LVEF) <35 %. This is largely based on studies using echocardiography. Cardiac magnetic resonance imaging (CMR) is increasingly utilised for LVEF assessment, but several studies have shown differences between LVEF assessed by CMR and echocardiography. The present study compared LVEF assessment by CMR and echocardiography in a heart failure population and evaluated effects on eligibility for device therapy.Methods
152 patients (106 male, mean age 65.5 ± 9.9 years) referred for device therapy were included. During evaluation of eligibility they underwent both CMR and echocardiographic LVEF assessment. CMR volumes were computed from a stack of short-axis images. Echocardiographic volumes were computed using Simpson’s biplane method.Results
The study population demonstrated an underestimation of end-diastolic volume (EDV) and end-systolic volume (ESV) by echocardiography of 71 ± 53 ml (mean ± SD) and 70 ± 49 ml, respectively. This resulted in an overestimation of LVEF of 6.6 ± 8.3 % by echocardiography compared with CMR (echocardiographic LVEF 31.5 ± 8.7 % and CMR LVEF 24.9 ± 9.6 %). 28 % of patients had opposing outcomes of eligibility for cardiac device therapy depending on the imaging modality used.Conclusion
We found EDV and ESV to be underestimated by echocardiography, and LVEF assessed by CMR to be significantly smaller than by echocardiography. Applying an LVEF cut-off value of 35 %, CMR would significantly increase the number of patients eligible for device implantation. Therefore, LVEF cut-off values might need reassessment when using CMR. 相似文献20.