共查询到20条相似文献,搜索用时 375 毫秒
1.
S. Cetrullo A. Facchini I. Stanic B. Tantini C. Pignatti C. M. Caldarera F. Flamigni 《Amino acids》2010,38(2):525-531
Recent studies have shown that aldosterone may play a critical role in the transition to heart failure and that heart is a
direct target of the action of aldosterone, which can provoke hypertrophy and apoptosis of isolated cardiomyocytes and also
increase the expression of genes that favor tissue fibrosis. Early work from this and other laboratories has established a
link between the aliphatic polyamines and cardiac hypertrophy, while more recently an involvement of polyamines even in cell
death and survival has emerged. In the present study we have treated cardiac cells, i.e. rat H9c2 cardiomyoblasts and neonatal
cardiomyocytes, with (d,l)-2-(difluoromethyl)ornithine, a specific inhibitor of polyamine biosynthesis, to investigate the effects of polyamines in
relation to the hypertrophic, pro-fibrotic and pro-apoptotic actions of aldosterone. The results indicate that inhibition
of polyamine biosynthesis may prevent or attenuate the adverse actions of aldosterone, by modulating the expression of genes
related to cardiac hypertrophy and fibrosis, as well as the levels of proteins and the activities of enzymes that control
apoptosis. 相似文献
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Takao K Rickhag M Hegardt C Oredsson S Persson L 《The international journal of biochemistry & cell biology》2006,38(4):621-628
The polyamines are essential for cellular growth and differentiation. Ornithine decarboxylase (ODC), which catalyses the first step in the biosynthesis of the polyamines, has a very fast turnover and is subject to a strong feedback control by the polyamines. In the present study, we show that overexpression of a metabolically stable ODC in CHO cells induced a massive cell death unless the cells were grown in the presence of the ODC inhibitor alpha-difluoromethylornithine (DFMO). Cells overexpressing wild-type (unstable) ODC, on the other hand, were not dependent on the presence of DFMO for their growth. The induction of cell death was correlated with a dramatic increase in cellular putrescine levels. Analysis using flow cytometry revealed perturbed cell cycle kinetics, with a large accumulation of cells with sub-G1 amounts of DNA, which is a typical sign of apoptosis. Another strong indication of apoptosis was the finding that one of the key enzymes in the apoptotic process, caspase-3, was induced when DFMO was omitted from the growth medium. Furthermore, inhibition of the caspase activity significantly reduced the recruitment of cells to the sub-G1 fraction. In conclusion, deregulation of polyamine homeostasis may negatively affect cell proliferation and eventually lead to cell death by apoptosis if putrescine levels become too high. 相似文献
4.
Expression of constitutively active phosphatidylinositol 3-kinase inhibits activation of caspase 3 and apoptosis of cardiac muscle cells 总被引:7,自引:0,他引:7
Wu W Lee WL Wu YY Chen D Liu TJ Jang A Sharma PM Wang PH 《The Journal of biological chemistry》2000,275(51):40113-40119
Apoptosis of cardiac muscle cells contributes to the development of cardiomyopathy. Recent studies showed that insulin-like growth factor I (IGF-I) inhibits apoptosis of cardiac muscle cells and improves myocardial function in experimental heart failure. This study was carried out to elucidate the role of phosphatidylinositol 3-kinase (PI 3-kinase) in the anti-apoptotic actions of IGF-I in cardiomyocytes and to explore whether expression of constitutively active PI 3-kinase can inhibit apoptosis in cardiomyocytes. Apoptosis of primary cardiomyocytes was induced by doxorubicin treatment and serum withdrawal. Transduction of cardiomyocytes with constitutively active PI 3-kinase specifically lead to serine phosphorylation of Akt, whereas phosphorylation of IGF-I receptor, IRS1/2 and p44/42 mitogen-activated protein kinase were not increased. In the cardiomyocytes transduced with constitutively active PI 3-kinase, activation of the pro-apoptotic caspase 3 was attenuated and fragmentation of DNA was reduced. Preincubating cells with PI 3-kinase inhibitor LY294002 was associated with loss of anti-apoptotic actions of IGF-I and PI 3-kinase. Neither IGF-I nor constitutively active PI 3-kinase lead to serine phosphorylation of Bad, suggesting that the anti-apoptotic effects of PI 3-kinase are not mediated through Bad phosphorylation in cardiac muscle cells. To determine whether activation of caspase 3 is sufficient to induce apoptosis in cardiomyocytes, an engineered TAT-caspase 3 protein was introduced to cardiomyocytes. Significant reduction of cell viability occurred in the cardiomyocytes transduced with active caspase 3, indicating that activation of caspase 3 is sufficient to cause cardiomyocyte death. These findings indicate the existence of an IGF-I receptor-PI 3-kinase-caspase 3 pathway in cardiomyocytes that plays an important role in the anti-apoptotic actions of IGF-I in heart. Moreover, these data suggest that modulation of PI 3-kinase activities may represent a potential therapeutic strategy to counteract the occurrence of apoptosis in cardiomyopathy. 相似文献
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Shi J Gu P Zhu Z Liu J Chen Z Sun X Chen W Gao X Zhang Z 《Biochemical and biophysical research communications》2012,418(4):792-798
Calcium (Ca(2+)) influx through Ca(v)1.2 L-type Ca(2+) channels is an important event for cardiac excitation-contraction (E-C) coupling. The functional regulation of Ca(v)1.2 is controlled by multiple kinases and phosphatases. It has been well documented that phosphorylation of Ca(v)1.2 by PKA or other kinases is sufficient for the upregulation of channel activity. However, little is known about the role of protein phosphatases in counterbalancing the phosphorylation of Ca(v)1.2, especially the degree to which protein phosphatase 2A (PP2A)-mediated dephosphorylation is involved in the regulation of Ca(v)1.2 in the mouse heart. Here, we report a physical interaction between PP2A and the C-terminus of Ca(v)1.2 in mouse heart extracts as revealed by coimmunoprecipitation. This interaction was further confirmed by the observation that PP2A and Ca(v)1.2 are colocalized in isolated mouse cardiomyocytes. Specifically, PP2A was bound at serine 1866 in the C-terminus of Ca(v)1.2, and PP2A-induced Ca(v)1.2 dephosphorylation at serine 1866 was observed in mouse cardiomyocytes. Importantly, the density of L-type calcium current increased in line with the increase in the phosphorylation at serine 1866 of Ca(v)1.2 in cardiac-specific PP2A Cα knockout mice. These phenomena were reproduced by treatment with okadaic acid, a PP2A inhibitor, in H9c2 cells. In summary, our data reveal the functional role of PP2A in cardiac Ca(v)1.2 regulation. 相似文献
7.
Small molecule inhibitors of cyclin-dependent kinases (CDKs) show high therapeutic potential in various cancer types which are characterized by the accumulation of transformed cells due to impaired apoptotic machinery. Roscovitine, a CDK inhibitor showed to be a potent apoptotic inducer in several cancer cells. Polyamines, putrescine, spermidine and spermine, are biogenic amines involved in many cellular processes, including apoptosis. In this study, we explored the potential role of polyamines in roscovitine-induced apoptosis in HCT116 colon cancer cells. Roscovitine induced apoptosis by activating mitochondrial pathway caspases and modulating the expression of Bcl-2 family members. Depletion of polyamines by treatment with difluoromethylornithine (DFMO) increased roscovitine-induced apoptosis. Transient silencing of ornithine decarboxylase, polyamine biosynthesis enzyme and special target of DFMO also increased roscovitine-induced apoptosis in HCT116 cells. Interestingly, additional putrescine treatment was found pro-apoptotic due to the presence of non-functional ornithine decarboxylase (ODC). Finally, roscovitine altered polyamine catabolic pathway and led to decrease in putrescine and spermidine levels. Therefore, the metabolic regulation of polyamines may dictate the power of roscovitine induced apoptotic responses in HCT116 colon cancer cells. 相似文献
8.
Monica Carmosino Silvia Torretta Giuseppe Procino Andrea Gerbino Cinzia Forleo Stefano Favale Maria Svelto 《Biology of the cell / under the auspices of the European Cell Biology Organization》2014,106(10):346-358
Lamin A/C is a structural protein of the nuclear envelope (NE) and cardiac involvement in Lamin A/C mutations was one of the first phenotypes to be reported in humans, suggesting a crucial role of this protein in the cardiomyocytes function. Mutations in LMNA gene cause a class of pathologies generically named ‘Lamanopathies’ mainly involving heart and skeletal muscles. Moreover, the well‐known disease called Hutchinson–Gilford Progeria Syndrome due to extensive mutations in LMNA gene, in addition to the systemic phenotype of premature aging, is characterised by the death of patients at around 13 typically for a heart attack or stroke, suggesting again the heart as the main site sensitive to Lamin A/C disfunction. Indeed, the identification of the roles of the Lamin A/C in cardiomyocytes function is a key area of exploration. One of the primary biological roles recently conferred to Lamin A/C is to affect contractile cells lineage determination and senescence. Then, in differentiated adult cardiomyocytes both the ‘structural’ and ‘gene expression hypothesis’ could explain the role of Lamin A in the function of cardiomyocytes. In fact, recent advances in the field propose that the structural weakness/stiffness of the NE, regulated by Lamin A/C amount in NE, can ‘consequently’ alter gene expression. 相似文献
9.
Ruli Li Xiaoxiao Wang Sisi Wu Yao Wu Hongying Chen Juanjuan Xin He Li Jie Lan Kunyue Xue Xue Li Caili Zhuo Jinhan He Chao-Shu Tang Wei Jiang 《Journal of cellular physiology》2019,234(10):17578-17588
Cardiac hypertrophy is the main cause of heart failure and sudden death in patients. But the pathogenesis is unclear. Angiotensin II may contribute to cardiac hypertrophy in response to pressure overload. In angiotensin II-treated cardiomyocytes, there is a larger cross-sectional area, more apoptosis cells, and a reduction of irisin expression. An increase in P62, an autophagy flux index, as well as LC3II, were observed in cardiomyocytes after angiotensin II-induced injury. Surprisely, irisin supplementation increased LC3II expression and decreased P62 expression, consisted of results of RFP-GFP-LC3B adenovirus transfection, and reduced cardiomyocyte apoptosis, meanwhile, the protection of irisin was reversed by the autophagy inhibitor 3-methyladenine. In animal experiments, overexpression of irisin reduced cardiomyocyte apoptosis and alleviated myocardial hypertrophy caused by pressure overload. The above results indicate that irisin-induced protective autophagy and alleviated the apoptosis signaling pathway in cardiomyocytes, consequently reducing cardiomyocyte apoptosis after angiotensin II-induced injury. Hence, increasing irisin expression may be a new way to improve cardiac function and quality of life in patients with cardiac hypertrophy. 相似文献
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Yajima N Yamada S Morisaki T Toyokuni S Yonehara S Sakamaki K 《Transgenic research》2005,14(5):593-604
Baculovirus p35 protein protects cells from apoptotic cell death by inhibiting caspase activation. We have established transgenic
mouse lines specifically expressing p35 in cardiomyocytes, and primary cardiomyocytes isolated from these mice exhibit resistance
to staurosporine-induced apoptosis. In a previous study, we observed defects in heart formation associated with abdominal
hemorrhage and cardiomyocyte cell death in caspase-8-deficent animals. In order to better understand the etiology of the cardiac
defects and embryonic lethality in caspase-8-deficient mice, we crossed these mice with the p35 transgenic animals. Although
the newly generated mice still died in utero and exhibited some cardiac defects, cardiomyocyte apoptosis was suppressed and ventricular trabeculation was restored. Thus,
cardiomyocyte expression of p35 prevented cell death induced by staurosporine or caspase-8 deficiency. Additionally, our data
suggest that caspase-8 plays multiple roles in cardiac development. 相似文献
12.
Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis 总被引:5,自引:0,他引:5
Shen T Zheng M Cao C Chen C Tang J Zhang W Cheng H Chen KH Xiao RP 《The Journal of biological chemistry》2007,282(32):23354-23361
An inexorable loss of terminally differentiated heart muscle cells is a crucial causal factor for heart failure. Here, we have provided several lines of evidence to demonstrate that mitofusin-2 (Mfn-2; also called hyperplasia suppressor gene), a member of the mitofusin family, is a major determinant of oxidative stress-mediated cardiomyocyte apoptosis. First, oxidative stress with H(2)O(2) led to concurrent increases in Mfn-2 expression and apoptosis in cultured neonatal rat cardiomyocytes. Second, overexpression of Mfn-2 to a level similar to that induced by H(2)O(2) was sufficient to trigger myocyte apoptosis, which is associated with profound inhibition of Akt activation without altering ERK1/2 signaling. Third, Mfn-2 silencing inhibited oxidative stress-induced apoptosis in H9C2 cells, a cardiac muscle cell line. Furthermore, Mfn-2-induced myocyte apoptosis was abrogated by inhibition of caspase-9 (but not caspase-8) and by overexpression of Bcl-x(L) or enhanced activation of phosphatidylinositol 3-kinase-Akt, suggesting that inhibition of Akt signaling and activation of the mitochondrial death pathway are essentially involved in Mfn-2-induced heart muscle cell apoptosis. These results indicate that increased cardiac Mfn-2 expression is both necessary and sufficient for oxidative stress-induced heart muscle cell apoptosis, suggesting that Mfn-2 deregulation may be a crucial pathogenic element and a potential therapeutic target for heart failure. 相似文献
13.
Y Murakami S Matsufuji Y Miyazaki S Hayashi 《The Journal of biological chemistry》1992,267(19):13138-13141
The degradation of ornithine decarboxylase (ODC) is stimulated by polyamines in a protein synthesis-dependent manner. It has been suggested that antizyme, an ODC-inhibiting protein induced by polyamines, is involved in the process of polyamine-stimulated ODC decay. In this study, we investigated the direct effect of antizyme on ODC decay in hepatoma tissue culture (HTC) cells. A truncated rat antizyme cDNA, Z1, was inserted into an expression vector at a site under the control of a glucocorticoid-inducible promoter and transfected into HTC cells. In the transfected cells dexamethasone increased the amount of Z1 mRNA and induced active antizyme in the absence of exogenous polyamines. When dexamethasone was added to cells with a high level of ODC, rapid decays of ODC activity and protein were elicited after a lag time. Cycloheximide abolished the effect of dexamethasone. These effects of dexamethasone were not observed in control HTC cells transfected with the chloramphenicol acetyltransferase gene. This study indicated that, once induced, antizyme stimulated ODC degradation independently of polyamines and strongly supported our previous hypothesis that the ODC decay-accelerating action of polyamines is mediated by antizyme. 相似文献
14.
C Oetken T Pessa-Morikawa M Autero L C Andersson T Mustelin 《Experimental cell research》1992,202(2):370-375
Onset of cell proliferation is associated with enhanced turnover of the polyamines putrescine, spermidine, and spermine, particularly evident in the massive increase in the activity of the rate-limiting enzyme in their production, ornithine decarboxylase (ODC). The physiological functions of these polyamines, however, have remained unclear. Here we report that treatment of LSTRA cells for 2-18 h with alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, decreased the amount of phosphotyrosine in several cellular substrates including the T cell protein tyrosine kinase p56lck. No reductions in the amount of p56lck, overall synthesis of protein and DNA, or cell viability were observed until much later. DFMO did not affect the catalytic activity of p56lck in vitro and the activity of p56lck immunoprecipitated from DFMO-treated cells was unaltered. Addition of putrescine, the reaction product of ODC, completely reversed the effect of DFMO on tyrosine phosphorylation. Finally, we provide evidence that polyamines reduce the activity of cellular protein tyrosine phosphatases toward endogenous substrates. Our results suggest that polyamines may influence the extent of tyrosine phosphorylation during cell proliferation and malignant transformation, perhaps by modulating the rate of dephosphorylation of specific target proteins. 相似文献
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Chun-Juan Chen Wei Yu Yu-Cai Fu Ji-Lin Li 《Biochemical and biophysical research communications》2009,378(3):389-533
Loss of cardiomyocytes through apoptosis has been proposed as a cause of ventricular remodeling and heart failure. Ischemia- and hypoxia-induced apoptosis of cardiomyocytes reportedly plays an important role in many cardiac pathologies. We investigated whether resveratrol (Res) has direct cytoprotective effects against ischemia/hypoxia for cardiomyocytes. Exposure of H9c2 embryonic rat heart-derived cells to hypoxia for 24 h caused a significant increase in apoptosis, as evaluated by TUNEL and flow cytometry, while treatment with 20 μM Res greatly decreased hypoxia-induced apoptosis in these cells. Exposure of the cells to Res (20 μM) caused rapid activation of SIRT1, which had a dual effect on FoxO1 function: SIRT1 increased FoxO1’s ability to induce cell cycle arrest, but inhibited FoxO1’s ability to induce cell death. This effect could be reversed by SIRT1 inhibition. Results of our study indicate that Res inhibits hypoxia-induced apoptosis via the SIRT1-FoxO1 pathway in H9c2 cells. This polyphenol may have potential in preventing cardiovascular disease, especially in coronary artery disease (CAD) patients. 相似文献
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Norepinephrine induces apoptosis in neonatal rat endothelial cells via a ROS-dependent JNK activation pathway 总被引:1,自引:0,他引:1
Fu YC Yin SC Chi CS Hwang B Hsu SL 《Apoptosis : an international journal on programmed cell death》2006,11(11):2053-2063
Our previous study demonstrated that norepinephrine (NE) induces endothelial apoptosis mainly through down-regulation of Bcl-2
protein and activation of the β-adrenergic and caspase-2 pathways. However, whether reactive oxygen species (ROS) and mitogen-activated
protein kinases (MAPKs) are involved in this signal transduction remains unknown. Endothelial cells cultured from neonatal
rat heart were treated with 100 μM NE. Proteins of MAPKs and Bcl-2 family were assayed by Western blotting. Apoptosis was
determined by terminal deoxynucleotidyl transferase-mediated nick end-labeling assay. ROS was analyzed with flow cytometry.
Caspase activity was measured using specific fluorogenic substrates. Treatment with NE increased intracellular ROS level and
extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 phosphorylation. Whereas the phosphorylated
form of Akt was decreased. The NE-induced apoptosis was abrogated by SP600125 (a specific inhibitor of JNK). Antioxidants
such as vitamin C and N-acetyl cysteine inhibited NE-induced ROS production, JNK phosphorylation, caspase activation and apoptosis.
Exogenously added superoxide dismutase or catalase markedly diminished NE-induced ROS production and cell death. In conclusions,
our study is the first report documenting that NE induces apoptosis in neonatal rat endothelial cells via a ROS-dependent
JNK activation pathway. Antioxidants may be useful in the prevention and management of NE-mediated endothelial apoptosis during
heart failure. 相似文献
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Shimojo N Jesmin S Zaedi S Soma M Maeda S Yamaguchi I Goto K Miyauchi T 《Experimental biology and medicine (Maywood, N.J.)》2006,231(6):932-936
Human heart failure is preceded by a process called cardiac remodeling, in which heart chambers progressively enlarge and contractile function deteriorates. Programmed cell death (apoptosis) of cardiac muscle cells has been identified as an essential process in the progression to heart failure. The execution of the apoptotic program entails complex interactions between and execution of multiple molecular subprograms. Endothelin (ET)-1, a potent vasoconstrictor peptide, is synthesized and secreted by cardiomyocytes and induces hypertrophy of cardiomyocytes. The cardiovascular benefit of fish oil containing eicosapentaenoic acid (EPA) in humans and experimental animals was reported. Recently, we found that ET-1-induced cardiomyocytic remodeling could be prevented by pretreatment with EPA. The aim of the present study is to investigate whether there would be any alteration in the expression of important apoptosis-related molecules in ET-1-administered hypertrophied cardiomyocytes. We also sought to determine, if there are alterations in apoptotic molecules, what type of role for EPA would then exist. Ventricular cardiomyocytes were isolated from 2-day-old Sprague-Dawley rats and were cultured for 3 days. At Day 4 of culture, the cardiomyocytes were divided into three groups: control, the ET-1 (0.1 nM)-treated group, and the ET-1 group pretreated with EPA (10 microM). Twenty-four hours after the treatment, the gene expressions of three important molecules related to apoptosis (caspase-3, Bax, and Bcl-2) in three experimental groups were evaluated by real-time polymerase chain reaction. The present study could not demonstrate any significant or representative alteration in any of the above three apoptosis-related important markers in either ET-1-induced hypertrophied cardiomyocytes with or without EPA pretreatment. The present study would at least be able to exclude the involvement of some representative molecules related to apoptosis in ET-1-induced hypertrophied cardiomyocytes. In addition, the present study demonstrates that the antihypertrophic effect of EPA to ET-1-administered cardiomyocytes appears not to modulate the apoptosis signaling cascade. 相似文献