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81.
Qing Chu Ying Xiao Xin Song Y James Kang 《Experimental biology and medicine (Maywood, N.J.)》2021,246(24):2579
A significant amount of cardiomyocytes in subendocardial region survive from ischemic insults. In order to understand the mechanism by which these cardiomyocytes survive, the present study was undertaken to examine changes in these surviving cardiomyocytes and their extracellular matrix. Male C57BL/6 mice aged 8–12 weeks old were subjected to a permanent left anterior descending coronary artery ligation to induce ischemic injury. The hearts were collected at 1, 4, 7, or 28 days after the surgery and examined by histology. At day 1 after left anterior descending ligation, there was a significant loss of cardiomyocytes through apoptosis, but a proportion of cardiomyocytes were surviving in the subendocardial region. The surviving cardiomyocytes were gradually changed from rod-shaped to round-shaped, and appeared disconnected. Connexin 43, an important gap junction protein, was significantly decreased, and collagen I and III deposition was significantly increased in the extracellular matrix. Furthermore, lysyl oxidase, a copper-dependent amine oxidase catalyzing the cross-linking of collagens, was significantly increased in the extracellular matrix, paralleled with the surviving cardiomyocytes. Inhibition of lysyl oxidase activity reduced the number of surviving cardiomyocytes. Thus, the extracellular matrix remodeling is correlated with the deformation of cardiomyocytes, and the electrical disconnection between the surviving cardiomyocytes due to connexin 43 depletion and the increase in lysyl oxidase would help these deformed cardiomyocytes survive under ischemic conditions. 相似文献
82.
Takahisa Matsuda 《Biochemical and biophysical research communications》2004,326(1):228-232
Mechanical stretch has been implicated as the growth stimuli in the heart. Physiologically, mechanical stretch is reported to contribute to the orientation of cardiomyocytes, though the molecular mechanism remains to be elucidated. This study was designed to make clear functional significances of N-cadherin in plasticity of cell alignment in response to mechanical stretch. Neonatal rat cardiomyocytes, cultured on silicone dishes, were subjected to artificial uniaxial cyclic stretch. Mechanical stretch was started at certain times (3-75 h) after seeding and continued for 24 h. Stretch stimulation in 3 h after cultivation promoted cell orientation running parallel to tension direction. In contrast, cardiac myocytes fail to align when exposed to stretch 24-75 h after cultivation. To address the importance of N-cadherin in the responsiveness to stretch, the expression and distribution of N-cadherin were analyzed. Immediately after seeding, N-cadherin showed dispersed distributions. During cultivation, N-cadherin localized to cell-cell contacts accompanied by the upregulation of its protein. Next, to investigate influence of cell-cell adhesion, cardiomyocytes cultured for 72 h were replated by trypsin treatment and exposed to stretch 3 h after replating. The cardiomyocytes replated by trypsinization were oriented in parallel to tension direction by mechanical stretch. Finally, adenoviral transfection of dominant-negative N-cadherin recovered the ability to exhibit cell orientation in response to stretch. Our results suggested that N-cadherin was involved in the oriented responses of cardiomyocytes induced by mechanical stretch. 相似文献
83.
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
84.
Satoshi Sakai Nobutake Shimojo Taizo Kimura Kazuko Tajiri Hidekazu Maruyama Satoshi Homma Keisuke Kuga Taro Mizutani Kazutaka Aonuma Takashi Miyauchi 《Life sciences》2014
Aims
Cardiac hypertrophy is elicited by endothelin (ET)-1 as well as other neurohumoral factors, hemodynamic overload, and oxidative stress; HMG-CoA reductase inhibitors (statins) were shown to inhibit cardiac hypertrophy partly via the anti-oxidative stress. One of their common intracellular pathways is the phosphorylation cascade of MEK signaling. Pin1 specifically isomerizes the phosphorylated protein with Ser/Thr-Pro bonds and regulates their activity through conformational changes. There is no report whether the Pin1 activation contributes to ET-1-induced cardiomyocyte hypertrophy and whether the Pin1 inactivation contributes to the inhibitory effect of statins. The aim of this study was to reveal these questions.Main methods
We assessed neonatal rat cardiomyocyte hypertrophy using ET-1 and fluvastatin by the cell surface area, ANP mRNA expression, JNK and c-Jun phosphorylation, and [3H]-leucine incorporation.Key findings
Fluvastatin inhibited ET-1-induced increase in the cell surface area, ANP expression, and [3H]-leucine incorporation; and it suppressed the signaling cascade from JNK to c-Jun. The phosphorylated Pin1 level, an inactive form, was decreased by ET-1; however, it reached basal level by fluvastatin. Furthermore, Pin1 overexpression clearly elicited cardiomyocyte hypertrophy, which was inhibited by fluvastatin.Significance
This is the first report that ET-1-induced cardiomyocyte hypertrophy is mediated through the Pin1 activation and that the inhibitory effect of fluvastatin on cardiomyocyte hypertrophy would partly be attributed to the suppression of the Pin1 function. This study firstly suggests that Pin1 determines the size of hypertrophied cardiomyocyte by regulating the activity of phosphorylated molecules and that statins exert their pleiotropic effects partly via Pin1 inactivation. 相似文献85.
Anthony Yiu-Ho Woo Krzysztof Jozwiak Lawrence Toll Mary J. Tanga Joseph A. Kozocas Lucita Jimenez Ying Huang Ying Song Anita Plazinska Karolina Pajak Rajib K. Paul Michel Bernier Irving W. Wainer Rui-Ping Xiao 《The Journal of biological chemistry》2014,289(28):19351-19363
Interaction of a given G protein-coupled receptor to multiple different G proteins is a widespread phenomenon. For instance, β2-adrenoceptor (β2-AR) couples dually to Gs and Gi proteins. Previous studies have shown that cAMP-dependent protein kinase (PKA)-mediated phosphorylation of β2-AR causes a switch in receptor coupling from Gs to Gi. More recent studies have demonstrated that phosphorylation of β2-AR by G protein-coupled receptor kinases, particularly GRK2, markedly enhances the Gi coupling. We have previously shown that although most β2-AR agonists cause both Gs and Gi activation, (R,R′)-fenoterol preferentially activates β2-AR-Gs signaling. However, the structural basis for this functional selectivity remains elusive. Here, using docking simulation and site-directed mutagenesis, we defined Tyr-308 as the key amino acid residue on β2-AR essential for Gs-biased signaling. Following stimulation with a β2-AR-Gs-biased agonist (R,R′)-4′-aminofenoterol, the Gi disruptor pertussis toxin produced no effects on the receptor-mediated ERK phosphorylation in HEK293 cells nor on the contractile response in cardiomyocytes expressing the wild-type β2-AR. Interestingly, Y308F substitution on β2-AR enabled (R,R′)-4′-aminofenoterol to activate Gi and to produce these responses in a pertussis toxin-sensitive manner without altering β2-AR phosphorylation by PKA or G protein-coupled receptor kinases. These results indicate that, in addition to the phosphorylation status, the intrinsic structural feature of β2-AR plays a crucial role in the receptor coupling selectivity to G proteins. We conclude that specific interactions between the ligand and the Tyr-308 residue of β2-AR stabilize receptor conformations favoring the receptor-Gs protein coupling and subsequently result in Gs-biased agonism. 相似文献
86.
Uwe Kirchhefer Christiane Brekle John Eskandar Gunnar Isensee Dana Ku?erová Frank U. Müller Florence Pinet Jan S. Schulte Matthias D. Seidl Peter Boknik 《The Journal of biological chemistry》2014,289(49):33862-33873
Dephosphorylation of important myocardial proteins is regulated by protein phosphatase 2A (PP2A), representing a heterotrimer that is comprised of catalytic, scaffolding, and regulatory (B) subunits. There is a multitude of B subunit family members directing the PP2A holoenzyme to different myocellular compartments. To gain a better understanding of how these B subunits contribute to the regulation of cardiac performance, we generated transgenic (TG) mice with cardiomyocyte-directed overexpression of B56α, a phosphoprotein of the PP2A-B56 family. The 2-fold overexpression of B56α was associated with an enhanced PP2A activity that was localized mainly in the cytoplasm and myofilament fraction. Contractility was enhanced both at the whole heart level and in isolated cardiomyocytes of TG compared with WT mice. However, peak amplitude of [Ca]i did not differ between TG and WT cardiomyocytes. The basal phosphorylation of cardiac troponin inhibitor (cTnI) and the myosin-binding protein C was reduced by 26 and 35%, respectively, in TG compared with WT hearts. The stimulation of β-adrenergic receptors by isoproterenol (ISO) resulted in an impaired contractile response of TG hearts. At a depolarizing potential of −5 mV, the ICa,L current density was decreased by 28% after administration of ISO in TG cardiomyocytes. In addition, the ISO-stimulated phosphorylation of phospholamban at Ser16 was reduced by 27% in TG hearts. Thus, the increased PP2A-B56α activity in TG hearts is localized to specific subcellular sites leading to the dephosphorylation of important contractile proteins. This may result in higher myofilament Ca2+ sensitivity and increased basal contractility in TG hearts. These effects were reversed by β-adrenergic stimulation. 相似文献
87.
Peter L. Pedersen 《Journal of bioenergetics and biomembranes》2009,41(2):95-98
The human/animal heart, comprised of cells called “myocytes” is an incredible organ that to remain beating must be fueled
constantly via the hydrolysis of adenosine tri-phosphate (ATP). Deriving most of its ATP from mitochondrial oxidative phosphorylation
(ox phos), and a smaller amount from “glycolysis”, i.e., glucose conversion to pyruvate or lactate, the heart helps in the
delivery of oxygen (via hemoglobin) to every organ/tissue in our body. Then, the empty (deoxy) hemoglobin returns to load
more oxygen and the journey to tissues is repeated 24 h a day, year after year, until “death do us part”. To support this
essential “pumping” process the heart must work constantly, i.e., 70–80 years (life expectancy in the U.S.). This is a remarkable
feat when compared with one of our most costly people-made technologies, i.e., automobiles (cars). In the past century, it
was rare to see the family car survive more than 10–15 years unless it had been subjected to motor replacement surgery. Most
were laid to rest at a much earlier age. Now, in this new millennium should a brilliant car manufacturer succeed in constructing
a car engine as efficient as the human heart, each family member requiring a car would need only one per life time. With this
in mind, one of the major future “matters of the heart” is to keep it pumping, not only for the current 70–80 year life span
but much longer. To do this depends on, among other matters, the two processes noted above, i.e., oxidative phosphorylation
and glycolysis. The former is strictly a mitochondrial process that works only in the presence of oxygen whereas glycolysis,
dependent on mitochondrial bound hexokinase 2 (MB-HK-2), works either in the presence or absence of oxygen. In addition, the
MB-HK 2 is anti-apoptotic and helps with other factors to retard cell death. Current estimates reveal that the human heart
of an individual living 70–80 years will have undergone 2.5–3.0 billion beats, a feat that is energetically feasible only
due to the heart cells’ (cardiomyocytes) large population of mitochondria with bound HK-2. 相似文献
88.
Sa Shi Qing-song Li Hong Li Li Zhang Man Xu Jia-li Cheng Cheng-hai Peng Chang-qing Xu Ye Tian 《Cell biology international》2009,33(10):1095-1101
The mechanism of action of Hydrogen sulfide (H2S) as a novel endogenous gaseous messenger and potential cardioprotectant is not fully understood. We therefore investigated the prevention of cardiomyocyte apoptosis by exogenous H2S and the signaling pathways leading to cardioprotection. Using a simulated ischemia–reperfusion (I/Re) model with primary cultured rat neonatal cardiomyocytes, I/Re induced a rapid, time-dependent phosphorylation of c-Jun N-terminal kinase (JNK), with significant elevation at 0.25 h and a peak at 0.5 h during reperfusion. NaHS (H2S donor) significantly inhibited the early phosphorylation of JNK, especially at 0.5 h. Both NaHS and SP600125 (specific JNK inhibitor) decreased the number of apoptotic cells, lowered cytochrome C release and enhanced Bcl-2 expression. When NaHS application was delayed 1 h after reperfusion, the inhibition of apoptosis by H2S was negated. In conclusion, this is novel evidence that early JNK inhibition during reperfusion is associated with H2S-mediated protection against cardiomyocyte apoptosis. 相似文献
89.
Yi-hua Sun Yong-quan Li Shan-li Feng Zhen-wei Pan Ting-ting Li 《Biochemical and biophysical research communications》2010,394(4):955-30646
Capacitative calcium entry (CCE) refers to the influx of calcium through plasma membrane channels activated on depletion of endoplasmic sarcoplasmic/reticulum (ER/SR) Ca2+ stores, which is performed mainly by the transient receptor potential (TRP) channels. TRP channels are expressed in cardiomyocytes. Calcium-sensing receptor (CaR) is also expressed in rat cardiac tissue and plays an important role in mediating cardiomyocyte apoptosis. However, there are no data regarding the link between CaR and TRP channels in rat heart. In this study, in rat neonatal myocytes, by Ca2+ imaging, we found that the depletion of ER/SR Ca2+ stores by thapsigargin (TG) elicited a transient rise in cytoplasmic Ca2+ ([Ca2+]i), followed by sustained increase depending on extracellular Ca2+. But, TRP channels inhibitor (SKF96365), not L-type channels or the Na+/Ca2+ exchanger inhibitors, inhibited [Ca2+]i relatively high. Then, we found that the stimulation of CaR with its activator gadolinium chloride (GdCl3) or by an increased extracellular Ca2+([Ca2+]o) increased the concentration of intracelluar Ca2+, whereas, the sustained elevation of [Ca2+]i was reduced in the presence of SKF96365. Similarly, the duration of [Ca2+]i increase was also shortened in the absence of extracellular Ca2+. Western blot analysis showed that GdCl3 increased the expression of TRPC6, which was reversed by SKF96365. Additionally, SKF96365 reduced cardiomyocyte apoptosis induced by GdCl3. Our results suggested that CCE exhibited in rat neonatal myocytes and CaR activation induced Ca2+-permeable cationic channels TRPCs to gate the CCE, for which TRPC6 was one of the most likely candidates. TRPC6 channel was functionally coupled with CaR to enhance the cardiomyocyte apoptosis. 相似文献
90.
To investigate the roles that the community effect and entrainment function of cultured cardiomyocyte play in decreasing beating fluctuation and reestablishing synchronized beating, we developed a single-cell-based two-dimensional network culture assay to measure and compare the dynamics of beating rhythm synchronization of individual cells before and after they form networks. Studying the formation of two-cell networks, we found that their synchronized beating tended to be determined by the cardiomyocyte whose beat rate fluctuated less than that of the other cardiomyocyte. We further found that the strength of this tendency increased with the number of cells in the network. These results indicate that (1) beating fluctuation is one of the important factors influencing the reestablishment of a stable synchronous beating rhythm, (2) the larger networks reduce fluctuation, and (3) the formation of a spatial network can itself stabilize cardiomyocyte beat rates. 相似文献