共查询到20条相似文献,搜索用时 15 毫秒
1.
Catalina Carrasco-Pozo Edgar Pastene Carola Vergara Moises Zapata Cristian Sandoval Martin Gotteland 《Biochimica et Biophysica Acta (BBA)/General Subjects》2012
Background
The effect of indomethacin (INDO) on Ca2 + mobilization, cytotoxicity, apoptosis and caspase activation and the potential protective effect of quercetin (QUE), resveratrol (RES) and rutin (RUT) were determined in Caco-2 cells.Methods
Caco-2 cells were incubated with INDO in the presence or absence of QUE, RES or RUT. The concentrations of Ca2 + in the cytosol (Fluo-3 AM) and mitochondria (Rhod-2 AM) were determined as well as the cytotoxicity (MTT reduction and LDH leakage), apoptosis (TUNEL) and caspase-3 and 9 activities.Results
INDO promoted Ca2 + efflux from the endoplasmic reticulum (ER), resulting in an early, but transient, increment of cytosolic Ca2 + at 3.5 min, followed by a subsequent increment of intra-mitochondrial Ca2 + at 24 min. INDO also induced cytotoxicity, apoptosis, and increased caspase activities and cytochrome c release. All these alterations were prevented by the inhibitors of the IP3R and RyR receptors, 2-Aminoethoxydiphenyl borate (2-APB) and dantrolene. QUE was the most efficient polyphenol in preventing Ca2 + mobilization induced by INDO and all of its consequences including cytotoxicity and apoptosis.Conclusions
In Caco-2 cells, INDO stimulates ER Ca2 + mobilization, probably through the activation of IP3R and RyR receptors, and the subsequent entry of Ca2 + into the mitochondria. Polyphenols protected the cells against the Ca2 + mobilization induced by INDO and its consequences on cytotoxicity and apoptosis.General significance
These results confirm the possibility of using polyphenols and particularly QUE for the protection of the gastroduodenal mucosa in subjects consuming NSAIDs. 相似文献2.
Background
In recent years, as our understanding of the various roles played by Ca2 + signaling in development and differentiation has expanded, the challenge of imaging Ca2 + dynamics within living cells, tissues, and whole animal systems has been extended to include specific signaling activity in organelles and non-membrane bound sub-cellular domains.Scope of review
In this review we outline how recent advances in genetics and molecular biology have contributed to improving and developing current bioluminescence-based Ca2 + imaging techniques. Reporters can now be targeted to specific cell types, or indeed organelles or domains within a particular cell.Major conclusions
These advances have contributed to our current understanding of the specificity and heterogeneity of developmental Ca2 + signaling. The improvement in the spatial resolution that results from specifically targeting a Ca2 + reporter has helped to reveal how a ubiquitous signaling messenger like Ca2 + can regulate coincidental but different signaling events within an individual cell; a Ca2 + signaling paradox that until now has been hard to explain.General significance
Techniques used to target specific reporters via genetic means will have applications beyond those of the Ca2 + signaling field, and these will, therefore, make a significant contribution in extending our understanding of the signaling networks that regulate animal development. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signalling. 相似文献3.
Aims
We previously reported that fluvoxamine, a selective serotonin reuptake inhibitor with high affinity for the σ1-receptor (σ1R), ameliorates cardiac hypertrophy and dysfunction via σ1R stimulation. Although σ1R on non-cardiomyocytes interacts with the IP3 receptor (IP3R) to promote mitochondrial Ca2 + transport, little is known about its physiological and pathological relevance in cardiomyocytes.Main methods
Here we performed Ca2 + imaging and measured ATP production to define the role of σ1Rs in regulating sarcoplasmic reticulum (SR)-mitochondrial Ca2 + transport in neonatal rat ventricular cardiomyocytes treated with angiotensin II to promote hypertrophy.Key finding
These cardiomyocytes exhibited imbalances in expression levels of σ1R and IP3R and impairments in both phenylephrine-induced mitochondrial Ca2 + mobilization from the SR and ATP production. Interestingly, σ1R stimulation with fluvoxamine rescued impaired mitochondrial Ca2 + mobilization and ATP production, an effect abolished by treatment of cells with the σ1R antagonist, NE-100. Under physiological conditions, fluvoxamine stimulation of σ1Rs suppressed intracellular Ca2 + mobilization through IP3Rs and ryanodine receptors (RyRs). In vivo, chronic administration of fluvoxamine to TAC mice also rescued impaired ATP production.Significance
These results suggest that σ1R stimulation with fluvoxamine promotes SR-mitochondrial Ca2 + transport and mitochondrial ATP production, whereas σ1R stimulation suppresses intracellular Ca2 + overload through IP3Rs and RyRs. These mechanisms likely underlie in part the anti-hypertrophic and cardioprotective action of the σ1R agonists including fluvoxamine. 相似文献4.
Thanutchaporn Kumrungsee Tomomi SaikiSayaka Akiyama Kentaro NakashimaMitsuru Tanaka Yutaro KobayashiToshiro Matsui 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Tryptophan-histidine (Trp-His) was found to suppress the activity of the Ca2 +/calmodulin (CaM)-dependent protein kinases II (CaMKII), which requires the Ca2 +-CaM complex for an initial activation. In this study, we attempted to clarify whether Trp-His inhibits Ca2 +-CaM complex formation, a CaMKII activator.Methods
The ability of Trp-His and other peptides to inhibit Ca2 +-CaM complex formation was investigated by a Ca2 +-encapsulation fluorescence assay. The peptide-CaM interactions were illustrated by molecular dynamic simulation.Results
We showed that Trp-His inhibited Ca2 +-CaM complex formation with a 1:1 binding stoichiometry of the peptide to CaM, considering that Trp-His reduced Hill coefficient of Ca2 +-CaM binding from 2.81 to 1.92. His-Trp also showed inhibitory activity, whereas Trp + His, 3-methyl His-Trp, and Phe-His did not show significant inhibitory activity, suggesting that the inhibitory activity was due to a peptide skeleton (irrespective of the sequence), a basic amino acid, a His residue, the N hydrogen atom of its imidazole ring, and Trp residue. In silico studies suggested the possibility that Trp-His and His-Trp interacted with the Ca2 +-binding site of CaM by forming hydrogen bonds with key Ca2 +-binding residues of CaM, with a binding free energy of − 49.1 and − 68.0 kJ/mol, respectively.Conclusions
This is the first study demonstrating that the vasoactive dipeptide Trp-His possesses inhibitory activity against Ca2 +-CaM complex formation, which may elucidate how Trp-His inhibited CaMKII in a previous study.General significance
The results provide a basic idea that could lead to the development of small peptides binding with high affinity to CaM and inhibiting Ca2 +-CaM complex formation in the future. 相似文献5.
Bicheng Yang Xiaolu Duan Wenzheng Wu Weidong JiWenqi Wu Wen ZhongZhijian Zhao Shujue LiYang Liu Guohua Zeng 《Life sciences》2014
Aim
Promoter-targeted small activating RNAs (saRNAs) have been shown to be able to induce target gene expression, a mechanism known as RNA activation (RNAa). The present study tested whether saRNA can induce the overexpression of TRPV5 in human cells derived from the kidney and subsequently manipulate cell calcium uptake.Main methods
Three saRNAs complementary to the TRPV5 promoter were synthesized and transfected into cells. TRPV5 expression at the RNA and protein levels was analyzed by quantitative real-time PCR and Western blotting respectively. For functional study, transcellular Ca2 + transportation was tested by fura-2 analysis. Dihydrotestosterone (DHT), a suppressor of cellular calcium transportation, was administered to challenge the activating effect of selected saRNA.Key findings
One of these synthesized saRNAs, ds-2939, significantly induced the expression of TRPV5 at both mRNA and protein levels. Fura-2 analysis revealed that the intracellular Ca2 + concentration was elevated by ds-2939. DHT treatment reduced transmembrane Ca2 + transport, which was partially antagonized by ds-2939.Significance
Our results suggest that a saRNA targeting TRPV5 promoter can be utilized to manipulate the transmembrane Ca2 + transport by upregulating the expression of TRPV5 and may serve as an alternative for the treatment of Ca2 + balance-related diseases. 相似文献6.
Kevin Thurley Alexander Skupin Rüdiger Thul Martin Falcke 《Biochimica et Biophysica Acta (BBA)/General Subjects》2012
Background
Ca2 + is a ubiquitous and versatile second messenger that transmits information through changes of the cytosolic Ca2 + concentration. Recent investigations changed basic ideas on the dynamic character of Ca2 + signals and challenge traditional ideas on information transmission.Scope of review
We present recent findings on key characteristics of the cytosolic Ca2 + dynamics and theoretical concepts that explain the wide range of experimentally observed Ca2 + signals. Further, we relate properties of the dynamical regulation of the cytosolic Ca2 + concentration to ideas about information transmission by stochastic signals.Major conclusions
We demonstrate the importance of the hierarchal arrangement of Ca2 + release sites on the emergence of cellular Ca2 + spikes. Stochastic Ca2 + signals are functionally robust and adaptive to changing environmental conditions. Fluctuations of interspike intervals (ISIs) and the moment relation derived from ISI distributions contain information on the channel cluster open probability and on pathway properties.General significance
Robust and reliable signal transduction pathways that entail Ca2 + dynamics are essential for eukaryotic organisms. Moreover, we expect that the design of a stochastic mechanism which provides robustness and adaptivity will be found also in other biological systems. Ca2 + dynamics demonstrate that the fluctuations of cellular signals contain information on molecular behavior. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signaling. 相似文献7.
Toshitaka Ikehara Hirotaka Nishisako Yuki Minami Hiromi Ichinose Tairo Shiraishi Mitsuo Kitamura Masayuki Shono Hitoshi Houchi Kazuyoshi Kawazoe Kazuo Minakuchi Kazuo Yoshizaki Yohsuke Kinouchi Hiroshi Miyamoto 《Biochimica et Biophysica Acta (BBA)/General Subjects》2010
Background
It has been reported that exposure to electromagnetic fields influences intracellular signal transduction. We studied the effects of exposure to a time-varying 1.5 T magnetic field on membrane properties, membrane cation transport and intracellular Ca2+ mobilization in relation to signals. We also studied the mechanism of the effect of exposure to the magnetic field on intracellular Ca2+ release from Ca2+ stores in adrenal chromaffin cells.Methods
We measured the physiological functions of ER, actin protein, and mitochondria with respect to a neurotransmitter-induced increase in Ca2+ in chromaffin cells exposed to the time-varying 1.5 T magnetic field for 2 h.Results
Exposure to the magnetic field significantly reduced the increase in [Ca2+]i. The exposure depolarized the mitochondria membrane and lowered oxygen uptake, but did not reduce the intracellular ATP content. Magnetic field-exposure caused a morphological change in intracellular F-actin. F-actin in exposed cells seemed to be less dense than in control cells, but the decrease was smaller than that in cytochalasin D-treated cells. The increase in G-actin (i.e., the decrease in F-actin) due to exposure was recovered by jasplakinolide, but inhibition of Ca2+ release by the exposure was unaffected.Conclusions and general significance
These results suggest that the magnetic field-exposure influenced both the ER and mitochondria, but the inhibition of Ca2+ release from ER was not due to mitochondria inhibition. The effect of eddy currents induced in the culture medium may indirectly influence intracellular actin and suppress the transient increase in [Ca2+]i. 相似文献8.
Background
Calcium (Ca2 +) oscillations are ubiquitous signals present in all cells that provide efficient means to transmit intracellular biological information. Either spontaneously or upon receptor ligand binding, the otherwise stable cytosolic Ca2 + concentration starts to oscillate. The resulting specific oscillatory pattern is interpreted by intracellular downstream effectors that subsequently activate different cellular processes. This signal transduction can occur through frequency modulation (FM) or amplitude modulation (AM), much similar to a radio signal. The decoding of the oscillatory signal is typically performed by enzymes with multiple Ca2 + binding residues that diversely can regulate its total phosphorylation, thereby activating cellular program. To date, NFAT, NF-κB, CaMKII, MAPK and calpain have been reported to have frequency decoding properties.Scope of review
The basic principles and recent discoveries reporting frequency decoding of FM Ca2 + oscillations are reviewed here.Major conclusions
A limited number of cellular frequency decoding molecules of Ca2 + oscillations have yet been reported. Interestingly, their responsiveness to Ca2 + oscillatory frequencies shows little overlap, suggesting their specific roles in cells.General significance
Frequency modulation of Ca2 + oscillations provides an efficient means to differentiate biological responses in the cell, both in health and in disease. Thus, it is crucial to identify and characterize all cellular frequency decoding molecules to understand how cells control important cell programs. 相似文献9.
Jae Hong Park Jung Min Ryu Seung Pil Yun Mi Ok Kim Ho Jae Han 《Biochimica et Biophysica Acta (BBA)/General Subjects》2012
Background
Extracellular matrix (ECM) components and intracellular pH (pHi) may serve as regulators of cell migration in various cell types.Methods
The Oris migration assay was used to assess the effect of fibronectin (FN) on cell motility. The Na+/H+ exchanger (NHE)-1 activity was evaluated by measuring pHi and [22Na+] uptake. To examine activated signaling molecules, western blot analysis and immunoprecipitation was performed.Results
ECM components (FN, laminin, fibrinogen, and collagen type I) increased [22Na+] uptake, pHi, and cell migration. In addition, FN-induced increase of cell migration was inhibited by NHE-1 inhibitor amiloride or NHE-1-specific siRNA. FN selectively increased the mRNA and protein expression of NHE-1, but not that of NHE-2 or NHE-3. FN binds integrin β1 and subsequently stimulates caveolin-1 phosphorylation and Ca2 + influx. Then, NHE-1 is phosphorylated by RhoA and Rho kinases, and Ca2 +/calmodulin (CaM) signaling elicits complex formation with NHE-1, which is enriched in lipid raft/caveolae microdomains of the plasma membrane. Activation of NHE-1 continuously induces an increase of [22Na+] uptake and pHi. Finally, NHE-1-dependent extracellular signal-regulated kinase (ERK) 1/2 phosphorylation enhanced matrix metalloproteinase-2 (MMP-2) and filamentous-actin (F-actin) expression, partially contributing to the regulation of embryonic stem cells (ESCs) migration.Conclusions
FN stimulated mESCs migration and proliferation through NHE-1 activation, which were mediated by lipid raft-associated caveolin-1, RhoA/ROCK, and Ca2 +/CaM signaling pathways.General significance
The precise role of NHE in the modulation of ECM-related physiological functions such as proliferation and migration remains poorly understood. Thus, this study analyzed the relationship between FN and NHE in regulating the migration of mouse ESCs and their related signaling pathways. 相似文献10.
Aims
We have previously demonstrated that propyl gallate has a Ca2 + sensitizing effect on the force generation in membrane-permeabilized (skinned) cardiac muscle fibers. However, in vivo beneficial effects of propyl gallate as a novel Ca2 + sensitizer remain uncertain. In the present study, we aim to explore in vivo effects of propyl gallate.Main methods
We compared effects of propyl gallate on ex vivo intact cardiac muscle fibers and in vivo hearts in healthy mice with those of pimobendan, a clinically used Ca2 + sensitizer. The therapeutic effect of propyl gallate was investigated using a mouse model of dilated cardiomyopathy (DCM) with reduced myofilament Ca2 + sensitivity due to a deletion mutation ΔK210 in cardiac troponin T.Key findings
Propyl gallate, as well as pimobendan, showed a positive inotropic effect. Propyl gallate slightly increased the blood pressure without changing the heart rate in healthy mice, whereas pimobendan decreased the blood pressure probably through vasodilation via inhibition of phosphodiesterase and increased the heart rate. Propyl gallate prevented cardiac remodeling and systolic dysfunction and significantly improved the life-expectancy of knock-in mouse model of DCM with reduced myofilament Ca2 + sensitivity due to a mutation in cardiac troponin T. On the other hand, gallate, a similarly strong antioxidant polyphenol lacking Ca2 + sensitizing action, had no beneficial effects on the DCM mice.Significance
These results suggest that propyl gallate might be useful for the treatment of inherited DCM caused by a reduction in the myofilament Ca2 + sensitivity. 相似文献11.
Ana M. Rossi Stephen C. ToveyTaufiq Rahman David L. ProleColin W. Taylor 《Biochimica et Biophysica Acta (BBA)/General Subjects》2012
Background
Inositol 1,4,5-trisphosphate receptors (IP3R) are expressed in almost all animal cells. Three mammalian genes encode closely related IP3R subunits, which assemble into homo- or hetero-tetramers to form intracellular Ca2 + channels.Scope of the review
In this brief review, we first consider a variety of complementary methods that allow the links between IP3 binding and channel gating to be defined. How does IP3 binding to the IP3-binding core in each IP3R subunit cause opening of a cation-selective pore formed by residues towards the C-terminal? We then describe methods that allow IP3, Ca2 + signals and IP3R mobility to be examined in intact cells. A final section briefly considers genetic analyses of IP3R signalling.Major conclusions
All IP3R are regulated by both IP3 and Ca2 +. This allows them to initiate and regeneratively propagate intracellular Ca2 + signals. The elementary Ca2 + release events evoked by IP3 in intact cells are mediated by very small numbers of active IP3R and the Ca2 +-mediated interactions between them. The spatial organization of these Ca2 + signals and their stochastic dependence on so few IP3Rs highlight the need for methods that allow the spatial organization of IP3R signalling to be addressed with single-molecule resolution.General significance
A variety of complementary methods provide insight into the structural basis of IP3R activation and the contributions of IP3-evoked Ca2 + signals to cellular physiology. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signaling. 相似文献12.
Liwei Zhang Dangsheng Huang Dong Shen Chunhong Zhang Yongjiang Ma Sara A. Babcock Bingyang Chen Jun Ren 《Life sciences》2014
Aims
Accumulation of advanced glycation endproduct (AGE) contributes to diabetic complication including diabetic cardiomyopathy although the precise underlying mechanism still remains elusive. Recent evidence depicted a pivotal role of protein kinase C (PKC) in diabetic complications. To this end, this study was designed to examine if PKCβII contributes to AGE-induced cardiomyocyte contractile and intracellular Ca2 + aberrations.Main methods
Adult rat cardiomyocytes were incubated with methylglyoxal-AGE (MG-AGE) in the absence or presence of the PKCβII inhibitor LY333531 for 12 h. Contractile and intracellular Ca2 + properties were assessed using an IonOptix system including peak shortening (PS), maximal velocity of shortening/relengthening (± dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), rise in intracellular Ca2 + Fura-2 fluorescence intensity and intracellular Ca2 + decay. Oxidative stress, O2− production and mitochondrial integrity were examined using TBARS, fluorescence imaging, aconitase activity and Western blotting.Key findings
MG-AGE compromised contractile and intracellular Ca2 + properties including reduced PS, ± dL/dt, prolonged TPS and TR90, decreased electrically stimulated rise in intracellular Ca2 + and delayed intracellular Ca2 + clearance, the effects of which were ablated by the PKCβII inhibitor LY333531. Inhibition of PKCβII rescued MG-AGE-induced oxidative stress, O2− generation, cell death, apoptosis and mitochondrial injury (reduced aconitase activity, UCP-2 and PGC-1α). In vitro studies revealed that PKCβII inhibition-induced beneficial effects were replicated by the NADPH oxidase inhibitor apocynin and were mitigated by the mitochondrial uncoupler FCCP.Significance
These findings implicated the therapeutic potential of specific inhibition of PKCβII isoform in the management of AGE accumulation-induced myopathic anomalies. 相似文献13.
Yasushi Sakai Michio Hashimoto Budbazar Enkhjargal Hisashi Mitsuishi Hiromi Nobe Ichiro Horie Takahiro Iwamoto Kenichi Yanagimoto 《Life sciences》2014
Aims
To investigate the effects of n − 3 polyunsaturated fatty acids on cerebral circulation, ovariectomized (OVX) rats were administered with phospholipids in krill oil (KPL) or triglycerides in fish oil (FTG); effects on the Ca2 + regulating system in their basilar artery (BA) were then analyzed.Main methods
The rats were divided into 4 groups: control, OVX, OVX given KPL (OVXP), and OVX given FTG (OVXT) orally, daily for 2 weeks. Time dependent relaxation (TDR) of contractile response to 5HT in BA was determined myographically, Na+/Ca2 + exchanger (NCX) 1 mRNA expression was determined by real time PCR, and nucleotides were analyzed by HPLC.Key findings
The level of TDR in OVX that was significantly lower in the control was inhibited by l-NAME and indomethacin; TEA inhibited TDR totally in the control but only partly in OVXP and OVXT. Relaxation induced by the addition of 5 mM KCl to the BA pre-contracted with 5-HT was inhibited by TEA in the controls, OVXP and OVXT, but not in OVX. Overexpression of NCX1 mRNA in the BA from OVX was significantly inhibited by FTG. The ratio of ADP/ATP in cerebral arteries from OVX was significantly inhibited by KPL and FTG. Levels of triglyceride and arachidonic acid in the plasma of OVX increased, but were significantly inhibited by KPL and FTG.Significance
Ovarian dysfunction affects Ca2 + activated-, ATP-sensitive-K+ channels and NCX1, which play crucial roles in the autoregulation of cerebral blood flow. Also, KPL may become as good a supplement as FTG for postmenopausal women. 相似文献14.
Karin C. Larsson Peter KjällAgneta Richter-Dahlfors 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
A major challenge when creating interfaces for the nervous system is to translate between the signal carriers of the nervous system (ions and neurotransmitters) and those of conventional electronics (electrons).Scope of review
Organic conjugated polymers represent a unique class of materials that utilizes both electrons and ions as charge carriers. Based on these materials, we have established a series of novel communication interfaces between electronic components and biological systems. The organic electronic ion pump (OEIP) presented in this review is made of the polymer–polyelectrolyte system poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). The OEIP translates electronic signals into electrophoretic migration of ions and neurotransmitters.Major conclusions
We demonstrate how spatio-temporally controlled delivery of ions and neurotransmitters can be used to modulate intracellular Ca2 + signaling in neuronal cells in the absence of convective disturbances. The electronic control of delivery enables strict control of dynamic parameters, such as amplitude and frequency of Ca2 + responses, and can be used to generate temporal patterns mimicking naturally occurring Ca2 + oscillations. To enable further control of the ionic signals we developed the electrophoretic chemical transistor, an analog of the traditional transistor used to amplify and/or switch electronic signals. Finally, we demonstrate the use of the OEIP in a new “machine-to-brain” interface by modulating brainstem responses in vivo.General significance
This review highlights the potential of communication interfaces based on conjugated polymers in generating complex, high-resolution, signal patterns to control cell physiology. We foresee widespread applications for these devices in biomedical research and in future medical devices within multiple therapeutic areas. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine. 相似文献15.
16.
Shu-Chung Hsieh Chi-Hao Wu Chun-Chi Wu Jung-Hsing Yen Mei-Chun Liu Chi-Mei Hsueh Shih-Lan Hsu 《Life sciences》2014
Aims
The activation of hepatic stellate cells (HSCs) in response to liver injury is critical to the development of liver fibrosis, thus, the blockage of the activation of HSCs is considered as a rational approach for anti-fibrotic treatment. In this report, we investigated the effects and the underlying mechanisms of gallic acid (GA) in interfering with the activation of HSCs.Main methods
The primary cultured rat HSCs were treated with various doses of GA for different time intervals. The morphology, viability, caspase activity, calcium ion flux, calpain I activity, reactive oxygen species generation and lysosomal functions were then investigated.Key findings
GA selectively killed HSCs in both dose- and time-dependent manners, while remained no harm to hepatocytes. Besides, caspases were not involved in GA-induced cell death of HSCs. Further results showed that GA toxicity was associated with a rapid burst of reactive oxygen species (ROS) and a subsequent increase of intracellular Ca2 + and calpain activity. Addition of calpain I but not calpain II inhibitor rescued HSCs from GA-induced death. In parallel, pretreatment with antioxidants or an intracellular Ca2 + chelator eradicated GA responses, implying that GA-mediated cytotoxicity was dependent on its pro-oxidative properties and its effect on Ca2 + flux. Furthermore, application of ROS scavengers also reversed Ca2 + release and the disruption of lysosomal membranes in GA-treated HSCs.Significance
These results provide evidence for the first time that GA causes selective HSC death through a Ca2 +/calpain I-mediated necrosis cascade, suggesting that GA may represent a potential therapeutic agent to combat liver fibrosis. 相似文献17.
Hideaki Tagashira Chen Zhang Ying-mei Lu Hideyuki Hasegawa Hiroshi Kanai Feng Han Kohji Fukunaga 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
We previously reported that the σ1-receptor (σ1R) is down-regulated following cardiac hypertrophy and dysfunction in transverse aortic constriction (TAC) mice. Here we address how σ1R stimulation with the selective σ1R agonist SA4503 restores hypertrophy-induced cardiac dysfunction through σ1R localized in the sarcoplasmic reticulum (SR).Methods
We first confirmed anti-hypertrophic effects of SA4503 (0.1–1 μM) in cultured cardiomyocytes exposed to angiotensin II (Ang II). Then, to confirm the ameliorative effects of σ1R stimulation in vivo, we administered SA4503 (1.0 mg/kg) and the σ1R antagonist NE-100 (1.0 mg/kg) orally to TAC mice for 4 weeks (once daily).Results
σ1R stimulation with SA4503 significantly inhibited Ang II-induced cardiomyocyte hypertrophy. Ang II exposure for 72 h impaired phenylephrine (PE)-induced Ca2 + mobilization from the SR into both the cytosol and mitochondria. Treatment of cardiomyocytes with SA4503 largely restored PE-induced Ca2 + mobilization into mitochondria. Exposure of cardiomyocytes to Ang II for 72 h decreased basal ATP content and PE-induced ATP production concomitant with reduced mitochondrial size, while SA4503 treatment completely restored ATP production and mitochondrial size. Pretreatment with NE-100 or siRNA abolished these effects. Chronic SA4503 administration also significantly attenuated myocardial hypertrophy and restored ATP production in TAC mice. SA4503 administration also decreased hypertrophy-induced impairments in LV contractile function.Conclusions
σ1R stimulation with the specific agonist SA4503 ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca2 + mobilization and ATP production via σ1R stimulation.General significance
Our observations suggest that σ1R stimulation represents a new therapeutic strategy to rescue the heart from hypertrophic dysfunction. 相似文献18.
Santosh Kumar Sahu Gopala Krishna Aradhyam Sathyanarayana N. Gummadi 《Biochimica et Biophysica Acta (BBA)/General Subjects》2009
Background
Phospholipid scramblases are a group of four homologous proteins conserved from C. elegans to human. In human, two members of the scramblase family, hPLSCR1 and hPLSCR3 are known to bring about Ca2+ dependent translocation of phosphatidylserine and cardiolipin respectively during apoptotic processes. However, affinities of Ca2+/Mg2+ binding to human scramblases and conformational changes taking place in them remains unknown.Methods
In the present study, we analyzed the Ca2+ and Mg2+ binding to the calcium binding motifs of hPLSCR1–4 and hPLSCR1 by spectroscopic methods and isothermal titration calorimetry.Results
The results in this study show that (i) affinities of the peptides are in the order hPLSCR1 > hPLSCR3 > hPLSCR2 > hPLSCR4 for Ca2+ and in the order hPLSCR1 > hPLSCR2 > hPLSCR3 > hPLSCR4 for Mg2+, (ii) binding of ions brings about conformational change in the secondary structure of the peptides. The affinity of Ca2+ and Mg2+ binding to protein hPLSCR1 was similar to that of the peptide I. A sequence comparison shows the existence of scramblase-like motifs among other protein families.Conclusions
Based on the above results, we hypothesize that the Ca2+ binding motif of hPLSCR1 is a novel type of Ca2+ binding motif.General significance
Our findings will be relevant in understanding the calcium dependent scrambling activity of hPLSCRs and their biological function. 相似文献19.
Si Chen Ping Zhu Hui-Ming Guo Raquel Sancho Solis Yanqing Wang Yina Ma Jinli Wang Junjie Gao Ji-Mei Chen Ying Ge Jian Zhuang Ji Li 《Life sciences》2014
Aims
The specific role of AMPKα1 or AMPKα2 in mediating cardiomyocyte contractile function remains elusive. The present study investigated how AMPK activation modulates the contractility of isolated cardiomyocytes.Main methods
Mechanical properties and intracellular Ca2 + properties were measured in isolated cardiomyocytes. The stress signaling was evaluated using western blot and immunoprecipitation analysis.Key findings
AMPK activator, A-769662 induced maximal velocity of shortening (+ dL/dt) and relengthening (− dL/dt), peak height and peak shortening (PS) amplitude in both WT and AMPKα2 KO cardiomyocytes, but did not affect time-to-90% relengthening (TR90). AMPK KD cardiomyocytes demonstrated contractile dysfunction compared with cardiomyocytes from WT and AMPKα2 KO hearts. However, the rise of intracellular Ca2 + levels as well as intracellular ATP levels has no significant difference among WT, AMPKα2 KO and AMPK KD groups with and without the presence of A-769662. Besides, WT, AMPKα2 KO and AMPK KD group displayed a phosphorylated AMPK and downstream acetyl-CoA carboxylase (ACC) phosphorylation. Interestingly, A-769662 also triggered troponin I (cTnI) phosphorylation at Ser149 site which is related to contractility of cardiomyocytes. Furthermore, the immunoprecipitation analysis revealed that AMPKα1 of cardiomyocytes was phosphorylated by A-769662.Significance
This is the first study illustrating that activation of AMPK plays a significant role in mediating the contractile function of cardiomyocytes using transgenic animal models. AMPK activator facilitates the contractility of cardiomyocytes via activating AMPKα1 catalytic subunit. The phosphorylation of cTnI by AMPK could be a factor attributing to the regulation of contractility of cardiomyocytes. 相似文献20.
J.C. Souza E.C Vanzela R.A. Ribeiro L.F. Rezende C.A. de Oliveira E.M. Carneiro H.C.F. Oliveira A.C. Boschero 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2013,1831(4):769-775