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1.
Nef HM Möllmann H Skwara W Bölck B Schwinger RH Hamm Ch Kostin S Schaper J Elsässer A 《Molecular and cellular biochemistry》2006,282(1-2):53-63
Human hibernating myocardium (HHM) is characterized by reversible contractile dysfunction during chronic ischemia. A disturbed
calcium-homeostasis is a decisive factor for reduced functional capacity in heart diseases. We therefore investigated calcium-handling
proteins in HHM. In 12 patients suffering from multi-vessel coronary artery disease and contractile dysfunction with indication
for bypass surgery, HHM was detected preoperatively by thallium scintigraphy, radionuclide ventriculography and dobutamine
echocardiography. Transmural biopsies of these regions were taken and analyzed by immunohistochemistry and electron microscopy.
Furthermore, SR-calcium ATPase (SERCA2a), phospholamban (PLN), the phosphorylated forms of PLN (PLN-Ser16, PLN-Thr17) as well
as sodium-calcium exchanger (NCX) and ryanodine receptor (RyR2) were investigated by RT-PCR and Western-blotting. Additionally,
SERCA2a activity was measured by an enzyme-coupled assay. In all patients complete functional recovery could be documented
3 months after revascularization by repeating all preoperative investigations. In HHM maximal SERCA2a activity was significantly
reduced (HHM: 424.5± 33.9, control: 609.0± 48.5 nmol ATP mg protein−1 min−1, p≤ 0.05), whereas SERCA2a protein levels were unchanged. mRNA levels (HHM: 1.36± 0.08 vs. control: 0.78± 0.04, p≤ 0.05) and protein amount (HHM:1.67± 0.14 vs. control: 1.00± 0.04, p≤ 0.05) of PLN (A1) were increased resulting in an increased PLN:SERCA2a-ratio. PLN-Ser16 (HHM: 0.60± 0.08 vs. control: 1.00±
0.11, p≤ 0.05) and PLN-Thr17 (HHM: 0.63± 0.11 vs. control: 1.00± 0.06, p≤ 0.05) phosphorylation was significantly decreased. RyR2 and NCX showed no significant alteration. In HHM a decreased activity
of SERCA2a due to an impaired phosphorylation of PLN contributes to contractile dysfunction. The increase in the relative
ratio of PLN/SERCA2a leads to a decreased calcium affinity of SERCA2a. 相似文献
2.
《Phytomedicine》2015,22(5):568-572
BackgroundThe root of Asparagus cochinchinensis (Lour.) Merr. has been utilized as mucoregulators and expectorants for controlling the airway inflammatory diseases in folk medicine.Hypothesis/purposeWe investigated whether dioscin and methylprotodioscin isolated from the root of Asparagus cochinchinensis (Lour.) Merr. suppress the gene expression and production of airway MUC5AC mucin induced by phorbol ester and growth factor.Study designConfluent NCI-H292 cells were pretreated with dioscin or methylprotodioscin for 30 min and then stimulated with EGF or PMA for 24 h. The MUC5AC mucin gene expression was measured by RT-PCR. Production of MUC5AC mucin protein was measured by ELISA.Results(1) Dioscin and methylprotodioscin suppressed the expression of MUC5AC mucin gene induced by EGF or PMA; (2) dioscin suppressed the production of MUC5AC mucin induced by either EGF at 10−5 M (p < 0.05) and 10−6 M (p < 0.05) or PMA at 10−4 M (p < 0.05), 10−5 M (p < 0.05) and 10−6 M (p < 0.05); (3) methylprotodioscin also suppressed the production of MUC5AC mucin induced by either EGF at 10−4 M (p < 0.05) or PMA at 10−4 M (p < 0.05).ConclusionThese results suggest that dioscin and methylprotodioscin isolated from the root of Asparagus cochinchinensis suppress the gene expression and production of MUC5AC mucin, by directly acting on airway epithelial cells, and the results are consistent with the traditional use of Asparagus cochinchinensis as remedy for diverse inflammatory pulmonary diseases. 相似文献
3.
4.
In failing hearts, although protein phosphatase type 1 (PP1) activity has increased, information about the regulation and status of PP1 inhibitor-1 (INH-1) and inhibitor-2 (INH-2) is limited. In this study, we examined activity and protein expression of PP1, INH-1 and INH-2 and phosphorylation of sarcoplasmic reticulum (SR) phospholamban (PLB), a substrate of PP1 and modulator of SR Ca2+-ATPase activity, in failing and non-failing hearts. These studies were performed in LV myocardium of seven rats with chronic renal hypertension produced by Goldblatts one-kidney, one-clip procedure and seven age-matched sham-operated normal controls (CTR). Eight weeks after surgery, LV ejection fraction, LV hypertrophy, and pulmonary congestion were determined in all rats. PP1 activity (nmol 32P/min/mg non-collagen protein) was assessed in LV homogenates using 32P-labeled phosphorylase a as substrate. INH-1 and INH-2 activity was determined in the immunoprecipitate of LV homogenates and expressed as percentage inhibitory activity. Using a specific antibody, LV tissue levels of PP1C and calsequestrin (CSQ), a SR calcium binding protein, which is not altered in failing hearts, were also determined. Further, total and phosphorylated PLB, INH-1 and INH-2 protein levels were determined in the LV homogenate and phosphoprotein-enriched fraction, respectively. The band density of each protein was quantified in densitometric units and normalized to CSQ. Results: rats with chronic renal hypertension exhibited significantly reduced LV ejection fraction and increased LV hypertrophy and pulmonary congestion, characteristics of chronic heart failure (CHF). We found that compared to CTR, (1) both INH-1 (10.2 ± 2 versus 57.5 ± 1; p<0.05) and INH-2 activity (3.8 ± 0.4 versus 36.2 ± 4; p<0.05) were reduced, (2) total and phosphorylated PLB amount reduced, (3) protein level of phosphorylated INH-1 was reduced (2.32 ± 0.1 versus 0.73 ± 0.04; p<0.05) whereas that of phosphorylated INH-2 increased (3.05 ± 0.3 versus 1.42 ± 0.1; p<0.05), and (4) PP1 activity was increased approximately 2.6-fold in rats with CHF (1.59 ± 0.05 versus 0.61 ± 0.01; p<0.05) while protein level of the catalytic subunit of PP1 (PP1C) increased 3.85-fold (0.77 ± 0.05 versus 0.20 ± 0.02; p<0.05). These results suggest that reduced inhibitory INH-1 and INH-2 activity, increased PP1C protein level, and reduced PLB phosphorylation are associated with increased PP1 activity in failing hearts. (Mol Cell Biochem 269: 49–57, 2005) 相似文献
5.
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6.
Sarah Rouhana Charlotte Farah Jerome Roy Amanda Finan Glaucy Rodrigues de Araujo Patrice Bideaux Valérie Scheuermann Youakim Saliba Cyril Reboul Olivier Cazorla Franck Aimond Sylvain Richard Jérôme Thireau Nassim Fares 《生物化学与生物物理学报:疾病的分子基础》2019,1865(1):230-242
Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome associated with high morbidity and mortality. Therapeutic options are limited due to a lack of knowledge of the pathology and its evolution. We investigated the cellular phenotype and Ca2+ handling in hearts recapitulating HFpEF criteria. HFpEF was induced in a portion of male Wistar rats four weeks after abdominal aortic banding. These animals had nearly normal ejection fraction and presented elevated blood pressure, lung congestion, concentric hypertrophy, increased LV mass, wall stiffness, impaired active relaxation and passive filling of the left ventricle, enlarged left atrium, and cardiomyocyte hypertrophy. Left ventricular cell contraction was stronger and the Ca2+ transient larger. Ca2+ cycling was modified with a RyR2 mediated Ca2+ leak from the sarcoplasmic reticulum and impaired Ca2+ extrusion through the Sodium/Calcium exchanger (NCX), which promoted an increase in diastolic Ca2+. The Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA2a) and NCX protein levels were unchanged. The phospholamban (PLN) to SERCA2a ratio was augmented in favor of an inhibitory effect on the SERCA2a activity. Conversely, PLN phosphorylation at the calmodulin-dependent kinase II (CaMKII)-specific site (PLN-Thr17), which promotes SERCA2A activity, was increased as well, suggesting an adaptive compensation of Ca2+ cycling. Altogether our findings show that cardiac remodeling in hearts with a HFpEF status differs from that known for heart failure with reduced ejection fraction. These data also underscore the interdependence between systolic and diastolic “adaptations” of Ca2+ cycling with complex compensative interactions between Ca2+ handling partner and regulatory proteins. 相似文献
7.
Hill M Vrbíková J Zárubová J Kancheva R Velíková M Kancheva L Kubátová J Dušková M Marusič P Pařízek A Stárka L 《Steroids》2011,76(12):1351-1357
Background
Epilepsy in women may be associated with reproductive disorders and alterations in serum steroid levels. Some steroids can be induced by epilepsy and/or treatment with antiepileptic drugs; however, there are still limited data available concerning this effect on the levels of other neuroactive steroid metabolites such as 3a-hydroxy-5a/b-reduced androstanes.Aim
To evaluate steroid alterations in women with epilepsy (WWE) on lamotrigine monotherapy.Subjects and methods
Eleven WWE and 11 age-matched healthy women underwent blood sampling in both phases of their menstrual cycles (MCs). The steroid metabolome, which included 30 unconjugated steroids, 17 steroid polar conjugates, gonadotropins, and sex hormone-binding globulin (SHBG), was measured using gas chromatography–mass spectrometry (GC–MS) and radioimmunoassay (RIA).Results
WWE had lower cortisol levels (status p < 0.001), but elevated levels of unconjugated 17-hydroxypregnenolone (status p < 0.001). Progesterone was higher in the follicular menstrual phase (FP) in WWE than in the controls (status × menstrual phase p < 0.05, Bonferroni multiple comparisons p < 0.05), whereas 17-hydroxyprogesterone was higher in WWE in both menstrual phases (status p < 0.001). The steroid conjugates were mostly elevated in WWE. The levels of 5α/β-reduced androstanes in WWE that were significantly higher than the controls were etiocholanolone (status p < 0.001), 5α-androstane-3α,17β-diol (status p < 0.001), and the 5α/β-reduced androstane polar conjugates (status p < 0.001).Conclusions
WWE showed a trend toward higher circulating 3α-hydroxy-5α/β-reduced androstanes, increased activity of 17α-hydroxylase/17,20 lyase in the Δ5-steroid metabolic pathway, and increased levels of the steroid polar conjugates. 相似文献8.
Background
Patients with diabetes mellitus (DM) suffer from an increased risk of cardiovascular events caused by thrombotic conditions. Adipose tissue might play a crucial role in this pathogenesis by synthesis of procoagulant mediators. This study was performed to elucidate the role of the adipocytokines leptin and resistin in the development of hypercoagulability and hypofibrinolysis under diabetic conditions.Methods
Sixty two patients with or without DM were included in our study to measure leptin, resistin and tissue factor (TF) plasma concentrations. Moreover, flow chamber experiments were performed to assess factor Xa and plasmin activity on the surface of HUVECs. Western blot and real-time PCR were performed to determine mRNA and protein expression of main factors of the coagulation and fibrinolytic system.Results
Patients with diabetes showed increased levels of leptin and resistin (leptin: 25.69 ± 13.9 vs. 15.98 ± 17.5 ng/mL, p < 0.05; resistin: 2.61 ± 0.6 vs. 1.19 ± 0.7 ng/mL, p < 0.05), which were positively correlated with TF. In vitro, leptin and resistin induced increased factor Xa activity (leptin: 4.29 ± 0.57-fold, p < 0.05; resistin 4.19 ± 0.7-fold, p < 0.05 vs. control) on HUVECs as also reflected by elevated TF mRNA and protein expression. Moreover, stimulatory (plasminogen activator inhibitor 1) and inhibitory (tissue plasminogen activator) mediators of the fibrinolytic cascade were induced by leptin and resistin, leading to a balanced plasmin activity regulation.Conclusions
Leptin and resistin lead to a procoagulant state in HUVECs by inducing TF expression. This mechanism might be one explanation for the prothrombotic state observed under diabetic conditions. 相似文献9.
Sara Vandenwijngaert Peter Pokreisz Hadewich Hermans Hilde Gillijns Marijke Pellens Noortje A. M. Bax Giulia Coppiello Wouter Oosterlinck Agnes Balogh Zoltan Papp Carlijn V. C. Bouten Jozef Bartunek Jan D'hooge Aernout Luttun Erik Verbeken Marie Christine Herregods Paul Herijgers Kenneth D. Bloch Stefan Janssens 《PloS one》2013,8(3)
Background
The intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC).Methodology/Principal Findings
In patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5-TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dtmax and dP/dtmin with prolonged tau (P<0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro.Conclusions/Significance
Myocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target. 相似文献10.
Although hypercholesterolemia is a well-known risk factor for atherosclerosis, little is known about the effect of hypercholesterolemia on cardiac contractile function. The objective of this study was to examine the effect of hypercholesterolemia on myocardial contractility. Fifteen New Zealand white rabbits were fed standard chow (control group) and another 15 were fed a cholesterolenriched diet (HC group) for 12 weeks. The contractile response of ventricular muscle strips was measured in various extracellular calcium concentrations and at different pacing rates. The whole-cell calcium current recording, and mRNA and protein levels of cellular calcium-handling proteins were also analyzed. With 2 mM Ca2+ and stimulation at 3 Hz, the contractile force of HC strips was less than that of the controls (3.63±0.20 vs. 4.61±0.50 mN, p<0.05). The time to peak tension was longer for HC strips (93.3±2.16 vs. 82.2±2.81 ms, p < 0.05). The peak L-type calcium inward current density was slightly higher in HC myocytes but did not reach statistical significance (–14.90±0.94 vs. –12.44±0.84 pA/pF, p=0.15). The mRNA level of sarcoplasmic reticulum Ca2+-ATPase (SERCA), normalized to GAPDH, was significantly lower in the HC than that in the control group (2.85±0.14 vs. 7.67±0.67, p<0.05), as was the ryanodine receptor (RyR; 0.42±0.06 vs. 0.71±0.13, p<0.05). The mRNA of the Na+/Ca2+ exchanger (NCX) was statistically higher in the HC group (0.90±0.12 vs. 0.48±0.05, p<0.05). Western blot experiments revealed that protein expression of SERCA in the HC strips decreased, but that of the NCX increased. The protein expression of the dihydropyridine receptor was similar between these two groups. We concluded that hypercholesterolemia results in suppression of the maximal contractile function and in a longer systolic contractile time course. These changes may partially be mediated through a decrease in SERCA and RyR but an increase in NCX expression. 相似文献
11.
Lelio Morricone Alexis Elias Malavazos Calin Coman Cristina Donati Tamin Hassan Francesco Caviezel 《Obesity (Silver Spring, Md.)》2002,10(6):489-498
Objective: To evaluate the relationship of echocardiographic characteristics and visceral adipose tissue (VAT) distribution in normotensive obese patients. Research Methods and Procedures: Echocardiographic parameters were assessed in 28 normotensive obese patients [7 men, 21 women, mean age, 43.2 years; mean body mass index (BMI), 37.2 kg/m2; 10 with impaired glucose tolerance (IGT); 6 with type 2 diabetes] and 18 sex‐ and age‐matched healthy, normal‐weight controls (4 men, 14 women; mean age, 45.8 years; mean BMI, 22.4 kg/m2) by an M‐mode, color‐doppler videofluoroscope. VAT in the obese patients was assessed by computed tomography (at L4 level). Results: The obese patients had a significantly larger internal diastolic left ventricular (LV) diameter (p < 0.05), a thicker end‐diastolic septum (p < 0.001) and posterior wall (p < 0.001), a greater indexed (g/m2.7) LV mass (p < 0.001), a higher atrial diastolic filling wave velocity (p < 0.001), a lower ratio between early and atrial diastolic filling wave velocities (p < 0.01), and a prolonged isovolumic relaxation time (p < 0.05). End‐diastolic septum and posterior wall thickness and the LV mass were significantly greater in patients with a VAT area >130 cm2 than with <130 cm2. In the multivariate regression analysis, only VAT (p < 0.0001), waist‐to‐hip ratio (p < 0.001), and sex (p < 0.001) were associated with the most important echocardiographic alterations. Discussion: The morphological and functional echocardiographic alterations usually found in normotensive obese patients closely correlate with the amount of intra‐abdominal fat deposition, even in the presence of diabetes or IGT. 相似文献
12.
Background
The role of olfactory marker protein (OMP), a hallmark of mature olfactory sensory neurons (OSNs), has been poorly understood since its discovery. The electrophysiological and behavioral phenotypes of OMP knockout mice indicated that OMP influences olfactory signal transduction. However, the mechanism by which this occurs remained unknown.Principal Findings
We used intact olfactory epithelium obtained from WT and OMP−/− mice to monitor the Ca2+ dynamics induced by the activation of cyclic nucleotide-gated channels, voltage-operated Ca2+ channels, or Ca2+ stores in single dendritic knobs of OSNs. Our data suggested that OMP could act to modulate the Ca2+-homeostasis in these neurons by influencing the activity of the plasma membrane Na+/Ca2+-exchanger (NCX). Immunohistochemistry verifies colocalization of NCX1 and OMP in the cilia and knobs of OSNs. To test the role of NCX activity, we compared the kinetics of Ca2+ elevation by stimulating the reverse mode of NCX in both WT and OMP−/− mice. The resulting Ca2+ responses indicate that OMP facilitates NCX activity and allows rapid Ca2+ extrusion from OSN knobs. To address the mechanism by which OMP influences NCX activity in OSNs we studied protein-peptide interactions in real-time using surface plasmon resonance technology. We demonstrate the direct interaction of the XIP regulatory-peptide of NCX with calmodulin (CaM).Conclusions
Since CaM also binds to the Bex protein, an interacting protein partner of OMP, these observations strongly suggest that OMP can influence CaM efficacy and thus alters NCX activity by a series of protein-protein interactions. 相似文献13.
The aim of the present study is to evaluate the status of plasma essential trace element selenium (Se), manganese (Mn), copper
(Cu), zinc (Zn), and iron (Fe) concentrations and the effect of these elements on oxidative status in patients with childhood
asthma. Plasma Se, Mn, Cu, and Zn concentrations were determined by atomic absorption spectrophotometry (AAS) and Fe concentrations,
malondialdehyde (MDA), and total antioxidant capacity (TAC) were determined by the colorimetric method. The plasma MDA/TAC
ratio was calculated as an index of oxidative status. Plasma albumin levels were measured to determine nutritional status.
Plasma Fe concentrations, MDA levels and the MDA/TAC ratio were significantly higher (p<0.001, p<0.001, and p<0.01, respectively) and Se and Mn concentrations and TAC were lower (p<0.01, p<0.05, and p<0.01, respectively) in patients when compared to the healthy subjects. Plasma Zn, Cu, and albumin levels were not found to
be significantly different in patients and controls (p>0.05). There were positive relationships between plasma MDA and Fe (r=0.545, p<0.001) and TAC and Se (r=0.485, p<0.021), and a negative correlation between TAC and MDA values (r= −0.337, p<0.031) in patients with childhood asthma. However, there was no correlation between these trace elements and albumin content
in patient groups. These observations suggest that increased Fe and decreased Se concentrations in patients with childhood
asthma may be responsible for the oxidant/antioxidant imbalance. 相似文献
14.
Plasma membrane calcium ATPase 4 (PMCA4) co‐ordinates calcium and nitric oxide signaling in regulating murine sperm functional activity
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Kristine E. Olli Kun Li Deni S. Galileo Patricia A. Martin‐DeLeon 《Journal of cellular physiology》2018,233(1):11-22
Reduced sperm motility (asthenospermia) and resulting infertility arise from deletion of the Plasma Membrane Ca2+‐ATPase 4 (Pmca4) gene which encodes the highly conserved Ca2+ efflux pump, PMCA4. This is the major Ca2+ clearance protein in murine sperm. Since the mechanism underlying asthenospermia in PMCA4's absence or reduced activity is unknown, we investigated if sperm PMCA4 negatively regulates nitric oxide synthases (NOSs) and when absent NO, peroxynitrite, and oxidative stress levels are increased. Using co‐immunoprecipitation (Co‐IP) and Fluorescence Resonance Energy Transfer (FRET), we show an association of PMCA4 with the NOSs in elevated cytosolic [Ca2+] in capacitated and Ca2+ ionophore‐treated sperm and with neuronal (nNOS) at basal [Ca2+] (ucapacitated sperm). FRET efficiencies for PMCA4‐eNOS were 35% and 23% in capacitated and uncapacitated sperm, significantly (p < 0.01) different, with the molecules being <10 nm apart. For PMCA4‐nNOS, this interaction was seen only for capacitated sperm where FRET efficiency was 24%, significantly (p < 0.05) higher than in uncapacitated sperm (6%). PMCA4 and the NOSs were identified as interacting partners in a quaternary complex that includes Caveolin1, which co‐immunoprecipitated with eNOS in a Ca2+‐dependent manner. In Pmca4?/? sperm NOS activity was elevated twofold in capacitated/uncapacitated sperm (vs. wild‐type), accompanied by a twofold increase in peroxynitrite levels and significantly (p < 0.001) increased numbers of apoptotic germ cells. The data support a quaternary complex model in which PMCA4 co‐ordinates Ca2+ and NO signaling to maintain motility, with increased NO levels resulting in asthenospermia in Pmca4?/? males. They suggest the involvement of PMCA4 mutations in human asthenospermia, with diagnostic relevance. 相似文献
15.
Yan Lv Yongkui Ren Lufan Sun Shaojun Wang Minjie Wei Dalin Jia 《Cell biochemistry and biophysics》2013,66(2):357-363
Reverse-mode activation of the Na+/Ca2+ exchanger (NCX) during reperfusion following ischemia contributes to Ca2+ overload and cardiomyocyte injury. KB-R7943, a selective reverse-mode NCX inhibitor, reduces lethal reperfusion injury under non-ischemic conditions. However, the effectiveness of this compound under ischemic conditions is unclear. In the present study, we studied the effects of KB-R7943 in an animal model of hyperlipidemia. We further assessed whether the K ATP + channels are involved in potential protective mechanisms of KB-R7943. Twelve rats were fed normal chow, while 48 animals were fed a high cholesterol diet. The hearts from the control and hypercholesterolemic rats were subjected to 25 min of global ischemia followed by a 120-min reperfusion. Before this, hearts from hypercholesterolemic rats either received no intervention (cholesterol control group) or were pre-treated with 1 μM KB-R7943 and 0.3 μM of K ATP + blocker glibenclamide or glibenclamide alone. The infarction sizes (triphenyltetrazolium assay) were 35 ± 5.0 % in the control group, 46 ± 8.7 % in the cholesterol control group (p < 0.05 vs. control group), 28.6 ± 3.3 % in the KB-R7943 group (p < 0.05 vs. cholesterol control group), 44 ± 5 % in the KB-R7943 and glibenclamide group, and 47 ± 8.5 % in the glibenclamide group (p < 0.05 vs. control group). Further, KB-R7943 attenuated the magnitude of cell apoptosis (p < 0.05 vs. cholesterol control group). These beneficial effects were abolished by glibenclamide. In conclusion, diet-induced hypercholesterolemia enhances myocardial injury. Selective reverse-mode NCX inhibitor KB-R7943 reduces the infarction size and apoptosis in hyperlipidemic animals through the activation of K ATP + channels. 相似文献
16.
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17.
Objectives
The purpose of this study was to explore the relationship between left ventricular (LV) dysfunction and arterial wall stiffening.Methods
A total of 218 patients over the age of 45 diagnosed with hypertension in Jinan City and hospitalised between 2010 and 2011 were included in this study. LV function was evaluated using echocardiography (ECHO). Blood pressure was monitored with an automated tonometric device, and the parameters of arterial wall stiffness were measured. In addition, the metabolic parameters of blood samples, such as glucose and lipids, were also determined using the Cobas E601 analyser.Results
Stiffness parameter beta positively correlated with LV diastolic function (E/Em ratio) (r?=?0.255, p?<?0.001). LV end-diastolic diameter not only related to the E/Em ratio (r?=?0.196, p?=?0.009) but also with beta (r?=?0.220, p?=?0.002). The stiffness parameter beta was an early indicator of E/Em ratio as determined by multiple regression analysis (R 2?=?0.381, p?<?0.01). Age, blood pressure and fasting blood glucose contributed to stiffness parameter beta (p?<?0.05), as well as the E/Em ratio (p?<?0.01).Conclusions
Our findings suggested that LV dysfunction may have a direct relationship to arterial stiffening, independently of having similar risk factors. In addition, arterial stiffness can be an independent predictor of LV diastolic function, suggesting that the severity of arterial stiffness directly correlates with the severity of LV dysfunction. 相似文献18.
Bracken N.K. Woodall A.J. Howarth F.C. Singh J. 《Molecular and cellular biochemistry》2004,261(1):235-243
Cardiac contractile dysfunction is frequently reported in human patients and experimental animals with type-1 diabetes mellitus. The aim of this study was to investigate the voltage-dependence of contraction in ventricular myocytes from the streptozotocin (STZ)-induced diabetic rat. STZ-induced diabetes was characterised by hyperglycaemia and hypoinsulinaemia. Other characteristics included reduced body and heart weight and raised blood osmolarity. Isolated ventricular myocytes were patched in whole cell, voltage-clamp mode after correcting for membrane capacitance and series resistance. From a holding membrane potential of –40 mV, test pulses were applied at potentials between –30 and +50 mV in 10 mV increments. L-type Ca2+ current (I
Ca,L) density and contraction were measured simultaneously using a video-edge detection system. Membrane capacitance was not significantly altered between control and STZ-induced diabetic myocytes. The I
Ca,L density was significantly (p < 0.05) reduced throughout voltage ranges (–10 mV to +10 mV) in myocytes from STZ-treated rats compared to age-matched controls. Moreover, the amplitude of contraction was significantly reduced (p < 0.05) in myocytes from STZ-treated rats at all test potentials between –20 mV and +30 mV. However, in electrically field-stimulated (1 Hz) myocytes, the amplitude of contraction was not altered by STZ-treatment. It is suggested that in field-stimulated myocytes taken from STZ-induced diabetic hearts, prolonged action potential duration may promote increased Ca2+ influx via the sodium-calcium exchanger (NCX), which may compensate for a reduction in Ca2+ trigger through L-type-Ca2+-channels and lead to normalised contraction. (Mol Cell Biochem 261: 235–243, 2004) 相似文献
19.
In previous studies, we have shown that cerebral hypoxia results in increased activity of caspase-9, the initiator caspase,
and caspase-3, the executioner of programmed cell death. We have also shown that cerebral hypoxia results in high affinity
Ca2+–ATPase-dependent increase in nuclear Ca2+-influx in the cerebral cortex of newborn piglets. The present study tests the hypothesis that inhibiting nuclear Ca2+-influx by pretreatment with clonidine, an inhibitor of high affinity Ca2+–ATPase, will prevent the hypoxia-induced increase in caspase-9 and caspase-3 activity in the cerebral cortex of newborn piglets.
Thirteen newborn piglets were divided into three groups, normoxic (Nx, n = 4), hypoxic (Hx, n = 4), and hypoxic treated with clonidine (100 mg/kg) (Hx–Cl, n = 5). Anesthetized, ventilated animals were exposed to an FiO2 of 0.21 (Nx) or 0.07 (Hx) for 60 min. Cerebral tissue hypoxia was documented biochemically by determining levels of ATP and
phosphocreatine (PCr). Caspase-9 and -3 activity were determined spectrofluoro-metrically using specific fluorogenic synthetic
substrates. ATP (μmoles/g brain) was 4.6 ± 0.3 in Nx, 1.7±0.4 in Hx (P < 0.05 vs. Nx), and 1.5 ± 0.2 in Hx–Cl (P < 0.05 vs. Nx). PCr (μmoles/g brain) was 3.6 ± 0.4 in Nx, 1.1 ± 0.3 in Hx (P < 0.05 vs. Nx), and 1.0 ± 0.2 in Hx–Cl (P < 0.05 vs. Nx). Caspase-9 activity (nmoles/mg protein/h) was 0.548 ± 0.0642 in Nx and increased to 0.808 ± 0.080 (P < 0.05 vs. Nx and Hx–Cl) in the Hx and 0.562 ± 0.050 in the Hx–Cl group (p = NS vs. Nx). Caspase-3 activity (nmoles/mg protein/h)
was 22.0 ± 1.3 in Nx and 32 ± 6.3 in Hx (P < 0.05 vs. Nx) and 18.8 ± 3.2 in the Hx–Cl group (P < 0.05 vs. Hx). The data demonstrate that clonidine administration prior to hypoxia prevents the hypoxia-induced increase
in the activity of caspase-9 and caspase-3. We conclude that the high afinity Ca2+–ATPase-dependent increased nuclear Ca2+ during hypoxia results in increased caspase-9 and caspase-3 activity. 相似文献
20.
Agnese Secondo Alba Esposito Rossana Sirabella Francesca Boscia Anna Pannaccione Pasquale Molinaro Maria Cantile Roselia Ciccone Maria Josè Sisalli Antonella Scorziello Gianfranco Di Renzo Lucio Annunziato 《The Journal of biological chemistry》2015,290(3):1319-1331
NGF induces neuronal differentiation by modulating [Ca2+]i. However, the role of the three isoforms of the main Ca2+-extruding system, the Na+/Ca2+ exchanger (NCX), in NGF-induced differentiation remains unexplored. We investigated whether NCX1, NCX2, and NCX3 isoforms could play a relevant role in neuronal differentiation through the modulation of [Ca2+]i and the Akt pathway. NGF caused progressive neurite elongation; a significant increase of the well known marker of growth cones, GAP-43; and an enhancement of endoplasmic reticulum (ER) Ca2+ content and of Akt phosphorylation through an early activation of ERK1/2. Interestingly, during NGF-induced differentiation, the NCX1 protein level increased, NCX3 decreased, and NCX2 remained unaffected. At the same time, NCX total activity increased. Moreover, NCX1 colocalized and coimmunoprecipitated with GAP-43, and NCX1 silencing prevented NGF-induced effects on GAP-43 expression, Akt phosphorylation, and neurite outgrowth. On the other hand, the overexpression of its neuronal splicing isoform, NCX1.4, even in the absence of NGF, induced an increase in Akt phosphorylation and GAP-43 protein expression. Interestingly, tetrodotoxin-sensitive Na+ currents and 1,3-benzenedicarboxylic acid, 4,4′-[1,4,10-trioxa-7,13-diazacyclopentadecane-7,13-diylbis(5-methoxy-6,12-benzofurandiyl)]bis-, tetrakis[(acetyloxy)methyl] ester-detected [Na+]i significantly increased in cells overexpressing NCX1.4 as well as ER Ca2+ content. This latter effect was prevented by tetrodotoxin. Furthermore, either the [Ca2+]i chelator(1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid) (BAPTA-AM) or the PI3K inhibitor LY 294002 prevented Akt phosphorylation and GAP-43 protein expression rise in NCX1.4 overexpressing cells. Moreover, in primary cortical neurons, NCX1 silencing prevented Akt phosphorylation, GAP-43 and MAP2 overexpression, and neurite elongation. Collectively, these data show that NCX1 participates in neuronal differentiation through the modulation of ER Ca2+ content and PI3K signaling. 相似文献