Membrane fluidity and hypertension.
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Animals↗
Biomedical subjects
Ichiro Nishio
Publications and source records attributed to Ichiro Nishio.
Nitric oxide is a determinant of membrane fluidity of erythrocytes in postmenopausal women: an electron paramagnetic resonance investigation.
In the present study, to determine a possible role of nitric oxide (NO) in the regulation of membrane functions, we examined the relationship between plasma NO level and membrane fluidity of erythrocytes in postmenopausal women. We evaluated the membrane fluidity of erythrocytes obtained from hypertensive and normotensive postmenopausal women by means of an electron paramagnetic resonance (EPR) and spin labeling method. The EPR study revealed that the order parameter (S) for 5-nitroxide stearate in erythrocyte membranes was significantly greater in hypertensive postmenopausal women than in normotensive postmenopausal women. The finding indicated that the membrane fluidity of erythrocytes was decreased in hypertensive postmenopausal women compared with normotensive postmenopausal women. The plasma level of the NO metabolites (nitrite and nitrate) while fasting was significantly lower in hypertensive postmenopausal women than in normotensive postmenopausal women. In addition, the order parameter (S) in the EPR spectra of erythrocyte membranes was inversely correlated with the plasma NO metabolite level, which indicated that the lower membrane fluidity of erythrocytes was associated with the lower plasma NO level in postmenopausal women. These results are consistent with the hypothesis that NO may have a crucial role in the regulation of membrane fluidity of erythrocytes in postmenopausal women.
Aged↗
Hormone replacement therapy improves membrane fluidity of erythrocytes in postmenopausal women: an electron paramagnetic resonance investigation.
BACKGROUND: Many studies have shown that hormone replacement therapy (HRT) might provide protection against the development of hypertension and arteriosclerosis in postmenopausal women. However, the precise mechanism underlying its benefits is unclear. This question was addressed in an electron spin resonance (EPR) study of membrane function of erythrocytes in postmenopausal women. The purpose of this study was to investigate the effects of HRT on membrane fluidity of erythrocytes in postmenopausal women by means of the EPR and spin-labeling method. METHODS: The healthy postmenopausal women were randomly divided into the HRT group (n = 14) receiving the conjugated estrogen with medroxyprogesterone for 3 months and the non-HRT control group (n = 14). We measured membrane fluidity of erythrocytes in postmenopausal women before and after the trial period. RESULTS: The HRT group showed a significant decrease in blood pressure (BP) after treatment (systolic BP 145.7 +/- 5.5 v 123.3 +/- 5.1 mm Hg, n = 14, mean +/- SEM, P <.05). The order parameter (S) for 5-nitroxide stearate in the EPR spectra of erythrocyte membranes decreased significantly in the HRT group (S: 0.718 +/- 0.002 v 0.695 +/- 0.002, n = 14, P <.01). The finding indicated that HRT increased the membrane fluidity of erythrocytes and improved the microviscosity of the cell membranes in postmenopausal women. CONCLUSIONS: These results are consistent with the hypothesis that HRT might have a beneficial effect on the membrane rheologic behavior of erythrocytes and the microcirculation in postmenopausal women.
Arteriosclerosis↗
Inhibition of nuclear translocation of transcription factor nuclear factor-kappa B induces FAS- as well as tumour necrosis factor-alpha-mediated apoptosis through downregulation of a conserved family of inhibitor of apoptosis 1.
1. In the present study, we examined whether the nuclear transcription factor (NF)-kappaB activity plays a role in the determination of sensitivity to tumour necrosis factor (TNF)-alpha or agonistic Fas antibody (Ab) in human vascular smooth muscle cells (hVSMC). 2. To inhibit agonist-induced NF-kappaB activation in hVSMC, a cell-permeable peptide (SN50), which carried the nuclear localization sequence of the NF-kappaB p50 subunit, was used. Nuclear factor-kappaB activity was examined by both immunoblot analysis of nuclear extracts and by ELISA. The hVSMC were treated with TNF-alpha or agonistic Fas Ab (CH11) and then apoptosis was determined by cell death ELISA for DNA fragmentation. To investigate the mechanisms for protection against apoptosis in hVSMC, we analysed the expression of a conserved family of inhibitor of apoptosis 1 (c-IAP1) protein using immunoblot analysis. 3. Although both CH11 and TNF-alpha alone failed to induce hVSMC death in the presence of SN50, they markedly increased the apoptotic hVSMC estimated by cell death ELISA. In addition, these effects could be blocked with the pan-caspase inhibitor z-VAD.fmk. Western blotting analysis indicated that TNF-alpha alone increased c-IAP1 protein levels, whereas CH11 alone had no effect. Inhibition of NF-kappaB activation by SN50 suppressed c-IAP1 protein expression and enhanced apoptosis induced by either TNF-alpha or CH11. 4. These findings suggest that c-IAP1 is an important intracellular modulator of Fas as well as TNF-alpha death signalling pathways in hVSMC. The expression of c-IAP1 is regulated by a NF-kappaB-mediated phenomenon.
Active Transport, Cell Nucleus↗
Oxidized low-density lipoprotein sensitizes human vascular smooth muscle cells to FAS (CD95)-mediated apoptosis.
1. It was investigated in the present study whether oxidized low-density lipoprotein (oxLDL) was implicated in the susceptibility of human vascular smooth muscle cells (VSMC) to Fas-mediated death. Human fetal aorta smooth muscle cells were treated with agonistic anti-Fas antibody (CH11) and oxLDL and cell death was then determined by viability and DNA fragmentation. 2. The results of the present study show that cross-linking of Fas receptor with anti-Fas antibody in the presence of oxLDL induced death and DNA fragmentation in human VSMC, which were blocked by the caspase inhibitor z-VAD.fmk, followed by the upregulation of cell surface Fas. 3. The data indicate that oxLDL is implicated in death in VSMC and provide evidence that oxLDL is involved in Fas signal transduction. The present study proposes a novel mechanism(s) by which VSMC become susceptible to Fas ligand. 4. One of the mechanisms proposed by which oxLDL upregulates cell surface Fas is by inhibiting the degradation of Fas through the ubiquitin-proteasome pathway.
Amino Acid Chloromethyl Ketones↗
Oxidized low-density lipoprotein inhibits vascular endothelial growth factor-induced endothelial progenitor cell differentiation.
1. Bone marrow-derived endothelial progenitor cells (EPC) in the peripheral blood of adult animals and humans have been shown to be incorporated into neovascularization. In contrast, hypercholesterolaemia impairs angiogenesis and collateral vessel formation in response to regional tissue ischaemia. We investigated whether oxidized LDL (oxLDL) affected human EPC differentiation. 2. When isolated human mononuclear cells (MNC) were incubated with vascular endothelial growth factor (VEGF), the number of differentiated, adherent EPC, as assessed by an in vitro culture assay, was increased in a dose-dependent manner (P < 0.01). When MNC were incubated with oxLDL at 1, 5 and 10 microg/mL in the presence of 100 ng/mL VEGF for 24 h, oxLDL dose-dependently reduced the number of differentiated, adherent EPC. 3. Vascular endothelial growth factor-induced EPC differentiation was significantly inhibited by pharmacological phosphatidylinositol 3-kinase blockers (either 10 nmol/L wortmannin or 10 micromol/L LY294002). Interestingly, immunoblotting analysis revealed that oxLDL dose-dependently led to dephosphorylation and, thus, deactivation of Akt in the presence of VEGF. Finally, these inhibitory effects induced by oxLDL were abolished by pretreatment with 1 micromol/L atorvastatin (P < 0.01). 4. Our data indicate that oxLDL inhibits VEGF-induced EPC differentiation through the dephosphorylation of Akt.
Cell Differentiation↗
Role of protein kinase C in the regulation of acetylcholine release in the central nervous system of spontaneously hypertensive rats.
Previous studies have shown that the central cholinergic nervous system may be involved in blood pressure control. In the present study, we investigated the role of protein kinase C in the regulation of cholinergic nervous activity in the central nervous system in hypertension. In superfused slices of the striatum obtained from spontaneously hypertensive rats and age-matched Wistar-Kyoto rats, we examined the effects of the protein kinase C inhibitor H-7 on the release of [3H]-acetylcholine in vitro. The stimulation-evoked [3H]-acetylcholine release was not different between spontaneously hypertensive rats and Wistar-Kyoto rats. The protein kinase C inhibitor H-7 reduced the stimulation-evoked [3H]-acetylcholine release to a greater extent in spontaneously hypertensive rats than in Wistar-Kyoto rats. The results of the present study showed that the enhanced calcium-protein kinase C system might actively participate in the regulation of cholinergic nervous activity in the central nervous system in hypertension.
Acetylcholine↗
Molecular mechanism of emotional stress-induced and catecholamine-induced heart attack.
Emotional or physical stress triggers 'tako-tsubo' cardiomyopathy or 'transient left ventricular apical ballooning', but the pathogenesis is unclear. In response to the immobilization stress of rats, a useful model of emotional stress, rapid activation of p44/p42 mitogen-activated protein kinase was observed in the heart, followed by a transient upregulation of immediate early genes in the smooth muscle cells of coronary arteries, the endothelial cells and the myocardium. Heat shock protein 70 was induced in the aortic and coronary arterial smooth muscle cells and in the myocardium. Natriuretic peptide genes were also upregulated in the myocardium. Sequential gene expression can be considered as an adaptive response to emotional stress. Blocking of both alpha-adrenoceptors and beta-adrenoceptors eliminated the upregulation of immediate early genes induced by stress, while alpha-agonists and beta-agonists upregulated immediate early genes in the perfused heart. Activation of alpha-adrenoceptors and beta-adrenoceptors is the primary trigger of emotional stress-induced molecular changes in the heart.
Animals↗
Leptin improves membrane fluidity of erythrocytes in humans via a nitric oxide-dependent mechanism--an electron paramagnetic resonance investigation.
Abnormalities in physical properties of the cell membranes may underlie the defects that are strongly linked to hypertension, stroke, and other cardiovascular diseases. Recently, there has been an indication that leptin, the product of the human obesity gene, actively participates not only in the metabolic regulations but also in the control of cardiovascular functions. In the present study, to assess the role of leptin in the regulation of membrane properties, the effects of leptin on membrane fluidity of erythrocytes in humans are examined. The membrane fluidity of erythrocytes in healthy volunteers by means of an electron paramagnetic resonance (EPR) and spin-labeling method is determined. In an in vitro study, leptin decreased the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (ho/h-1) for 16-NS obtained from EPR spectra of erythrocyte membranes in a dose-dependent manner in healthy volunteers. The finding indicated that leptin increased the membrane fluidity and improved the microviscosity of erythrocytes. The effect of leptin on the membrane fluidity was significantly potentiated by the nitric oxide (NO) donors, L-arginine and S-nitroso-N-acetylpenicillamine (SNAP), and a cyclic guanosine monophosphate (cGMP) analog, 8-bromo-cGMP. In contrast, the change evoked by leptin was significantly attenuated in the presence of the NO synthase inhibitors, N(G)-nitro-L-arginine-methyl-ester (L-NAME) and asymmetric dimethyl-L-arginine (ADMA). The results of the present study showed that leptin increased the membrane fluidity and improved the rigidity of cell membranes to some extent via an NO- and cGMP-dependent mechanism. Furthermore, the data also suggest that leptin might have a crucial role in the regulation of rheological behavior of erythrocytes and microcirculation in humans.
Arginine↗
Leukemia inhibitory factor relaxes arteries through endothelium-dependent mechanism.
Leukemia inhibitory factor (LIF) is a cytokine, which inhibits angiogenesis and decreases endothelial cell proliferation and migration, suggesting that LIF may modulate vascular tone. In this study, we examined the effects of LIF on the tone of rat arteries. The isometric tension of ring preparations from rat superior mesenteric arteries was continuously measured. LIF relaxed the mesenteric arteries in a dose-dependent manner, when the arterial rings were precontracted with phenylephrine. The relaxation was totally inhibited by mechanical removal of endothelium. N(G)-nitro-L-arginine methyl ester did not affect the relaxation by LIF. Ca(2+)-dependent K channel (KCa) blockers, apamin with charybdotoxin, inhibited the relaxation by LIF. Catalase, an enzyme which scavenges hydrogen peroxide, also inhibited the relaxation by LIF. Endothelium-derived hyperpolarizing factor relaxes smooth muscle cells and the effect is blocked by KCa and catalase. Our results suggest that LIF regulates vascular tone through the effect of this factor.
Animals↗
Blood pressure response to heart rate during exercise test and risk of future hypertension.
Previous works have shown that exaggerated blood pressure response to exercise is a valid risk marker for future hypertension, yet the use of an exercise test as a means of early prediction of hypertension still requires methodological development and confirmation. The purpose of this study was to determine abnormal ranges of blood pressure responses in relation to heart rate increase during exercise and to examine the clinical utility of exercise blood pressure measurement in evaluating individual risk for developing hypertension. We examined exercise test data from a population-based sample of 1033 nonmedicated normotensive men (mean age, 42.9+/-8.5 years; range, 20 to 59 years). Percentile curves of systolic and diastolic blood pressure responses to relative heart rate increments during submaximal exercise were constructed using a third-order polynomial model with multiple regression analysis. Of the original study sample, a cohort of 726 subjects was followed for hypertensive outcome for an average period of 4.7 years. Progression to hypertension, defined as a blood pressure of > or =140/90 mm Hg or the initiation of antihypertensive therapy, was found in 114 subjects (15.4%). Kaplan-Meier survival estimates showed that the cumulative incidence of hypertension increased progressively with higher percentiles of systolic and diastolic blood pressure response (both, P<0.01). A Cox proportional survival analysis revealed a significantly increased risk for developing hypertension associated with exaggerated blood pressure response to exercise after multivariable adjustments for traditional risk factors (relative risk, 3.8; 95% confidence interval, 2.3 to 6.1). These results suggest that an exaggerated blood pressure response to heart rate during exercise is predictive of future hypertension independent of other important risk factors and lend further support to the concept that blood pressure measurement during exercise test is a valuable means of identifying normotensive individuals at high risk for developing hypertension.
Adolescent↗
Apoptosis of vascular smooth muscle cells is induced by Fas ligand derived from monocytes/macrophage.
Fas and its ligand (FasL), are a receptor-ligand pair identified as promoting cell death in several tissues. Apoptosis of vascular smooth muscle cells (VSMCs) in human atherosclerotic plaque may contribute to weakening of the fibrous cap, ultimately resulting in plaque rupture. We investigated the ability of monocytes to induce apoptosis of cultured VSMCs through Fas/FasL pathway. In addition, we examined the association of FasL with apoptosis in human coronary plaques. Both activated monocytes and the supernatant obtained from activated monocytes were able to kill cultured VSMCs. The apoptotic response of VSMCs was almost completely blocked by the caspase inhibitor z-VAD-fmk and was partially blocked by incubation with antagonistic anti-Fas IgG1 which suggests that Fas/FasL system was involved in the induction of cell death. An approximate 30 kDa protein, which represents a cleaved, soluble form of FasL, was identified in culture medium from activated monocytes, but not in culture medium from control, unactivated monocytes. Immunohistochemical analysis of human atherosclerotic coronary lesions showed that FasL is expressed by macrophages, and microvessels in the adventitia as well as in the plaque. Finally, double-staining with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and FasL antibody showed that FasL enriched lesions always included a number of TUNEL-positive cells. These data suggest that Fas/FasL pathway can be employed by monocytes/macrophages to induce VSMC apoptosis in the atherosclerotic lesions.
Antigen-Antibody Complex↗
Synergistic role of progesterone and nitric oxide in the regulation of membrane fluidity of erythrocytes in humans: an electron paramagnetic resonance investigation.
BACKGROUND: It has been shown that progesterone may actively participate in the regulation of blood pressure and other cardiovascular regulations. However, the precise mechanism underlying its effects is unclear. METHODS: In the present study, we examined the effects of progesterone on membrane fluidity of erythrocytes in healthy volunteers by means of an electron paramagnetic resonance (EPR) and spin-labeling method. RESULTS: In an in vitro study, progesterone significantly decreased the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (ho/h-1) for 16-NS obtained from EPR spectra of erythrocyte membranes. The finding indicates that progesterone might increase the membrane fluidity and improve the membrane microviscosity of erythrocytes. The effect of progesterone was significantly potentiated by the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine (SNAP) and a cyclic guanosine monophosphate (cGMP) analogue, 8-bromo-cGMP. In contrast, the change in the membrane fluidity evoked by progesterone was attenuated in the presence of the NO synthase inhibitors, N(G)-nitro-L-arginine-methyl-ester (L-NAME) and asymmetric dimethyl-L-arginine (ADMA). CONCLUSIONS: The results of the present study showed that progesterone increased the membrane fluidity of erythrocytes and ameliorated the rigidity of cell membranes, at least in part, by an NO-dependent mechanism. Furthermore, the data strongly suggest that progesterone might be involved in the regulation of rheological behavior of erythrocytes and have a crucial role in the improvement of microcirculation in humans.
Analysis of Variance↗
Effect of oestrone on membrane fluidity of erythrocytes is mediated by a nitric oxide-dependent pathway: An electron paramagnetic resonance study.
1. It has been recognized that hormone replacement therapy (HRT) may have a beneficial effect on protection against cardiovascular diseases. Oestrone is the major component of conjugated equiline oestrogens, which are commonly used in HRT. The present study was performed in order to investigate the effects of oestrone on the membrane fluidity of erythrocytes by means of an electron paramagnetic resonance (EPR) and spin-labelling method. 2. In an in vitro study, oestrone significantly decreased the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (ho/h-1) for 16-nitroxide stearate (16-NS) obtained from EPR spectra of erythrocyte membranes. This finding indicated that oestrone may increase the membrane fluidity and improve the membrane microviscosity of erythrocytes. 3. The effect of oestrone was significantly potentiated by the nitric oxide (NO) donor s-nitroso-N-acetylpenicillamine and the cGMP analogue 8-bromo-cGMP. 4. In contrast, the change in membrane fluidity induced by oestrone was antagonized by the NO synthase inhibitors NG-nitro-l-arginine methyl ester and asymmetric dimethyl-l-arginine. 5. The results of the present study show that oestrone significantly increases membrane fluidity and improves the rigidity of cell membranes, which is partially mediated by a NO- and cGMP-dependent pathway. Furthermore, the data may be consistent with the hypothesis that oestrone could have a beneficial effect on the rheological behaviour of erythrocytes and have a crucial role in the regulation of the microcirculation.
Analysis of Variance↗
Oxidized low density lipoprotein potentiation of Fas-induced apoptosis through lectin-like oxidized-low density lipoprotein receptor-1 in human umbilical vascular endothelial cells.
Under normal conditions, vascular endothelial cells are resistant to Fas-mediated apoptosis, although they express detectable Fas on their cell surface. Because oxidized Low density lipoprotein (Ox-LDL) is thought to promote atherogenesis, the potential role that Ox-LDL may play in Fas-mediated apoptosis was investigated in human umbilical vascular endothelial cells (HUVECs), focusing particularly on the involvement of the lectin-like Ox-LDL receptor-1 (LOX-1). HUVECs were treated with agonistic anti-Fas antibody (CH11) and Ox-LDL and then the degree of apoptosis was determined by cell death ELISA. Ox-LDL concentration-dependently sensitized Fas-mediated apoptosis. Flow cytometry demonstrated that Ox-LDL dose-dependently up-regulated cell surface Fas expression. On the other hand, treating HUVECs with Ox-LDL did not lead to any significant change in the expression of death mediators, including Fas, Fas ligand (FasL), FADD, and FLICE as assessed by multiplex polymerase chain reaction amplification. More importantly, these effects of Ox-LDL on Fas-mediated apoptosis were significantly blocked by a neutralizing LOX-1 monoclonal antibody, which can block LOX-1-mediated cellular uptake of Ox-LDL. Ox-LDL may be an important factor involved in the regulation of Fas-induced apoptosis via Ox-LDL/LOX-1 interaction in vascular endothelial cells. The results may provide insights into the pathogenesis of accelerated atherosclerosis in patients with hyperlipidemia.
Adaptor Proteins, Signal Transducing↗
Emotional stress induces transient left ventricular hypocontraction in the rat via activation of cardiac adrenoceptors: a possible animal model of 'tako-tsubo' cardiomyopathy.
The etiology of a novel cardiac syndrome 'tako-tsubo' cardiomyopathy, otherwise known as 'transient left ventricular (LV) apical ballooning' and which mimics acute myocardial infarction, is not clear; however, emotional or physical stress is known to precede the attack. Left ventriculography of rats experiencing emotional stress induced reversible LV apical ballooning, which was normalized by pretreatment with adrenoceptor blockade. Together with results of previous studies, activation of cardiac adrenoceptors in the absence of ischemia-reperfusion is proposed as the primary cause of this syndrome.
Animals↗
Acute effect of endothelin AB antagonist on sympathetic outflow in conscious rats with heart failure.
Although ET-1 antagonists have been beneficial in the treatment of heart failure (HF), their involvement in the effect on the sympathetic nervous system in HF remains unknown. The present study investigated the role of endogenous endothelin (ET) in the sympathetic nervous system in HF by observing the effect of ET AB antagonist (TAK-044) on renal sympathetic nerve activity (RSNA) in conscious rats with HF (n = 7). HF was induced by left coronary artery ligation and 6 weeks later, TAK-044 was intravenously administered in the conscious and freely moving rats. RSNA, mean arterial pressure (MAP) and heart rate were compared with rats with sham operations (sham; n = 7). MAP was significantly decreased in both groups; however, RSNA was significantly decreased only in the HF group at 5 min after administration, and this change continued until 10 min. There was also an effect of TAK-044 on the arterial baroreflex function indicated by the slope of RSNA to the changes in MAP during phenylephrine and nitroprusside injection in both groups. Compared with the sham group, the HF group showed impaired arterial baroreflex control of RSNA during phenylephrine injection, and intravenous administration of TAK-044 normalized this abnormality, whereas the function in the sham group was not changed. These data show that ET AB antagonist suppressed renal sympathetic activity in rats with HF, and improved arterial baroreflex function. The beneficial effect of endothelin antagonist on heart failure may involve improvement of the increased sympathoexcitation and impaired arterial baroreflex function in HF.
Animals↗
Antihypertensive effects of aerobic exercise in middle-aged normotensive men with exaggerated blood pressure response to exercise.
An exaggerated blood pressure (BP) response to physical exertion among normotensive subjects is considered a significant risk factor for future hypertension. The purpose of this study was to examine whether regular aerobic exercise can lead to a reduction in hypertensive risks in patients with such a high-risk profile. Thirty-five sedentary men (46 +/- 2 years old) with normal BP at rest but an exaggerated BP response during exercise were randomly assigned to an exercise or control group for 12 weeks followed by an 8-week washout period. The subjects were then crossed over to the alternate group for an additional 12-week period. The exercise training consisted of 3 days per week of stationary bicycling for 45 min at 50-60% of the heart rate reserve. The treatment effects were evaluated using the method of Hills and Armitage. The training-induced reduction in resting BP was not statistically significant. In ambulatory BP monitoring, the averages of 24-h and daytime systolic and diastolic BP were significantly lower, but nighttime BP remained unchanged after training. During ergometric exercise, significant decreases were observed in systolic and diastolic BP and plasma norepinephrine concentration measured at the submaximal workloads. M-mode echocardiographic and Doppler-derived left ventricular variables were not significantly affected by training. These findings suggest that regular aerobic exercise attenuates BP elevations during physical exertion and daytime activities mainly as a result of the reduction in enhanced sympathetic nervous tonus, which may in turn play a role in lowering the risk for hypertension in normotensive subjects with an exaggerated BP response to exercise.
Blood Pressure↗