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Tatsuo Shimosawa

Publications and source records attributed to Tatsuo Shimosawa.

At least 19 recordsLinked to original sources
PubMed2006

Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity.

We have demonstrated that adrenomedullin (AM) protects against angiotensin II (ANG II)-induced cardiovascular damage through the attenuation of increased oxidative stress observed in AM-deficient mice. However, the mechanism(s) that underlie this activity remain unclear. To address this question, we investigated the effect of AM on ANG II-stimulated reactive oxygen species (ROS) production in cultured rat aortic vascular smooth muscle cells (VSMCs). ANG II markedly increased ROS production through activation of NADPH oxidase. This effect was significantly attenuated by AM in a concentration-dependent manner. This effect was mimicked by dibutyl-cAMP and blocked by pretreatment with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-89), a protein kinase A inhibitor, and CGRP(8-37), an AM/CGRP receptor antagonist. This inhibitory effect of AM was also lost following the expression of a constitutively active Src. Moreover, AM intersected ANG II signaling by inducing COOH-terminal Src kinase (Csk) activation that, in turn, inhibits Src activation. These data, for the first time, demonstrate that AM attenuates the ANG II-induced increase in ROS in VSMCs via activation of Csk, thereby inhibiting Src activity.

Adrenomedullin↗
PubMed2006

Plasma agouti-related protein levels in women with anorexia nervosa.

Agouti-related protein (AGRP) is the competitive antagonist of alpha-melanocyte stimulating hormone (alpha-MSH) located at melanocortin receptors 3 and 4 (MC3R and MC4R), and also acts as an MC4R inverse agonist. Hypothalamic AGRP controls food intake and body weight in rodents. It has also been found in human plasma. To study the possibility of disturbances in melanocortin receptor-related peptides in eating disorders, plasma AGRP, alpha-MSH, and leptin levels were measured in 18 female patients with anorexia nervosa (AN) (age, 23.5+/-7.1 yr; body mass index (BMI) 14.5+/-1.8 kg/m(2)) and 17 age-matched female controls (age, 25.8+/-3.9 yr; BMI 20.2+/-1.6 kg/m(2)). Blood samples were collected after overnight fasting, and plasma peptides levels were measured using ELISA. Plasma AGRP levels increased significantly in AN patients when compared with controls (P<0.01) while plasma alpha-MSH levels were not significantly different. Plasma leptin levels decreased significantly in AN patients when compared with controls (P<0.001). In addition, plasma AGRP levels were negatively correlated with leptin (r=-0.41, P<0.01) and BMI (r=-0.40, P<0.05) in all subjects. In conclusion, plasma AGRP elevation may be related to energy homeostasis disturbance in AN, and in addition to leptin, peripheral AGRP levels could be used as a nutritional marker in AN patients.

Adolescent↗
PubMed2006

Protective effect of potassium against the hypertensive cardiac dysfunction: association with reactive oxygen species reduction.

Potassium supplementation has a potent protective effect against cardiovascular disease, but the precise mechanism of it against left ventricular abnormal relaxation, relatively early functional cardiac alteration in hypertensive subjects, has not been fully elucidated. In the present study, we investigated the effect of potassium against salt-induced cardiac dysfunction and the involved mechanism. Seven- to 8-week-old Dahl salt sensitive rats were fed normal diet (0.3% NaCl) or high-salt diet (8% NaCl) with or without high potassium (8% KCl) for 8 weeks. Left ventricular relaxation was evaluated by the deceleration time of early diastolic filling obtained from Doppler transmitral inflow, the slope of the pressure curve, and the time constant at the isovolumic relaxation phase. High-salt loading induced a significant elevation of blood pressure and impaired left ventricular relaxation, accompanied by augmentation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity in the cardiac tissue, measured by the lucigenin chemiluminescence method. Blood pressure lowering by hydralazine could not ameliorate NADPH oxidase activity and resulted in no improvement of left ventricular relaxation. Interestingly, although the blood pressure remained high, potassium supplementation as well as treatment with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a superoxide dismutase mimetic, not only reduced the elevated NADPH oxidase activity but also improved the left ventricular relaxation. In conclusion, a high-potassium diet has a potent protective effect on left ventricular active relaxation independent of blood pressure, partly through the inhibition of cardiac NADPH oxidase activity. Sufficient potassium supplementation might be an attractive strategy for cardiac protection, especially in the salt-sensitive hypertensive subjects.

Animals↗
PubMed2005

Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet.

Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation. Because the serum concentration and intestinal expression level of RELMbeta were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELMbeta on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. First, transgenic mice with hepatic RELMbeta overexpression were shown to exhibit significant hyperglycemia, hyperlipidemia, fatty liver, and pancreatic islet enlargement when fed a high fat diet. Hyperinsulinemic glucose clamp showed a decreased glucose infusion rate due to increased hepatic glucose production. In addition, the expression levels of IRS-1 and IRS-2 proteins as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELMbeta transgenic mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELMbeta, suggesting the insulin resistance-inducing effect of RELMbeta to be direct. Furthermore, it was shown that RELMbeta acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. This increased basal p38 phosphorylation level was also observed in the livers of RELMbeta transgenic mice. In conclusion, RELMbeta, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELMbeta may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus, RELMbeta is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents.

Animals↗
PubMed2005

Adrenomedullin as a potent antioxidative and antiatherosclerotic substance.

Adrenomedullin was originally discovered as a vasodilative peptide, but recent studies have revealed its pleiotropic effects. Among these studies, the antioxidative properties of adrenomedullin were observed in adrenomedullin knockout mice. Through its antioxidative effect, adrenomedullin can protect organs from damage induced by high blood pressure, ischemia and aging. This indicates that antioxidants that can inhibit reactive oxygen species production but do not have a scavenging effect could be a new effective therapeutic target for organ protection in hypertension as well as metabolic syndrome, in which higher oxidative stress plays a pivotal role.

Adrenomedullin↗
PubMed2005

Adrenomedullin as a potent antioxidative and antiatherosclerotic substance.

Adrenomedullin was originally discovered as a vasodilative peptide, but recent studies have revealed its pleiotropic effects. Among these studies, the antioxidative properties of adrenomedullin were observed in adrenomedullin knockout mice. Through its antioxidative effect, adrenomedullin can protect organs from damage induced by high blood pressure, ischemia and aging. This indicates that antioxidants that can inhibit reactive oxygen species production but do not have a scavenging effect could be a new effective therapeutic target for organ protection in hypertension as well as metabolic syndrome, in which higher oxidative stress plays a pivotal role.

Adrenomedullin↗
PubMed2005

[Magnesium and N-type calcium channel].

Magnesium has been known to inhibit calcium influx via L-type calcium channel in vascular smooth muscle cells and thus cause vasodilation and hypotension. Moreover, it was reported that magnesium also modulates barofunction. Therefore we speculated that magnesium has inhibitory effect on sympathetic tone and we showed that magnesium inhibit norepinephrine release from peripheral sympathetic nerve endings. Also we showed that this effect was by inhibiting calcium influx from N-type calcium channel. These effect may explain organ protective effect of magnesium in acute myocardial infarction and also a new therapeutic target in treating hypertensives.

Animals↗
PubMed2005

[Increasing oxidative stress in aging].

The balance between reactive oxigen species (ROS) production and degradation is important in defining oxidative stress. In aging process, ROS production increases and degradation is impaired and thus oxidative stress is accumulated. Oxidative stress damages organs both directly and indirectly. Protein, lipid, as well as DNA are directly react with ROS, more over, ROS interact with intracellular signaling system. It is reported that several transcription factors such as NF-kappaB, AP-1 and ASK-1 and also it interferes MAPK activity. Besides these signaling, we recently showed that insulin resistance is induced by accumulated oxidative stress in aged mice. Adrenomedullin deficient mice accumulate higher oxidative stress and insulin resistance developed in aging. Oxidative stress in aging relates not only direct organ damage but also induce risk factors for vascular damage such as metabolic syndrome.

Adrenomedullin↗
PubMed2005

[Antiatherosclerotic hopes of calcium channel blockers].

The antiatherosclerotic effects of a calcium channel blockers have been attracting attention for some time. It is shown by the animal studies that especially dihydropyridine calcium channel blockers have the antiatherosclerotic effects by an anti-oxidative properties and the direct action on vascular cells in addition to an original decrease blood pressure, and the validity is being further proved by the results of randomized clinical trials such as PREVENT and CAMELOT.

Animals↗
PubMed2004

Magnesium inhibits norepinephrine release by blocking N-type calcium channels at peripheral sympathetic nerve endings.

Although Mg2+ contributes to blood pressure regulation partly in terms of vasodilator action, its sympatholytic effect may also play an important role to control blood pressure. Thus, in the present study, we investigated the effect of Mg2+ on sympathetic tone and blood pressure. We studied its actions on the blood pressure response to hydralazine, a direct vasodilator, in conscious spontaneously hypertensive rats (SHRs), and to electrical stimulation in the pithed Sprague-Dawley rat; catecholamine release by peripheral sympathetic nerve endings; and the N-type Ca2+ channels of cultured neural cells. Intravenous Mg2+ infusion (MgSO4: 3x10(-6) mol/kg body weight/min) induced the greater hypotensive response to hydralazine with attenuated reflex tachycardia in SHRs. In pithed rats, Mg2+ infusion significantly attenuated the blood pressure elevation (2+/-2 mm Hg versus 27+/-6 mm Hg, P<0.01) in response to spinal electrical stimulation. In the perfused mesenteric arteries system, norepinephrine release was significantly attenuated (51+/-2%, P<0.01) by high Mg2+ concentration solution (4.8 mmol/L) compared with normal Mg2+ solution (1.2 mmol/L). When we applied the perforated whole-cell patch clamp method to nerve growth factor-treated PC12 cells, Mg2+ blocked voltage-gated Ca2+ currents in a concentration-dependent manner. The majority of the voltage-gated Ca2+ currents were carried through N-type channels, followed by L-type channels. Mg2+ blocked both of these channels. These findings suggest that Mg2+ blocks mainly N-type Ca2+ channels at nerve endings, and thus inhibits norepinephrine release, which decreases blood pressure independent of its direct vasodilating action.

Animals↗
PubMed2004

Angiotensin II-induced insulin resistance is enhanced in adrenomedullin-deficient mice.

Insulin resistance and hypertension are common disorders that are closely related. Among several factors, oxidative stress has been reported to be intimately related to these diseases. To elucidate the involvement of oxidative stress in the development of insulin resistance in a hypertensive model, we administered angiotensin II (Ang II), which raises blood pressure and induces reactive oxygen radicals, to adrenomedullin (AM)-knockout heterozygous mice and examined the resulting changes in blood pressure and insulin resistance. Ang II was administered ip at a dosage of 640 ng/kg.min for 4 wk. The systolic blood pressure was significantly elevated in both AM-knockout heterozygous and wild-type mice to the same extent. On the other hand, Ang II attenuated insulin sensitivity more strongly in AM-knockout heterozygous mice than in wild-type mice, when measured using 2- deoxyglucose uptakes in the soleus muscle. Ang II also induced a higher urinary excretion of isoprostane, a marker of oxidative stress. Furthermore, the production of oxidative stress in the soleus muscles of angiotensin-treated mice, measured using electronic spin resonance, was significantly higher than that in AM-knockout heterozygous mice. Moreover, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a superoxide scavenger mimetic, normalized the insulin resistance induced by Ang II without affecting the blood pressure in both groups. The present results suggest that, in an Ang II-treated mouse model, insulin resistance is induced by oxidative stress through a mechanism that is independent of blood pressure, and that AM can act as a protective peptide against insulin resistance via its intrinsic antioxidant effect.

Adrenomedullin↗
PubMed2004

Adrenomedullin can protect against pulmonary vascular remodeling induced by hypoxia.

BACKGROUND: Chronic hypoxia is one of the major causes of pulmonary vascular remodeling associated with stimulating reactive oxygen species (ROS) production. Recent studies have indicated that hypoxia upregulates expression of adrenomedullin (AM), which is not only a potent vasodilator but also an antioxidant. Thus, using heterozygous AM-knockout (AM+/-) mice, we examined whether AM could attenuate pulmonary vascular damage induced by hypoxia. METHODS AND RESULTS: Ten-week-old male wild-type (AM+/+) or AM+/- mice were housed under 10% oxygen conditions for 3 to 21 days. In AM+/+ mice, hypoxia enhanced AM mRNA expression, which was reduced by the administration of a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO). Hypoxia induced pulmonary vascular remodeling, which was associated with the increased production of oxidative stress measured by electron spin resonance and immunostaining of 3-nitrotyrosine. The media wall thickness of the pulmonary arteries was significantly greater in AM+/- mice housed under hypoxia than in AM+/+ mice under hypoxia. Concomitantly, pulmonary ROS production induced by hypoxia was more enhanced in AM+/- mice than in AM+/+ mice. The administration of both exogenous AM and hydroxy-TEMPO normalized pulmonary vascular media wall thickness in not only AM+/+ but also AM+/- mice under hypoxic conditions associated with the normalization of ROS overproduction in the lung. CONCLUSIONS: The present results suggest that an endogenous AM is a potential protective peptide against hypoxia-induced vascular remodeling, possibly through the suppression of ROS generation, which might provide an effective therapeutic strategy.

Adrenomedullin↗
PubMed2004

Endogenous adrenomedullin protects against vascular response to injury in mice.

BACKGROUND: In our previous study, adrenomedullin (AM) overexpression could limit the arterial intimal hyperplasia induced by cuff injury in rats. However, it remains to be elucidated whether endogenous AM plays a role against vascular injury. METHODS AND RESULTS: We used the AM knockout mice to investigate the effect of endogenous AM. Compared with wild-type (AM+/+) mice, heterozygous AM knockout (AM+/-) mice had the increased intimal thickening of the cuff-injured femoral artery, concomitantly with lesser AM staining. In AM+/- mice, cuff placement increased both the production of superoxide anions (O2-) measured by coelentarazine chemiluminescence and the immunostaining of p67phox and gp91phox, subunits of NAD(P)H oxidase in the adventitia, associated with the increment of CD45-positive leukocytes, suggesting that the stimulated formation of radical oxygen species accompanied chronic adventitial inflammation. Not only the AM gene transfection but also the treatment of NAD(P)H oxidase inhibitor apocynin and membrane-permeable superoxide dismutase mimetic tempol could limit cuff-induced intimal hyperplasia in AM+/- mice, associated with the inhibition of O2- formation in cuff-injured artery. CONCLUSIONS: The overproduction of oxidative stress induced by the increased NAD(P)H oxidase activity might be involved in cuff-injured arterial intimal hyperplasia in AM+/- mice. Thus, it is suggested that endogenous AM possesses a protective action against the vascular response to injury, possibly through the inhibition of oxidative stress production.

Acetophenones↗
PubMed2004

Adrenomedullin in vascular diseases.

A novel vasodilator, adrenomedullin (AM), which acts as an autocrine/paracrine factor in cardiovascular system, has antiproliferative and antimigrative effects. AM gene transfer prevents the development of cuff-induced vascular injury. Moreover, AM knockout mice exhibited an increase in angiotensin (Ang) II/salt loading-induced coronary arterial lesion, hypoxia-induced pulmonary vascular damage, and cuff-induced vascular injury associated with enhancement in reactive oxygen species (ROS) generation. In addition, AM expression was stimulated by ROS, and AM directly inhibits oxidative stress so that AM might be a negative feedback substance against ROS-induced organ damages. In addition, AM increases nitric oxide and ameliorates insulin resistance, leading to oxidative stress. Consequently, endogenous AM might compensatively inhibit the development of vascular diseases at least partly through an antioxidative effect.

Adrenomedullin↗