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Biomedical subjects

Hiromi Rakugi

Publications and source records attributed to Hiromi Rakugi.

At least 19 recordsLinked to original sources
PubMed2006

Adiponectin and renal function, and implication as a risk of cardiovascular disease.

The relation among adiponectin, renal function, and incident cardiovascular disease (CVD) in patients with different degrees of renal dysfunction was investigated. In total, 150 subjects were included in this study and followed prospectively for a mean of 32 months. At baseline, median adiponectin levels for chronic kidney disease (CKD) stages 1, 2, 3, 4 and 5, as estimated by creatinine clearance (> or =90, 60 to 90, 30 to 60, <30 ml/min), were 3.06, 4.04, 6.43, and 11.9 microg/ml, respectively (p for trend <0.01), and a significant association between adiponectin and CKD stages was also confirmed in multivariate regression analysis (F = 6.2, p <0.001). During follow-up, 31 subjects developed CVD, including myocardial infarction, angina pectoris, stroke, and transient ischemic attack. Gender-specific median values of adiponectin were used to separate the higher group from the lower group, and the Kaplan-Meier curve showed a significantly lower event-free survival rate in the lower adiponectin group (<4.39 microg/ml in men, <6.84 microg/ml in women, chi-square 4.88, p <0.03). The risk factor-adjusted Cox regression showed that an increase in adiponectin per 1 microg/ml was associated with a decrease in the risk of CVD to 0.86 (95% confidence interval 0.75 to 0.96, p = 0.004). In the subgroup with previous ischemic heart disease (IHD; n = 65), a significantly lower event-free survival rate of IHD was also observed in the lower adiponectin group (<4.45 microg/ml in men, <4.49 microg/ml in women, chi-square 3.96, p <0.05). The relative distribution of adiponectin isoforms was examined in patients with severe CKD, and the percentage of the high-molecular-weight form in patients with IHD during follow-up (n = 3) was significantly smaller than that in those without IHD (n = 4, p <0.02). In conclusion, renal function is a significant regulator of adiponectin when categorized by CKD stage, whereas hypoadiponectinemia is a predictor of CVD, including recurrent IHD.

Adiponectin↗
PubMed2006

Apop-1, a novel protein inducing cyclophilin D-dependent but Bax/Bak-related channel-independent apoptosis.

In the intrinsic pathway of apoptosis, mitochondria play a crucial role by releasing cytochrome c from the intermembrane space into the cytoplasm. Cytochrome c release through Bax/Bak-dependent channels in mitochondria has been well documented. In contrast, cyclophilin D (CypD), an important component of permeability transition pore-dependent protein release, remains largely undefined, and no apoptogenic proteins that act specifically in a CypD-dependent manner have been reported to date. Here, we describe a novel and evolutionarily conserved protein, apoptogenic protein (Apop). Mouse Apop-1 expression induces apoptotic death by releasing cytochrome c from mitochondria into the cytosolic space followed by activation of caspase-9 and -3. Apop-1-induced apoptosis is not blocked by Bcl-2 or Bcl-xL, inhibitors of Bax/Bak-dependent channels, whereas it is completely blocked by cyclosporin A, an inhibitor of permeability transition pore. Cells lacking CypD were resistant to Apop-induced apoptosis. Moreover, inhibition of Apop expression prevented the cell death induced by apoptosis-inducing substances. Our findings, thus, indicate that the expression of Apop-1 induces apoptosis though CypD-dependent pathway and that Apop-1 plays roles in cell death under physiological conditions.

Amino Acid Sequence↗
PubMed2006

Klotho protein promotes adipocyte differentiation.

Mice with homozygous disruption of the klotho exhibit multiple age-related disorders and have barely detectable amounts of white adipose tissue. Although klotho expression in cultured adipocytes has been reported, little is known about its function in adipocytes. In the present study, we investigated the role of klotho on adipocyte differentiation. Adipocyte differentiation was induced by incubation of confluent 3T3-L1 cells with insulin, dexamethasone, and 1-methyl-3-isobutyl-xanthin. Klotho-siRNA and expression vector were produced for klotho suppression and overexpression, respectively. Klotho protein was purified for determination of the hormonal effect of klotho. Klotho mRNA and protein expression increased up to the 3rd d of differentiation. A peroxisome proliferator-activated receptor-gamma agonist increased klotho expression during the early period of adipocyte differentiation. The mRNA expression of adipocyte differentiation markers, such as CCAAT/enhancer-binding protein (C/EBP)alpha, C/EBPbeta, C/EBPdelta, peroxisome proliferator-activated receptor-gamma, and fatty acid binding protein 4, was decreased by klotho suppression, and increased 1.9- to 3.8-fold by klotho overexpression. The results of Oil Red O staining also suggested that klotho overexpression promoted adipocyte differentiation. Klotho protein stimulation resulted in a 2.4- to 4.6-fold increase in mRNA expression of differentiation markers compared with control, and the time course depended on adipocyte induction status. Western blot analysis showed that protein levels of C/EBPalpha and C/EBPdelta were increased by Klotho protein stimulation. These results suggest that klotho works as a hormonal factor to promote adipocyte differentiation in the early days, during the period of transient proliferation in the differentiation process, and that klotho may play an essential role in adipocyte differentiation.

3T3-L1 Cells↗
PubMed2006

Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II.

Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that cleaves angiotensin II to angiotensin 1-7. Recently, it was reported that mice lacking ACE2 (ACE2(-/y) mice) exhibited reduced cardiac contractility. Because mechanical pressure overload activates the cardiac renin-angiotensin system, we used ACE2(-/y) mice to analyze the role of ACE2 in the response to pressure overload. Twelve-week-old ACE2(-/y) mice and wild-type (WT) mice received transverse aortic constriction (TAC) or sham operation. Sham-operated ACE2(-/y) mice exhibited normal cardiac function and had morphologically normal hearts. In response to TAC, ACE2(-/y) mice developed cardiac hypertrophy and dilatation. Furthermore, their hearts displayed decreased cardiac contractility and increased fetal cardiac gene induction, compared with WT mice. In response to chronic pressure overload, ACE2(-/y) mice developed pulmonary congestion and increased incidence of cardiac death compared with WT mice. On a biochemical level, cardiac angiotensin II concentration and activity of mitogen-activated protein (MAP) kinases were markedly increased in ACE2(-/y) mice in response to TAC. Administration of candesartan, an AT1 subtype angiotensin receptor blocker, attenuated the hypertrophic response and suppressed the activation of MAP kinases in ACE2(-/y) mice. Activation of MAP kinases in response to angiotensin II was greater in cardiomyocytes isolated from ACE2(-/y) mice than in those isolated from WT mice. ACE2 plays an important role in dampening the hypertrophic response to pressure overload mediated by angiotensin II. Disruption of this regulatory function may accelerate cardiac hypertrophy and shorten the transition period from compensated hypertrophy to cardiac failure.

Angiotensin II↗
PubMed2006

Beta2-adrenoceptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic activation.

BACKGROUND: Obesity is a growing public health problem. It has been reported that beta2-adrenoceptor polymorphisms are associated with obesity. This study examines the associations of beta2-adrenoceptor polymorphism with relationships between plasma norepinephrine (NE) and leptin to evaluate further the mechanisms of obesity. METHODS: In 329 normotensive (BP <140/90 mm Hg) men with a wide range of BMI (17.0 to 36.5 kg/m2), we measured BMI, total body fat mass, waist-to-hip ratio (W/H), BP, plasma NE, leptin, and the beta2-(Arg16Gly, Gln27Glu) adrenoceptor polymorphisms. The subjects consisted of 206 nonobese (BMI <25 kg/m2) and 123 overweight or obese (BMI >or=25 kg/m2) men. RESULTS: Overweight or obese subjects had a significantly higher frequency of Gly16 and Glu27 alleles compared with nonobese subjects. The subjects carrying Gly16 or Glu27 alleles regardless of BMI had greater total fat mass, W/H and plasma leptin compared with those without the Gly16 or Glu27 alleles, indicating that Gly16 and Glu27 alleles of the beta2-adrenoceptor gene are related to obesity and fat mass. Only in the nonobese subjects who carried the Gly16 and Glu27 alleles was there a high plasma NE level, but similar in overweight or obese subjects. To evaluate leptin-mediated sympathetic activation, we performed linear regression analyses between plasma leptin and NE. In groups with and without the Gly16 or Glu27 alleles, plasma leptin correlated with NE, but the slope in the group carrying the Gly16 or Glu27 allele was significantly lower than that without the Gly16 or Glu27. CONCLUSIONS: The findings demonstrate a strong and significant association of the Gly16 and Glu27 alleles with obesity. Lower slopes between leptin and NE in the subjects carrying these beta2-adrenoceptor polymorphisms indirectly indicate a blunted leptin-mediated sympathetic nerve activity. We propose that the beta2-adrenoceptor polymorphisms related to blunted leptin-mediated sympathetic activation offers further proof for the mechanisms of obesity.

Adult↗
PubMed2006

Adiponectin and inflammatory markers in peripheral arterial occlusive disease.

This study was designed to examine the plasma levels of adiponectin as well as markers of inflammation and endothelial function in peripheral arterial occlusive disease (PAOD), and to investigate the pathophysiological significance of adiponectin in this disease. Eighty-eight subjects with (n=40) and without PAOD (n=48) were enrolled. Multiple regression analysis including age, sex, body mass index, hypertension, diabetes, triglycerides, high-density lipoprotein cholesterol, creatinine, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cellular adhesion molecules-1 (sVCAM-1), von Willebrand factor, and high-sensitive C reactive protein (Hs-CRP) showed that adiponectin concentration was significantly lower in PAOD subjects (PAOD: 7.9+/-0.7 microg/mL versus without PAOD: 9.5+/-0.6 microg/mL, F=4.94, p<0.03). Furthermore, concentrations of adiponectin (F=8.5, p<0.01) as well as sICAM-1 (F=5.8, p<0.02), sVCAM-1 (F=5.9, p<0.02), and Hs-CRP (F=3.8, p=0.05) were independently associated with ankle-brachial index. In 27 subjects (10 with PAOD and 17 without PAOD), adiponectin levels in the femoral artery and saphenous vein were measured. A significant step-up of adiponectin from the artery to the vein was observed in subjects without PAOD (+13.0%, p<0.01), but not in subjects with PAOD (+0.4%, NS). Plasma adiponectin as well as Hs-CRP were followed before and after percutaneous transluminal angioplasty (PTA) in eight patients. Adiponectin showed a tendency to decrease after PTA (day 6, -30.6%), although Hs-CRP significantly increased. Adiponectin is decreased in patients with PAOD in proportion to the severity of the disease. Adiponectin concentration could be a marker of the existence of atherosclerosis, and measurement of its concentration may be helpful in assessment of the progress of atherosclerosis.

Adiponectin↗
PubMed2006

Tissue inhibitor of metalloproteinase-3 plays important roles in the kidney following unilateral ureteral obstruction.

Tissue inhibitor of metalloproteinase-3 (Timp-3), an inhibitor of matrix-degrading enzymes, is an important molecule for maintenance of the extracellular matrix. In this study, we generated Timp-3-deficient mice and used them to examine the effect of Timp-3-deficiency on blood pressure and to investigate the role of Timp-3 in the kidney following unilateral ureteral obstruction. The blood pressure and heart rate of Timp-3-deficient mice were not significantly different from those of wild-type mice. On the other hand, the obstructed kidneys of Timp-3-deficient mice developed more severe hydronephrosis than those of wild-type animals. Matrix metalloproteinase activities assessed by in situ zymography and transforming growth factor-beta expression were elevated in Timp-3-deficient mice. The renal tissues were thinner and the ratio of renal medulla to cortex was significantly lower in the obstructed Timp-3-deficient kidneys. These findings indicate that Timp-3-deficiency does not substantially affect the blood pressure in mice, and that Timp-3 plays an important role in the maintenance of renal macrostructure after unilateral ureteral obstruction.

Animals↗
PubMed2006

Impairment of instantaneous autonomic regulation relates to blood pressure fall immediately after standing in the elderly and hypertensives.

The relation between changes in blood pressure and changes in autonomic activity over a very short period of time has not been reported thus far. To examine this relation, we here introduced a new method of power spectrum analysis with wavelet transformation, which has very fine time resolution and is able to assess changes in autonomic activity quantitatively even during movement. Our subjects were 15 hypertensive and 17 normotensive subjects. A head-up tilt test was performed in all subjects, and during the test, electrocardiogram and blood pressure were recorded continuously. The power spectrums for both parameters were calculated simultaneously every 5 s using wavelet transformation. The high frequency of the RR interval of the electrocardiogram (RR-HF) and low frequency of systolic blood pressure (SBP-LF) were defined and calculated as markers of parasympathetic and alpha-1 receptor blocker, bunazosin-sensitive sympathetic activity, respectively. Focusing on the changes for 2 min immediately after head-up tilting, it was found that the changes in SBP-LF and RR-HF were significantly delayed, by at least 40 s, in hypertensives compared with normotensives and also in elderly compared with non-elderly subjects. Multiple regression analysis demonstrated that the instantaneous change in RR-HF was the most important confounding factor for a fall in blood pressure immediately after head-up tilting. In conclusion, real-time changes in autonomic activity calculated by wavelet transformation may provide sensitive and useful information about acute changes in cardiovascular regulation, such as delayed reaction of the autonomic regulation after head-up tilting, that may be major causes of the blood pressure fall in hypertensive and elderly subjects.

Adult↗
PubMed2006

[Recent multi-center clinical studies about calcium blockade and cardiovascular diseases].

Recently, a lot of multi-center clinical studies about calcium (Ca) blockade and cardiovascular diseases have been investigated. Though the ability to reduce blood pressure is the most important thing, much attention is also paid to the effect of organ protection effect beyond blood pressure lowering. Compared to angiotensin II receptor blocker (ARB) or angiotensin converting enzyme-inhibitor (ACE-I), amlodipine among Ca channel blockers shows excellent protective effect of cardiovascular disease. As specified to the kidney disease, renin-angiotensin (RA) inhibition by ARB or ACE-I is much effective than Ca blockade, however, Ca channel blocker is thought to be the first choice as for the blood pressure lowering of ischemic heart disease patients. From now on, further studies will be expected to prove not only the effect of RA system drugs, but also Ca channel blockers, moreover, to know the differences of benefit among many Ca channel blockers.

Adult↗
PubMed2006

[ANBP-2].

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Aged↗
PubMed2006

[VALISH].

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Aged↗
PubMed2005

Uric acid, left ventricular mass index, and risk of cardiovascular disease in essential hypertension.

Elevated serum uric acid (UA) is frequently encountered in individuals with hypertension, but whether the relationship between UA and cardiovascular events is circumstantial or causal remains to be answered. We examined the association between serum UA and left ventricular mass index (LVMI) and investigated prospectively whether the combination of UA and LVMI can predict the incidence of cardiovascular disease (CVD) in asymptomatic subjects with essential hypertension. A total of 619 subjects (mean age, 61 years; 52% female) free of prior CVD were included in this study. A significant association between UA and LVMI was also confirmed in multiple regression analysis (male: F=4.29, P<0.04; female: F=4.24, P<0.05). During follow-up (mean, 34 months), 28 subjects (14 female) developed CVD including myocardial infarction, angina pectoris, congestive heart failure, cerebral infarction, and transient cerebral ischemia. Sex-specific median values were used to separate the higher group from the lower group of UA and LVMI. Kaplan-Meier curves showed a significantly poorer survival rate in the group with higher UA and LVMI (LVMI, male: >126.9, female: >112.0 g/m2; UA, male: >374.7, female: >303.3 micromol/L; log-rank chi2=13.18; P<0.01). Multivariate Cox regression analysis showed that the combination of higher UA and LVMI was an independent predictor for CVD events (hazard ratio, 2.38; P<0.03). Our findings demonstrate that UA is independently associated with LVMI and suggest that the combination of hyperuricemia combined with left ventricular hypertrophy is an independent and powerful predictor for CVD. The association between UA and CVD events may be introduced in part because of a direct association of UA with LVMI.

Cardiovascular Diseases↗
PubMed2005

Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells.

Klotho-mutated mice manifest multiple age-related disorders that are observed in humans. A recent study suggested that Klotho protein might function as an anti-aging hormone in mammals. Because it has been reported that apoptosis and senescence in vascular endothelial cells are closely related to the progression of atherosclerosis, we investigated Klotho's ability to interfere with apoptosis and cellular senescence in human umbilical vascular endothelial cells (HUVEC). Klotho overexpression decreased H(2)O(2)-induced apoptosis in COS-1 cells and Jurkat cells. Klotho protein also reduced H(2)O(2)- and etoposide-induced apoptosis in HUVEC. Caspase-3 and caspase-9 activity was lower in Klotho-treated HUVEC than in control cells. Senescence-associated beta-gal staining showed that Klotho protein interferes with H(2)O(2)-induced premature cellular senescence. The expression of p53 and p21 was lower in Klotho-treated cells. Our study suggests that Klotho acts as a humoral factor to reduce H(2)O(2)-induced apoptosis and cellular senescence in vascular cells.

Apoptosis↗
PubMed2005

Beta2- and beta3-adrenergic receptor polymorphisms are related to the onset of weight gain and blood pressure elevation over 5 years.

BACKGROUND: The genes responsible for obesity are candidate genes for obesity-related diseases, such as hypertension. Functional polymorphisms in the beta2- and beta3-adrenergic receptors have been reported to be associated with hypertension and obesity. METHODS AND RESULTS: To longitudinally clarify the relevance to alterations in beta-adrenergic receptor polymorphisms related to weight gain, blood pressure (BP) elevation, and sympathetic nerve activity as measured by plasma norepinephrine level, we studied 160 young, nonobese, normotensive men. Changes in body weight, BP, plasma norepinephrine levels, and beta2-adrenergic (Arg16Gly, Gln27Glu) and beta3-adrenergic (Trp64Arg) receptor polymorphisms were measured periodically over a 5-year period. Weight gain and BP elevation were defined as > or =10% increases from entry levels over 5 years in body mass index or mean BP. The presence of the Gly16 allele of Arg16Gly was associated with a higher frequency of weight gain and BP elevation over the 5-year period. The subjects carrying the Glu27 allele of Gln27Glu and the Trp64 allele of Trp64Arg had a higher frequency of BP elevation. Significantly higher levels of plasma norepinephrine at entry and at year 5 were observed in the subjects with the Gly16 allele of Arg16Gly and the Glu27 allele of Gln27Glu compared with those without the Gly16 or the Glu27 alleles. CONCLUSIONS: These results demonstrate that the Gly16 allele is related to greater weight gain and BP elevation. Additionally, Glu27 and Trp64 alleles are linked to BP elevation. The subjects carrying the beta2-polymorphisms linked to weight gain and BP elevation also have higher plasma norepinephrine levels that are present at entry before weight gain and BP elevation. These findings suggest that beta2-adrenergic receptor polymorphisms in association with a heightened sympathetic nerve activity could predict the future onset of obesity and hypertension, as shown in the 5-year longitudinal study.

Adult↗
PubMed2005

Lys418Asn polymorphism of the alpha2-adrenoceptor gene relates to serum uric acid levels but not to insulin sensitivity.

Hyperuricemia is associated with cardiovascular risk. The present study examines the association between serum uric acid (UA) elevation and the alpha2-, beta2-, and beta3-adrenoceptor polymorphisms. In 219 nonobese, normotensive, normouricemic (serum UA <6.5 mg/dL at entry) men, serum UA, plasma norepinephrine (NE), the homeostasis model assessment of insulin resistance (HOMA-IR), body mass index, total body fat mass, the alpha2A(Lys418Asn)-, beta2(Arg16Gly, Gln27Glu)-, and beta3(Trp64Arg)-adrenoceptor polymorphisms were measured annually over 5 years. Hyperuricemia was defined as a serum UA level of > or =mean+1 SD of 5.0 mg/dL in the participants. At entry, there were 36 subjects who had hyperuricemia and 183 who had normal UA levels. A significant UA elevation for 5 years was defined as an increase in > or =10% in UA levels. There were 82 subjects who had significant UA elevations. The subjects who had hyperuricemia at entry in addition to the subjects who had significant UA elevations over the 5-year period carried a significantly higher frequency of the Asn418 allele of Lys418Asn. Additionally, subjects carrying the Asn418 allele had higher UA and plasma NE and greater elevations in UA over the study period, but HOMA-IR was similar. Insulin resistance at entry and during the study was associated with Arg16Gly polymorphisms but not with Lys418Asn polymorphisms. In conclusion, the Asn418 allele of Lys418Asn is associated with either established hyperuricemia or the progressive elevation of UA over time. This polymorphism was not associated with insulin resistance in nonobese, normotensive individuals. Although hyperuricemia is of known relevance to insulin resistance, it appears to have different genetic determinants from insulin resistance in terms of adrenoceptor polymorphisms.

Adult↗
PubMed2005

Association of hypoadiponectinemia with smoking habit in men.

Adiponectin is emerging as an important molecule in obesity, the metabolic syndrome, and cardiovascular disease. On the other hand, smoking habit is well known to be related to cardiovascular disease and hypertension. To examine the association between adiponectin concentration and smoking habit, we performed an epidemiological survey and an acute exposure test in humans and an experiment in adipocytes to elucidate the mechanism underlying the association between adiponectin and smoking. In the epidemiological study, we enrolled a total of 331 male subjects to examine chronic smoking exposure. Plasma adiponectin was significantly lower (P=0.01) in current smokers (5.3+/-0.3 microg/mL) than in never-smokers (6.5+/-0.4 microg/mL). A significant association between smoking and low adiponectin level was also confirmed in multiple regression analysis including age, body mass index, hypertension, diabetes, hyperlipidemia, and creatinine clearance (never-smokers 6.5+/-0.4 microg/mL; past smokers 5.6+/-0.3 microg/mL; current smokers 5.2+/-0.4 microg/mL; F=4.52; P=0.01). To examine the acute effect of smoking on adiponectin concentration for 12 hours, we measured plasma adiponectin level in 5 male never-smokers before smoking and 3, 6, and 12 hours after smoking, with the result that adiponectin showed a significant decrease after smoking (12 hours; -14.5+/-0.6%; P<0.01). In cultured mouse 3T3-L1 adipocytes, H2O2 and nicotine reduced the mRNA expression and secretion of adiponectin in a dose-dependent manner. Smoking habit is associated with adiponectin concentration in men, and its suppressive effect is mediated in part through direct inhibition of smoking on adiponectin expression in adipocytes.

3T3 Cells↗