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Biomedical subjects

Mitsuru Ohishi

Publications and source records attributed to Mitsuru Ohishi.

At least 19 recordsLinked to original sources
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

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↗
PubMed2005

AT1 receptor-activated signaling mediates angiotensin IV-induced renal cortical vasoconstriction in rats.

Angiotensin IV (ANG IV), an active ANG II fragment, has been shown to induce systemic and renal cortical effects by binding to ANG IV (AT(4)) receptors and activating unique signaling transductions unrelated to classical type 1 (AT(1)) or type 2 (AT(2)) receptors. We tested whether ANG IV exerts systemic and renal cortical effects on blood pressure, renal microvascular smooth muscle cells (VSMCs), and glomerular mesangial cells (MC) and, if so, whether AT(1) receptor-activated signaling is involved. In anesthetized rats, systemic infusion of ANG II, ANG III, or ANG IV (0.01, 0.1, and 1.0 nmol.kg(-1).min(-1) iv) caused dose-dependent increases in mean arterial pressure (MAP) and decreases in renal cortical blood flow (CBF; P < 0.01). ANG II also induced dose-dependent reductions in renal medullary blood flow (P < 0.01), whereas ANG IV did not. ANG IV-induced pressor and renal cortical vasoconstriction were completely abolished by AT(1) receptor blockade with losartan (5 mg/kg iv; P < 0.05). When ANG IV (1 nmol.kg(-1).min(-1)) was infused directly in the renal artery, CBF was reduced by >30%, and the response was also blocked by losartan (P < 0.01). In the renal cortex, unlabeled ANG IV displaced (125)I-labeled [Sar(1),Ile(8)]ANG II binding, whereas unlabeled ANG II (10 microM) inhibited (125)I-labeled Nle(1)-ANG IV (AT(4)) binding in a concentration-dependent manner (P < 0.01). In freshly isolated renal VSMCs, ANG IV (100 nM) increased intracellular Ca(2+) concentration, and the effect was blocked by losartan and U-73122, a selective inhibitor of phospholipase C/inositol trisphosphate/Ca(2+) signaling (1 microM). In cultured rat MCs, ANG IV (10 nM) induced mitogen-activated protein kinase extracellular/signal-regulated kinase 1/2 phosphorylation via AT(1) receptor- and phospholipase C-activated signaling. These results suggest that, at nanomolar concentrations, ANG IV can increase MAP and induce renal cortical effects by interacting with AT(1) receptor-activated signaling.

Angiotensin II↗
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↗
PubMed2005

Serum interleukin-15 concentration in patients with essential hypertension.

BACKGROUND: Interleukin (IL)-15 is one of the cytokines produced by neutrophils and monocytes/macrophages, and its expression is found immunohistochemically in inflammatory cells adjacent to vulnerable atherosclerotic plaques. However, the influence of systemic IL-15 on cardiovascular disease is still unclear. Therefore, we designed clinical investigations to clarify the relationship between cardiovascular complications and serum IL-15 levels. METHODS AND RESULTS: Three hundred ninety-nine patients with essential hypertension were analyzed. We divided the study subjects into the following three groups according to the modified World Health Organization-International Society of Hypertension classification of 1999: patients with no organ damage (n = 213), patients with mild organ damage (n = 128), and patients with severe organ damage (n = 58). We measured serum IL-15, highly sensitive C reactive protein, IL-6, soluble intercellular adhesion molecule, and soluble vascular cell adhesion molecule levels. Serum IL-15 concentration in patients with severe organ damage was significantly higher than that in those with no organ damage (P < .01) and those with mild organ damage (P < .01). Serum IL-15 concentration in patients with coronary artery disease or peripheral artery disease was significantly higher than that in those without coronary artery disease or peripheral artery disease. Moreover, serum IL-15 concentration in patients with lacunar infarction was significantly higher than that in those without lacunar infarction (P < .005). By multiple linear logistic regression analysis, serum IL-15 concentration was independently correlated with cardiovascular disease. CONCLUSIONS: These data suggest that a systemic inflammatory response involving IL-15 might be involved in the occurrence of cardiovascular disease in patients with essential hypertension.

Aged↗
PubMed2005

[Concept and clinical character of hypertension in the elderly].

Although blood pressure in the elderly was modulated by "physiological" changes due to aging, "pathological" changes in the elderly patients with essential hypertension cause to increase cardiovascular events and mortality. Hypertension in the elderly shows increase of pulse pressure, abnormal blood pressure daily profile and orthostatic hypotension. The importance of control of blood pressure in the elderly hypertensive patients is quite clear, however, the optimal blood pressure is still unclear. Very recently, clinical guideline of JSH 2004 by Japanese Society of Hypertension was published. We should try to control blood pressure in the elderly patients according to this guideline.

Aged↗
PubMed2004

Hypoadiponectinemia is an independent risk factor for hypertension.

Adiponectin is one of the key molecules in the metabolic syndrome, and its concentration is decreased in obesity, type-2 diabetes, and coronary artery disease. Genetic investigation has revealed that 2 polymorphisms (I164T and G276T) are related to adiponectin concentration and diabetes. To examine whether adiponectin affects hypertension genetically or biologically, we performed a case-control study. A total of 446 diagnosed cases of hypertension (HT) in men and 312 normotensive (NT) men were enrolled in this study. Plasma adiponectin concentration was measured using an enzyme-linked immunosorbent assay system. Single nucleotide polymorphisms were determined by TaqMan polymerase chain reaction method. After adjustment for confounding factors, adiponectin concentration was significantly lower in HT (HT: 5.2+/-0.2 microg/mL; NT: 6.1+/-0.2 microg/mL; P<0.001). Furthermore, multiple regression analysis indicated that hypoadiponectinemia was an independent risk factor for hypertension (P<0.001). Blood pressure was inversely associated with adiponectin concentration in normotensives regardless of insulin resistance. In subjects carrying the TC genotype of the I164T polymorphism, adiponectin concentration was significantly lower (TC: 2.6+/-0.9 microg/mL; TT: 5.5+/-0.1 microg/mL; P<0.01), and most of them had hypertension. In contrast, the G276T polymorphism was not associated with adiponectin concentration or hypertension. In conclusion, hypoadiponectinemia is a marker for predisposition to hypertension in men.

Adiponectin↗
PubMed2004

Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease.

OBJECTIVES: This study examined the association of mutations in adiponectin gene with the prevalence of coronary artery disease (CAD). BACKGROUND: Coronary artery disease is a major cause of mortality in the industrial countries. Adiponectin gene locus, chromosome 3q27, is the candidate site for CAD. We have reported that adiponectin has antiatherogenic and antidiabetic properties, and that the plasma levels negatively correlated with body mass index (BMI) are significantly low in patients with CAD or type 2 diabetes. METHODS: The study subjects were 383 consecutive patients with angiographically confirmed CAD and 368 non-CAD subjects adjusted for age and BMI in the Japanese population. Single nucleotide polymorphisms (SNPs) in the adiponectin gene were determined by Taqman polymerase chain reaction (PCR) method or a PCR-based assay for the analysis of restriction fragment length polymorphism. The plasma adiponectin concentration was measured by enzyme-linked immunosorbent assay. RESULTS: Among SNPs, the frequency of I164T mutation was significantly higher in CAD subjects (2.9%) than in the control (0.8%, p < 0.05). The plasma adiponectin levels in subjects carrying the I164T mutation were significantly lower than in those without the mutation, and were independent of BMI. In contrast, SNP94 and SNP276, which are reported to be associated with an increased risk of type 2 diabetes, were associated neither with CAD prevalence nor with plasma adiponectin level. Subjects with I164T mutation exhibited a clinical phenotype of the metabolic syndrome. CONCLUSIONS: The I164T mutation in the adiponectin gene was a common genetic background associated with the metabolic syndrome and CAD in the Japanese population.

Adiponectin↗
PubMed2004

A common polymorphism of uncoupling protein 2 gene is associated with hypertension.

OBJECTIVES: The genes responsible for obesity are also candidate genes for obesity-related conditions, such as hypertension and type 2 diabetes. A functional polymorphism in the uncoupling protein 2 (UCP2) promoter has been reported to be associated with obesity in Caucasians. To clarify the contribution of this polymorphism to obesity and related conditions, we studied the association of the -866 G/A polymorphism of the UCP2 gene with obesity, hypertension and type 2 diabetes mellitus. METHODS: A total of 632 unrelated Japanese subjects were studied: 342 type 2 diabetic patients (among them, 158 patients complicated with hypertension), 156 hypertensive patients without diabetes mellitus and 134 control subjects. The -866 G/A polymorphism of UCP2 was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). RESULTS: The frequency of the minor A allele was significantly higher in Japanese than in Caucasians (48.9 versus 37.2%, P=0.01). In contrast to the significant association with obesity in Caucasians, the polymorphism was not associated with obesity in Japanese. The polymorphism, however, was significantly associated with hypertension in Japanese (frequency of A allele: 51.8% in hypertensives versus 46.6% in normotensives, P<0.05). No significant difference was observed in body mass index (BMI), fasting insulin level or HOMA-R between patients with different genotypes. CONCLUSION: These data indicate that the polymorphism of the UCP2 gene is associated with hypertension, and suggest the possibility of UCP2 as a target molecule for studies on the etiology and treatment of hypertension.

Adult↗
PubMed2004

G2736A polymorphism of thiazide-sensitive Na-Cl cotransporter gene predisposes to hypertension in young women.

OBJECTIVE: The thiazide-sensitive Na-Cl cotransporter (TSC) is located in the distal renal tubules. Several mutations of the TSC gene cause Gitelman's syndrome, which is an autosomal recessive disease characterized by low blood pressure and hypokalemia. Recently, an association between TSC gene polymorphisms (Arg904Gln, G2736A; Thr465Thr, C1420T; Gly264Ala, G816C) and essential hypertension has been reported in Sweden. We examined the genetic involvement of the TSC gene in essential hypertension in Japanese. DESIGN: Participants were recruited from outpatients of Osaka University Hospital. We investigated 386 hypertensive and 371 normotensive subjects. METHODS: Genotypes of TSC polymorphisms (G2736A, C1420T, G816C) were determined by the TaqMan polymerase chain reaction (PCR) method, and statistical significance was examined using JMP 5.0.1J (SAS Institute Inc., Cary, North Carolina, USA). The allele frequency of A2736 and T1420 was 6.0 and 3.0%, respectively, whereas we could not detect the G816C polymorphism in this study. Only the G2736A polymorphism was significantly associated with the prevalence of hypertension (P <0.04), and the estimated odds ratio was 1.8 (95% confidence interval, 1.1-3.0) in A2736 allele carriers. The odds ratio for hypertension in A2736 carriers was increased to 2.2 (1.1-4.9) in women (n=413), and further to 3.3 (1.4-8.0) in women with early onset of hypertension (< or = 50 years old). In addition, all subjects with the homozygous A2736 allele in this study (n=2) and the Swedish study (n=5) were hypertensive. CONCLUSION: G2736A polymorphism of the TSC gene is a genetic predisposing factor for essential hypertension in Japanese women.

Age Distribution↗
PubMed2004

Association between hepatocyte growth factor gene polymorphism and essential hypertension.

Hepatocyte growth factor (HGF) is a growth factor which contributes to protection and/or repair of vascular endothelial cells. Serum HGF level is elevated in response to hypertensive organ damage, which suggests that blood pressure regulation may be affected by HGF gene polymorphisms via serum HGF. To examine the interaction between a HGF gene polymorphism and hypertension, we carried out a case-control study. The present study was conducted in outpatients of Osaka University Hospital. Subjects (n=654) who gave informed consent to the study protocol and genetic analysis were recruited. A C to A nucleotide substitution in intron 13 of the HGF gene was determined by the TaqMan polymerase chain reaction (PCR) method using an MGB (Minor Groove Binder) probe. The genotype distribution of the C/A polymorphism of the HGF gene in total subjects was as follows: CC, 83%; CA, 16%; and AA 1%. This distribution was not significantly different from the predicted by Hardy-Weinberg's equilibrium. The prevalence of hypertension was significantly higher in subjects with the CC genotype than in those with an A allele, and the positive association remained after adjustment for confounding factors, with the estimated odds ratio for hypertension (CC vs. CA+AA) being 1.71 (95% confidence interval: 1.02-2.93). A significant association with hypertension was observed in lean or female subjects but not in obese or male subjects. In conclusion, our data suggested that C/A polymorphism in intron 13 of the HGF gene is associated with susceptibility to essential hypertension in lean or female subjects.

Aged↗
PubMed2004

Green coffee bean extract improves human vasoreactivity.

Our previous study revealed the antihypertensive effects of green coffee bean extract (GCE) ingestion in spontaneously hypertensive rats. We suggested that this antihypertensive action was due to the fact that GCE contains chlorogenic acid (CQA) as a major phenolic compound, and CQA in turn contains ferulic acid as a metabolic component that acts on nitric oxide (NO) derived from the vascular endothelium. In this study, the effects of GCE on blood vessels were evaluated in healthy males. The subjects were 20 healthy males with reduced vasodilation responses measured by strain gauge plethysmograms (SPG) to ischemic reactive hyperemia. Of the 20 subjects, 10 (mean age, 37.2 years) ingested a test drink containing GCE (CQA: 140 mg/day), and the other 10 (mean age, 34.8 years) ingested a placebo drink for 4 months. During the ingestion period, SPG, pulse wave velocity (PWV), and serum biochemical parameters were measured, and acceleration plethysmograms (APG) were taken. The reactive hyperemia ratio (RHR) in the test drink group began to increase after ingestion for 1 month and was significantly higher (p <0.05) than that in the placebo group after ingestion for 3 months and 4 months. In addition, after ingestion for 4 months, the test drink group showed a significant decrease (p <0.01) in the plasma total homocysteine level compared with the pre-ingestion level. However, there were no significant differences in PWV or APG between the test drink group and the placebo drink group. The improvement in RHR after ingestion of a drink containing GCE suggested an improvement in vasoreactivity by this component.

Adult↗
PubMed2004

Relationship of bradykinin B2 receptor gene polymorphism with essential hypertension and left ventricular hypertrophy.

The bradykinin B2 receptor shows a protective role in the development of hypertension and renal and cardiovascular complications. It was recently reported that a polymorphism of the bradykinin B2 receptor gene (BDKRB2) is a genetic predisposing factor for hypertension and cardiovascular disease. The aim of this study was to examine the relationship of a polymorphism (-58 T/C and exon 1 +9/-9) of BDKRB2, and an insertion/deletion polymorphism (I/D) of the angiotensin converting enzyme gene (ACE) with essential hypertension and cardiovascular mortality in the Japanese population. Genotyping was carried out in 275 hypertensive and 441 normotensive subjects. Left ventricular hypertrophy (LVH) was detected by ECG in 242 untreated patients with hypertension. All participants were Japanese and gave their written informed consent. The polymorphism (-58 T/C) in the promoter region of the BDKRB2 was determined using the TaqMan-polymerase chain reaction (PCR) method, the exon 1 +9/-9 polymorphism of the BDKRB2 and I/D polymorphism of the ACE were monitored by PCR and gel electrophoresis. The genotypes and allelic frequencies were in Hardy-Weinberg equilibrium. The polymorphism (-58 T/C) in the promoter of the BDKRB2 was associated with LVH in the hypertensive group (n =242) (p =0.048; chi2 =3.9; odds ratio: 1.8; 95% confidence interval (CI): 1.0-3.3). Furthermore, the frequency of LVH in hypertensives was significantly higher in the subjects with both the BDKRB2 CC and ACE D allele than those with other genotypes (p =0.002, chi2 =9.4). However, no relationship could be found between polymorphism of the BDKRB2 (p =0.86, chi2 =0.3) or the ACE (p =0.21, chi2 =3.1) and hypertension in this group of subjects. These results suggest that the polymorphism (-58 T/C) in the promoter region of BDKRB might be a risk factor and might have a synergetic effect with the ACE for LVH in hypertensives, but it is not associated with hypertension in the Japanese population.

Asian People↗
PubMed2003

Association of hypoadiponectinemia with impaired vasoreactivity.

Endothelial dysfunction is a crucial feature in the evolution of atherosclerosis. Adiponectin is an adipocyte-specific plasma protein with antiatherogenic and antidiabetic properties. In the present study, we investigated the relation between adiponectin and endothelium-dependent vasodilation. We analyzed endothelial function in 202 hypertensive patients, including those who were not taking any medication. Forearm blood flow was measured by strain-gauge plethysmography. Plasma adiponectin level was highly correlated with the vasodilator response to reactive hyperemia in the total (r=0.257, P<0.001) and no-medication (r=0.296, P=0.026) groups but not with nitroglycerin-induced hyperemia, indicating that adiponectin affected endothelium-dependent vasodilation. Multiple regression analysis of data from all hypertensive patients revealed that plasma adiponectin level was independently correlated with the vasodilator response to reactive hyperemia. Vascular reactivity was also analyzed in aortic rings from adiponectin-knockout (KO) and wild-type (WT) mice. Adiponectin-KO mice showed obesity, hyperglycemia, and hypertension compared with WT mice after 4 weeks on an atherogenic diet. Endothelium-dependent vasodilation in response to acetylcholine was significantly reduced in adiponectin-KO mice compared with WT mice, although no significant difference was observed in endothelium-independent vasodilation in response to sodium nitroprusside. Our observations suggest that hypoadiponectinemia is associated with impaired endothelium-dependent vasorelaxation and that the measurement of plasma adiponectin level might be helpful as a marker of endothelial dysfunction.

Acetylcholine↗