PubMed Health⌕ Search

Biomedical subjects

H Rakugi

Publications and source records attributed to H Rakugi.

At least 19 recordsLinked to original sources
PubMed1999

Angiotensin II type 1 receptor-mediated peroxide production in human macrophages.

Our previous experiments demonstrated upregulation of the renin-angiotensin system in macrophages, including angiotensin II type 1 (AT1) and type 2 (AT2) receptors, during transformation from monocytes. We investigated the role of angiotensin II in oxidative stress of monocytes/macrophages, which plays a role in the advance of atherosclerosis. THP1, a human monocytic leukemia cell line, was differentiated to macrophages by adding of phorbol 12-myristate 13-acetate for 24 hours. The intracellular production of peroxide was measured by a cytofluorometric assay with 2', 7'-dichlorofluorescein-diacetate with a flow cytometer scan. Peroxide was detected in monocytes and upregulated during the transformation to macrophages by 3.18+/-0.52 times in relative fluorescein of peak value (P<0.01). Angiotensin II (1 micromol/L) induced oxidative stress in macrophages, with the peak at 15 minutes by 451+/-223%, and returned to the control level within 1 hour. EC50 was 5.4x10(-9) mol/L. AT1 antagonist (CV11974, 1 micromol/L) significantly decreased angiotensin II-induced oxidative stress in macrophages, but AT2 antagonist (PD123319, 1 micromol/L) did not. Of interest, AT1 antagonist also decreased basal levels of peroxide production in macrophages in a dose-dependent manner. These results suggest that upregulation of the expression of AT1 receptor in macrophages contributes in part to upregulation of peroxide production. AT1 receptor antagonists may be useful to suppress oxidative stress of macrophages in atherosclerotic lesions.

Angiotensin II↗
PubMed1998

Cardiac angiotensin II receptors are upregulated by long-term inhibition of nitric oxide synthesis in rats.

It has been shown that nitric oxide (NO) may regulate angiotensin II (Ang II) receptors in vitro. To determine whether the chronic inhibition of NO synthesis upregulates cardiac Ang II receptors in a rat model, we evaluated the in vivo effect of Nomega-nitro-L-arginine methyl ester (L-NAME) on several Ang II receptors and on the expression of AT1 receptor mRNA in heart tissue. The chronic administration of L-NAME to normal rats increased the arterial blood pressure. The number of AT1 and AT2 receptors was increased, with no change in affinity, during the first week of L-NAME administration but returned to control levels after 4 weeks of treatment. The AT1 receptor mRNA was changed parallel to AT1 receptor number. Inflammatory changes (monocyte infiltration and myofibroblast formation) in perivascular areas surrounding coronary vessels and myocardial interstitial spaces were observed during the first week. The immunohistochemistry revealed that myofibroblasts expressed AT1 receptor. AT1 receptor blockade or cotreatment with L-arginine, but not cotreatment with hydralazine, prevented the L-NAME-induced increase in Ang II receptors and inflammatory changes. In conclusion, rat cardiac Ang II receptors are upregulated at an early phase of chronic inhibition of NO synthesis. This may contribute to cardiovascular inflammatory changes in an early phase and to remodeling at the later phase, which occurs after inhibition of NO synthesis.

Actins↗
PubMed1998

Angiotensin II type 1 receptor gene polymorphism is associated with increase of left ventricular mass but not with hypertension.

A genetic epidemiologic approach is useful to elucidate the genes responsible for hypertension. Genetic analyses of the components of the renin-angiotensin system have succeeded in showing an association between their polymorphism and hypertension. Recently, two types of angiotensin II receptor were cloned and characterized. To examine the genetic contribution of angiotensin II type 1 receptor (AT1) and type 2 receptor (AT2) genes in human essential hypertension, a case-control study was performed in Japanese subjects. The study comprised 321 subjects with hypertension who satisfied the criteria for essential hypertension, together with 215 age and sex matched controls. The significance of the differences in genotype distribution between hypertensive and normotensive subjects was examined by chi2 analysis. Neither AT1 nor AT2 gene variants were associated with human essential hypertension in the Japanese subjects. However, the AT1 receptor gene polymorphism was associated with left ventricular mass index in normotensive subjects. The study results suggest that gene polymorphisms of both angiotensin II receptors are not directly involved in the increase of genetic risk for hypertension, but that the AT1 receptor gene might contribute genetically to the increase of left ventricular mass.

Aged↗
PubMed1998

Methylenetetrahydrofolate reductase gene polymorphism: relation to blood pressure and cerebrovascular disease.

Hyperhomocysteinemia is reported to be associated with an increase in the incidence of ischemic heart disease and cerebrovascular disease. Genetic aberrations in methylenetetrahydrofolate reductase (MTHFR) may account for reduced enzyme activity and elevated plasma homocysteine level. A recent report revealed that a common mutation (677C to T; Ala to Val) in the MTHFR gene is associated with decreased specific MTHFR activity and with increased risk for coronary artery disease in the homozygous state (Val/Val). In the present study, we investigated whether the MTHFR gene is a genetic risk factor for cerebrovascular disease (CVD). To undertake a case-control study, we selected the patients with cerebral infarction (n = 48) or cerebral hemorrhage (n = 35) and examined the association between MTHFR gene polymorphism and CVD. The genotype distribution of the MTHFR gene was not significantly different between cases and controls. Because the possibility of matching the morbidity of the effects of hypertension, the lack of association could not be excluded in the first study; however, we also examined whether the MTHFR mutation was associated with any clinical risk factor for CVD or with hypertension. It turned out that the subjects with the Val allele of the MTHFR gene had significantly lower blood pressure than the subjects with other genotypes in the general population (P = .02), and that the frequency of the Val/Val genotype in hypertensive subjects (n = 173) was significantly lower than in control subjects (n = 184) (P = .03). From these results, we conclude that the Val/Val homozygous state of the MTHFR gene increased the risk of thrombosis, but reduced the blood pressure, which resulted in the lack of increased risk for CVD.

Cerebrovascular Disorders↗
PubMed1998

[A case of mild-type myotonic dystrophy with dementia and severe arteriosclerosis obliterans].

A 70-year-old man, with mild-type myotonic dystrophy (MyD) diagnosed by molecular genetic analysis when he was 68 years old, complained of worsening intermittent claudication during the past 2 years. Doppler examination revealed severe stenosis and obstruction in his leg arteries, which we diagnosed as arteriosclerosis obliterans (ASO). We then found him to be suffering from dementia, which was confirmed by dementia scale tests (Mini Mental State, 20/30; Hasegawas' Dementia Scale-Revision, 15/30). Even in mild-type MyD, as MyD is one of the progeria syndromes, the abnormal genes of MyD may accelerate the aging processes.

Aged↗
PubMed1998

[Vascular endothelial cells and renin-angiotensin system].

The vascular renin-angiotensin system (RAS) is regulated independently from circulating RAS and plays a role in the local regulation of vascular tone, the modulation of sympathetic activity and vascular remodeling. Endothelial cells are a major source of angiotensin converting enzyme (ACE), which produces angiotensin II and degrades bradykinin, in normal arteries. Mechanical stress such as transmural pressure, stretch stress and shear stress appear to contribute to the regulation of endothelial ACE activity. In contrast, vessels with intimal proliferation such as atheromatous plaque and neointima following balloon injury show expression of ACE in smooth muscle cells and macrophages in the intimal lesions. Activation of ACE in intimal SMC may relate to a phenotypic change of SMC from the contracting type of the synthetic type. Activation of ACE in macrophages is also related to the transformation of macrophages from monocytes. Concerning the role of the activated RAS, elevated blood pressure and vascular tonus by angiotensin II are candidates of vascular injury and plaque rupture. Angiotensin II stimulates migration and proliferation of smooth muscle cells and production of extracellular matrix. Furthermore, angiotensin II increases oxidized-LDL which may be related to the forming of macrophages. These evidence suggest that activation of vascular RAS following endothelial dysfunction/injury play an important role in the pathogenesis of vascular remodeling and atherosclerosis.

Animals↗
PubMed1997

Upregulation of angiotensin-converting enzyme during the healing process after injury at the site of percutaneous transluminal coronary angioplasty in humans.

BACKGROUND: Balloon injury models in rat have shown enhanced expression of ACE in the developing neointima. However, neointimal lesions in human coronary arteries are complex due to atherosclerosis and different types of wall laceration. This study was designed to investigate whether ACE is present in the neointima of humans, including patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA). METHODS AND RESULTS: Thirty-seven sites with angioplasty injury, obtained at autopsy, were studied using immunocytochemical techniques. Sites with injury limited to a fibrous plaque and those with injury extending into the media (<2 months after PTCA) showed fibrocellular repair tissue composed mainly of smooth muscle cells that were distinctly positive for ACE. In cellular reactions at the site of injury limited to the atheromatous plaque (<2 months after PTCA), the expression of ACE appeared first in accumulated macrophages; once smooth muscle cells appeared in the repair tissue, they also expressed ACE. At a later stage (3 months after PTCA), the number of cells with ACE expression decreased markedly; from 7 months on, ACE was no longer expressed within the repair tissue. Basically, there were no differences with regard to ACE expression during the healing process after PTCA between segments with and those without angiographic evidence of restenosis. CONCLUSIONS: These results show that PTCA injury in humans results in upregulation of ACE at sites of active repair and, therefore, ACE could play an important role as one of the mediators of the healing process after PTCA.

Aged↗
PubMed1997

Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population.

The Werner syndrome (WS) is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus (NIDDM), ocular cataracts and osteoporosis [Epstein et al., 1966]. The major cause of death (at a median age of 47) is myocardial infarction (MI) [Epstein et al., 1966]. The WS mutation involves a member (WRN) of the RecQ family of helicases and may perturb DNA replication, repair, recombination, transcription, or chromosomal segregation [Yu et al., 1996]. We now report data on 149 MI cases and age-matched controls suggesting that a polymorphic WRN variant is associated with increased risk for MI. Based on our data, homozygosity for a cysteine at amino acid 1367 (the most prevalent genotype) predicts a 2.78 times greater risk of MI (95% confidence intervals: 1.23 to 6.86). The variant was not significantly associated with NIDDM. The two alleles (cysteine vs. arginine) could influence helicase activity, turnover, macromolecular interactions or, alternatively, could be markers for haplotypes influencing WRN regulation or reflecting gene action at linked loci. However, given the caveats implicit in genetic association studies, it is imperative that the present results be replicated in independent populations.

Adult↗
PubMed1997

alpha 1-Antichymotrypsin as a risk modifier for late-onset Alzheimer's disease in Japanese apolipoprotein E epsilon 4 allele carriers.

In the Japanese population, sporadic late-onset Alzheimer's disease (LOAD) cases had significantly higher frequencies of the A allele of alpha 1-antichymotrypsin (ACT) gene as well as the epsilon 4 allele of apolipoprotein E (APOE) gene than controls. The odds ratio for LOAD in APOE4 carriers with the ACT-A allele was more than six times that in APOE4 carriers without the ACT-A allele (21.1 vs 3.2). These results indicate that the ACT-A allele is a risk modifier for LOAD in APOE4 carriers.

Age of Onset↗
PubMed1997

Trp64Arg mutation of beta3-adrenergic receptor in essential hypertension: insulin resistance and the adrenergic system.

A putative pathogenic mutation in the beta3-adrenergic receptor gene (Trp64Arg) has been reported to be associated with higher diastolic blood pressure as well as clinical features of the insulin resistance syndrome and an earlier onset of non-insulin-dependent diabetes mellitus (NIDDM) in Pima Indians and Finns. Because essential hypertension is reported to be associated with insulin resistance, we studied the mutation in Japanese patients with essential hypertension to clarify associations of this mutation with hypertension, insulin resistance, and basal adrenergic state in hypertensive subjects. The allele frequency of the mutation (Arg) in patients with essential hypertension was similar to that in control subjects (35 of 202 alleles [17.3%] v 27 of 146 [18.5%], respectively, P > .7). Insulin sensitivity measured by hyperinsulinemic euglycemic glucose clamp and plasma norepinephrine and epinephrine levels were also similar in hypertensive subjects with and without the mutation. These data suggest that Trp64Arg mutation in the beta3-adrenergic receptor gene does not play a major role in susceptibility to essential hypertension or in insulin resistance and basal adrenergic state in hypertension.

Adult↗
PubMed1997

Insulin resistance is related to silent cerebral infarction in patients with essential hypertension.

Recently, hyperinsulinemia or insulin resistance has been suggested to be a risk factor for cardiovascular diseases. We evaluated the role of insulin resistance in the occurrence of silent cerebral infarction in 28 patients with essential hypertension (40 to 75 years, 157 +/- 4/89 +/- 2 mm Hg). Patients with diabetes mellitus or obesity (BMI > or = 30) were excluded. Insulin resistance was evaluated by means of constant glucose infusion rate (M value) during euglycemic-hyperinsulinemic glucose clamp test. Infarction was defined as a focal area with prolonged T1 and T2 relaxation times that was > 5 mm in diameter on brain magnetic resonance imaging. The severity of periventricular hyperlucency was evaluated by the distribution of the high intensity area. The number of silent infarctions significantly correlated only with the M value (F = 7.58, R2 = 0.23, P = .01) in multiple regression analysis using all variables: age, blood pressure, smoking history, lipid profile, levels of plasma glucose and insulin on fasting, and total amounts during 75-g OGTT. However, the severity of periventricular hyperlucency did not show a correlation with any factors. The occurrence of cerebral infarction was significantly correlated with thickening of the intima-media complex (IMC) of the common carotid artery on B-mode ultrasonography (F = 8.43, R2 = 0.25, P < .01). In conclusion, insulin resistance and thickening of IMC show a close relationship with the occurrence of silent cerebral infarction. Therefore, it may be important to improve insulin resistance for prevention of cerebral infarction in essential hypertensives.

Carotid Arteries↗
PubMed1997

Polymorphism of angiotensin converting enzyme, angiotensinogen, and apolipoprotein E genes in a Japanese population with cerebrovascular disease.

The homozygous deletion allele of the angiotensin converting enzyme gene (ACE/DD), homozygous threonine allele of the angiotensinogen gene (AGN/TT), and the epsilon4 allele of the apolipoprotein E gene (apoE/epsilon4) are reported to be associated with ischemic heart disease. Cerebrovascular disease (CVD) is another atherosclerotic disease; and the effects of these polymorphisms on CVD have been confusing. In this study, we investigated whether ACE/DD, AGN/TT, and apoE/epsilon4 genotypes are associated with CVD and whether genetic risk is enhanced by the effect of one upon another. We ascertained these genotypes in patients with cerebral infarction (n = 55) and cerebral hemorrhage (n = 38), diagnosed by brain computed tomography. Control subjects for the infarction group and the hemorrhage group were randomly selected from 583 subjects matched for age, gender, and history of hypertension with patients. Frequency of ACE/DD genotype was higher in the patients with infarction than in the controls (chi2 = 6.1, P < .05). The AGN/TT genotype was not associated with either infarction or hemorrhage, but it increased the relative risk for cerebral infarction in the subjects with ACE/DD genotype (chi2 = 8.0, P < .01, odds ratio; 11.7, 95% confidence intervals: 1.4 to 96.0). There was no significant association between apoE/epsilon4 and CVD. These results suggest that ACE/DD predicts cerebral infarction, but not cerebral hemorrhage, and that AGN/TT enhances the risk for cerebral infarction associated with ACE/DD.

Adult↗
PubMed1997

Enhanced expression of angiotensin-converting enzyme is associated with progression of coronary atherosclerosis in humans.

BACKGROUND: The clinical usefulness of angiotensin converting enzyme (ACE) inhibitors in preventing the recurrence of myocardial infarction has been investigated in large randomized trials. Results from many studies using animal models have suggested that ACE inhibitors have vasculoprotective effects, which may contribute to the prevention of coronary atherosclerosis. OBJECTIVE: To examine the association between vascular angiotensin generation and the development of coronary atherosclerosis in humans. METHODS: We used immunocytochemical techniques to examine frozen sections from 44 coronary artery segments from 19 corpses. RESULTS: Three segments were sites of plaque rupture in patients who had died from acute myocardial infarction. Other specimens of coronary artery segments were characterized histologically to be normal artery segments with diffuse intimal thickening (n = 6), hypercellular lesions composed of smooth muscle cells with or without infiltration of macrophages (n = 11), atheromatous plaque (n = 12), and fibrosclerotic plaque (n = 12). In normal arteries with diffuse intimal thickening, ACE was expressed in endothelial cells. In those with hypercellular lesions and atheromatous plaques, however, enhanced ACE expression was found in macrophages and smooth muscle cells. In contrast, arteries with fibrosclerotic plaques exhibited little or no ACE expression within the plaque. All three ruptured plaques expressed ACE strongly in macrophages accumulated around the attenuated fibrous cap. CONCLUSION: The strong association of enhanced ACE expression with the histologic characteristics of plaques suggests that ACE in hypercellular lesions, atheromatous plaques, and ruptured plaques contributes greatly to the further progression of atherosclerosis via an increase in vascular angiotensin II formation and inactivation of bradykinin.

Adult↗
PubMed1997

Asp905Tyr polymorphism of protein phosphatase 1 G subunit gene in hypertension.

A possible pathogenic polymorphism in the gene for the G subunit of the glycogen-associated regulatory form of protein phosphatase 1 (PP1 G subunit), causing an Asp-to-Tyr substitution at codon 905 (Asp905Tyr), has been reported to be associated with insulin resistance and hypersecretion of insulin in the white population. Since marked heterogeneity has been reported in the association of mutations of candidate genes with essential hypertension between Japanese and other ethnic groups, we investigated the association of Asp905Tyr with essential hypertension in Japanese subjects. The frequency of the Tyr allele in Japanese control subjects (0.70) was much higher than that in the Danish population (0.10, P<1x10(-8)), indicating that the Tyr allele, previously reported as a rare variant in white subjects, is a common allele in our population. The genotype distribution in Japanese hypertensive patients (n=109; Asp/Asp=0.09, Asp/Tyr=0.39, Tyr/Tyr=0.52) was not significantly different (chi2=0.7, df=2, P>.6) from that in normotensive control subjects (n=148; Asp/Asp=0.12, Asp/Tyr=0.36, Tyr/Tyr=0.52). Among subjects with different PP1 G subunit genotypes, there was no difference in blood pressure, serum cholesterol, plasma glucose and insulin levels, and glucose disposal rate estimated by the euglycemic hyperinsulinemic clamp test. These data indicate that the Asp905Tyr polymorphism of the PP1 G subunit is not associated with essential hypertension, nor with insulin resistance and/or hyperinsulinemia in Japanese patients with essential hypertension, suggesting that the polymorphism plays little if any role in susceptibility to insulin resistance or hypertension.

Aged↗
PubMed1997

Association of variants in critical core promoter element of angiotensinogen gene with increased risk of essential hypertension in Japanese.

We examined the association between variants in the core promoter element 1 (AGCE1) of the human angiotensinogen gene (AGT), which acts as a critical regulator of AGT transcription, and the risk for hypertension. One hundred and eighty patients with documented essential hypertension and a family history of hypertension and 194 control subjects without hypertension were selected and frequency matched by age and sex. Genomic DNA from leukocytes was analyzed for genetic variants (position: -20 to -18) in AGCE1. The haplotype in AGCE1 was significantly associated with increased risk of essential hypertension (P<.05). The frequency of subjects with homozygous C allele at position -18(CC/C-18T) was significantly higher in case patients than in control subjects (P<.005), and the evaluated odds ratio for hypertension was 4.2 (95% confidence interval [CI]: 1.4 to 12.8, CC/C-18T versus CT/C-18T). The homozygous threonine allele at codon 235 (TT/M235T) in exon 2 of AGT was also associated with hypertension (P<.02; odds ratio, TT versus other genotypes, 1.8; 95% CI, 1.1 to 2.7). According to haplotype analysis between AGT polymorphisms, we identified linkage disequilibrium between M235T and A-20C and between M235T and C-18T. We conclude that C-18T polymorphism in AGCE1 is a genetic risk factor for essential hypertension in the Japanese and is more tightly and directly associated with hypertension than TT/M235T.

Aged↗
PubMed1997

Influence of aging on progression of cardiovascular complications associated with insulin resistance in patients with essential hypertension.

Hyperinsulinemia or insulin resistance is suggested to play a role in the pathogenesis of hypertension and its target organ diseases. It is also well documented that aging is associated with a decline in glucose tolerance and insulin sensitivity, but there are few reports on the relationship between aging and insulin sensitivity or on the effects of aging on the progression of cardiovascular complications in patients with essential hypertension. To clarify these effects of aging in essential hypertension, 44 patients were examined by the euglycemic hyperinsulinemic glucose clamp test and ultrasonography of the heart and carotid arteries. There was a significant negative correlation between aging and insulin sensitivity (r = -0.37, p < 0.05). Significant increases in left ventricular mass index and carotid wall thickening accompanied by insulin resistance were seen in only non-elderly patients but not in elderly patients. These results suggest that aging decreases insulin sensitivity even in essential hypertensive subjects and that insulin resistance does not affect the progression of cardiac hypertrophy and atherosclerosis in elderly patients with essential hypertension.

Aged↗
PubMed1997

Recognition of tissue- and subtype-specific modulation of angiotensin II receptors using antibodies against AT1 and AT2 receptors.

Polyclonal antibodies have been prepared against synthetic peptides of human angiotensin II type-1 (AT1) and type-2 (AT2) receptors. Synthetic peptides corresponded to amino acids 15-24 of AT1 receptor and amino acids 241-253 of AT2 receptor. Western blot analysis of membranes from cell homogenates of COS-7 cells transfected with expression plasmids for mouse AT1b receptor, human vascular smooth muscle cells, and rat peripheral tissue demonstrated a major band of MW 44,000 with AT1 receptor antibody. Cell homogenates of COS-7 cells transfected with expression plasmids for human AT2 receptor showed a band of MW 44,000 with AT2 receptor antibody. Tissue homogenate of rat adrenal medulla and human pheochromocytoma presented a major band of MW 52,000 and a minor band of MW 44,000 with AT2 receptor antibody. AT1 receptor expression was in the following order: rat aorta > > lung, kidney, spleen, adrenal cortex > adrenal medulla, heart. Expression of AT2 receptor was in the following order: rat adrenal medulla > cortex, kidney, heart. Three-day treatment with CS866, an AT1 receptor antagonist, and temocapril, an angiotensin-converting enzyme inhibitor, suppressed AT1 receptor expression in the rat adrenal cortex, but not in the heart or adrenal medulla. AT2 expression was not affected by treatment with these drugs. These results suggest that newly developed antibodies for AT1 and AT2 receptors are useful in elucidating the regulation of subtype-specific receptor expression, and that AT1 but not AT2 receptors in adrenal tissue are regulated by angiotensin II.

Adrenal Glands↗