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Biomedical subjects

Tetsuya Oshima

Publications and source records attributed to Tetsuya Oshima.

At least 19 recordsLinked to original sources
PubMed2006

AT2 receptor mediates the cardioprotective effects of AT1 receptor antagonist in post-myocardial infarction remodeling.

There are two subtypes of angiotensin (Ang) II receptors, AT1R and AT2R. It is established that clinical use of specific AT1R blocker (ARB) improves the long-term prognosis of heart failure. However, scientific basis for such effects of ARB is incompletely understood. The present study was designed to determine whether ARB inhibits the left ventricular (LV) remodeling that occurs early after myocardial infarction (MI) and whether the benefit of ARB is mediated by blockade of AT1R itself or by stimulation of AT2R resulting from AT1R blockade. MI was induced in AT2R-knockout mice and wild-type mice. Administration of valsartan, an ARB, or vehicle was started soon after the surgery and continued for two weeks. Infarction caused significant increase in end diastolic and end systolic LV dimensions, LV/body weight ratio, and myocyte cross-sectional area (MCSA) in both strains to a similar extent. Lung/body weight ratio, an index of pulmonary congestion, was also significantly increased in both strains, but the magnitude of increase was significantly larger in knockout mice. Valsartan significantly reduced LV dimensions, LV/body weight ratio, MCSA, and lung/body weight ratio in wild-type mice. In knockout mice, however, valsartan failed to inhibit the increases in LV dimensions and LV/body weight ratio. After the treatment, lung/body weight ratio in the mutant strain was significantly larger than that in the wild-type mice. Valsartan attenuates acute phase post-infarction remodeling and ameliorates heart failure, and a large part of its cardioprotective effect was mediated by AT2R.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Genetic ablation of the transcription repressor Bach1 leads to myocardial protection against ischemia/reperfusion in mice.

Bach1 is a transcriptional repressor of heme oxygenase-1 gene (Hmox-1) and beta-globin gene. Heme oxygenase (HO)-1 is an inducible cytoprotective enzyme that degrades pro-oxidant heme to carbon monoxide (CO) and biliverdin/bilirubin, which are thought to mediate anti-inflammatory and anti-oxidant actions of HO-1. In the present study, we investigated the role of Bach1 in tissue protection against myocardial ischemia/reperfusion (I/R) injury in vivo using mice lacking the Bach1 gene (Bach1(-/-)) and wild-type (Bach1(+/+)) mice. In Bach1(-/-) mice, myocardial expression of HO-1 protein was constitutively up-regulated by 3.4-fold compared to that in Bach1(+/+) mice. While myocardial I/R induced HO-1 protein in ischemic myocytes in both strains of mice, the extent of induction was significantly greater in Bach1(-/-) mice than in Bach1(+/+) mice. Myocardial infarction was markedly reduced in size by 48.4% in Bach1(-/-) mice. Pretreatment of Bach1(-/-) mice with zinc-protoporphyrin, an inhibitor of HO activity, abolished the infarction-reducing effect of Bach1 disruption, indicating that reduction in the infarct size was mediated, at least in part, by HO-1 activity. Thus, Bach1 plays a pivotal role in setting the levels of both constitutive and inducible expression of HO-1 in the myocardium. Bach1 inactivation during I/R appears to be a key mechanism controlling the activation level of cytoprotective program involving HO-1.

Animals↗
PubMed2006

Differential impact of family history on age-associated increase in the prevalence of hypertension and diabetes in male Japanese workers.

Family history and aging are independent risk factors for the development of hypertension as well as for the development of diabetes. However, it is unclear how the family histories influence the rate of age-associated increase in these diseases. Moreover, despite the fact that hypertension and diabetes often occur concomitantly, it is not known whether family history of hypertension increases the risk of diabetes or vice versa. To gain an insight into these questions, we investigated the cross-sectional prevalence and family history of hypertension and diabetes in 1,123 male subjects (mean age, 42.1 +/- 12 years; range, 20-60 years) who participated in annual medical check-ups. The data were analyzed by 10-year age groups (20s, 30s, 40s and 50s). The prevalence of hypertension increased with age group either in the absence (12% in the 20s and 39% in the 50s) or in the presence (21% in the 20s and 59% in the 50s) of family history of hypertension, and thus the increasing rate of prevalence with age was not affected by family history. The prevalence of diabetes in the absence of family history of diabetes was low until the 40s (< 1.2%) but it jumped in the 50s (4.3%). On the other hand, in the presence of family history, the prevalence was 4% in the 20s and progressively increased to 20% in the 50s. The impact of family history on the risk of diabetes was strong and appeared to increase with age. Family history of hypertension did not increase the risk of diabetes, and family history of diabetes did not increase the risk of hypertension. These results suggest that family history of hypertension has an additive impact on the age-associated increase in the risk of hypertension, whereas family history of diabetes has an exponential impact on aging-associated increase in the risk of diabetes.

Adult↗
PubMed2005

Smoking, endothelial function, and Rho-kinase in humans.

OBJECTIVE: Smoking is associated with endothelial dysfunction and activated Rho-kinase in vascular smooth muscle cells (VSMCs) in humans. The purpose of this study was to elucidate the relationship between endothelial function and Rho-kinase activity in forearm VSMCs in healthy young men. METHODS AND RESULTS: We evaluated the forearm blood flow (FBF) responses to acetylcholine (ACh), fasudil, a Rho-kinase inhibitor, and sodium nitroprusside (SNP) in male smokers (n=10) and nonsmokers (n=14). FBF was measured by using a strain-gauge plethysmography. The vasodilatory effect of ACh was significantly smaller in smokers than that in nonsmokers. The vasodilatory effect of fasudil was significantly greater in smokers than that in nonsmokers. The vasodilatory effects of SNP in the 2 groups were similar. There was a significant correlation between the maximal FBF response to fasudil and that to ACh (r=-0.67; P<0.01). There was no significant correlation between the maximal FBF response to fasudil and that to SNP. The intra-arterial coinfusion of fasudil significantly increased the FBF response to ACh in smokers but not in nonsmokers. There were no significant differences between FBF response to fasudil alone and that in combination with NG-monomethyl-L-arginine in smokers and in nonsmokers. The intra-arterial coinfusion ascorbic acid did not alter the FBF response to fasudil in both groups. CONCLUSIONS: These findings suggest that smoking is involved in not only endothelial dysfunction but also activation of Rho-kinase in VSMCs in forearm circulation, and that there is a significant correlation between endothelial function and Rho-kinase activity in VSMCs.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2005

Tetrahydrobiopterin improves aging-related impairment of endothelium-dependent vasodilation through increase in nitric oxide production.

Deficiency of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) synthase, decreases NO production and increases reactive oxygen species. The purpose of this study was to elucidate the effects of aging on endothelial function and to determine whether the degree of BH4 deficiency is related to aging and oxidative stress. We evaluated forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, before and after co-infusion of BH4 (500 mg/min) in 37 healthy men (mean age, 41+/-18 yr; range, 19-81 yr). FBF was measured using strain-gauge plethysmograph. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) were measured as indices of oxidative stress. Both ACh and ISDN increased the FBF in a dose-dependent manner in all subjects. Co-infusion of BH4 resulted in a significant increase in ACh-induced vasodilation (from 22.3+/-6.7 to 30.1+/-7.5 mL/min/100 mL tissue, P<0.05). Aging was found to be significantly correlated with ACh-induced vasodilation (r=-0.47, P=0.006), urinary 8-OHdG (r=0.38, P=0.02), serum MDA-LDL (r=0.36, P=0.02), and the change in ACh-induced vasodilation after co-infusion of BH4 (r=0.45, P=0.007). The FBF response to ISDN did not correlate with any parameters. Infusion of N(G)-monomethyl-L-arginine, an NO synthase inhibitor, abolished the BH4-induced enhancement of forearm vasorelaxation evoked by ACh. The increase in FBF after ISDN was not altered by BH4. These findings suggest that a deficiency of BH4 may be involved in the pathogenesis of disturbances in endothelium-dependent vasodilation related to aging through decrease in NO production and increase in oxidative stress.

Acetylcholine↗
PubMed2005

Role of the JNK pathway in thrombin-induced ICAM-1 expression in endothelial cells.

OBJECTIVE: Thrombin induces leukocyte adherence to endothelial cells via increased expression of intercellular adhesion molecule-1 (ICAM-1). Although ICAM-1 expression is regulated by NF-kappaB, recent studies have suggested that additional signaling mechanisms may also be involved. The goal of this study was to determine whether mitogen-activated protein (MAP) kinases, including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 MAP kinase (p38), mediate thrombin-induced ICAM-1 expression in endothelial cells. METHODS: Western blot analysis using anti-ICAM-1 antibody and luciferase assays were performed in cultured endothelial cells after addition of signal transduction inhibitors or transfection of various gene constructs. JNK kinase activity was determined by a kinase assay using c-Jun as a substrate or by Western blot analysis with anti-phospho-JNK antibody. RESULTS: Treatment of endothelial cells with the JNK-specific inhibitors, SP600125 or JNK inhibitory peptide 1 (JNKI1), resulted in a significant decrease in thrombin-induced ICAM-1 expression as demonstrated by Western blot analysis (67 +/- 3% and 72 +/- 7%, respectively). In contrast, inhibitors of MEK and p38 had only minimal effect. The combination of SP600125 and the NF-kappaB inhibitor, BAY11-7082, resulted in complete inhibition of thrombin-induced ICAM-1 expression. The Galpha(q) inhibitor, YM-254890, inhibited thrombin-induced JNK activation and ICAM-1 expression. Dominant-negative Ras and Rac1, but not Rho, inhibited thrombin-induced JNK activation and ICAM-1 promoter activity. Finally, thrombin-induced JNK activation and ICAM-1 promoter activity were inhibited by betaARK1ct (a Gbetagamma subunit scavenger) and Csk. CONCLUSIONS: These data suggest that, in concert with NF-kappaB, JNK regulates thrombin-induced ICAM-1 expression by a mechanism that is dependent on Galpha(q), Gbetagamma, Ras, Rac1 and the Src kinase family.

Animals↗
PubMed2005

Association of Helicobacter pylori infection with systemic inflammation and endothelial dysfunction in healthy male subjects.

OBJECTIVES: The goal of the present study was to determine whether seropositivity to Helicobacter pylori (HP), Chlamydia pneumoniae (CP), and cytomegalovirus (CMV) is associated with systemic inflammation and endothelial dysfunction in healthy male subjects. BACKGROUND: Chronic infection with certain bacteria and viruses may play an important role in inflammation as the pathogenesis of atherosclerosis. METHODS: The serum levels of immunoglobulin G antibodies to HP, CP, CMV, high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 were determined in 81 healthy Japanese men (40 +/- 10 years of age). High-frequency ultrasonographic imaging of the brachial artery was used to study endothelium-dependent (flow-mediated vasodilation) and endothelium-independent (nitroglycerin-induced) vasodilation. RESULTS: Prevalences of seropositive antibodies to HP, CP, and CMV were 67.9%, 61.7%, and 56.8%, respectively. Infection with HP, CP, or CMV had no relationship with age, blood pressure, or level of serum glucose, lipid, or soluble vascular cell adhesion molecule-1. The levels of C-reactive protein and soluble intercellular adhesion molecule-1 were significantly higher, and flow-mediated vasodilation was significantly lower in subjects with seropositive antibodies to HP than in subjects with seronegative antibodies to HP. Endothelium-independent vasodilation was similar in both groups. CONCLUSIONS: Chronic infection with HP may be involved in the development of the atherosclerosis via endothelial dysfunction and systemic and vascular inflammation.

Adult↗
PubMed2005

Relationship between endothelial function in the coronary and brachial arteries.

BACKGROUND: Endothelial dysfunction is the first step in the progression to atherosclerosis, but little is known regarding whether there is a correlation in endothelial function between the coronary and peripheral arteries. HYPOTHESIS: We investigated the relationship between coronary and peripheral endothelial function. METHODS: In 41 patients (mean age 63 years; 23 men, 18 women) with angiographically normal coronary arteries, changes in brachial artery diameter in response to hyperemic flow and sublingual nitroglycerin (NTG) were measured by high-resolution ultrasonography. During coronary angiography, acetylcholine (ACh, 3 and 30 microg/min) and NTG were infused into the left coronary ostium. The diameter of the coronary artery was quantitatively measured and coronary blood flow (CBF) was calculated by quantitative angiography and Doppler flow velocity measurements. Changes in these parameters in response to each drug infusion were expressed as the percent change from the baseline values. RESULTS: Flow-mediated dilation (FMD) of the brachial artery was 5.0 +/- 3.5% and correlated positively not only with the change in coronary diameter (ACh at 30 microg/min, r = 0.31, p < 0.05) but also with the change in CBF (ACh at 3 microg/min, r = 0.39, p < 0.05; ACh at 30 microg/min, r = 0.46, p < 0.01). Multivariate analysis demonstrated that FMD was one of the factors associated with the changes in coronary diameter and CBF. CONCLUSIONS: These results suggest that brachial endothelial function is associated with coronary endothelial function in patients with angiographically normal coronary arteries, suggesting that impairment of endothelial function may occur simultaneously in both coronary and peripheral arteries.

Acetylcholine↗
PubMed2005

The nicorandil-induced vasodilation in humans is inhibited by miconazole.

Nicorandil, N-(2-hydroxyethyl)-nicotinamide nitrate, exerts its vasodilatory effects by opening ATP-sensitive potassium (K-ATP) channels and by acting as the exogenous nitric oxide (NO). It is not clear, however, whether the actions of other endothelium-dependent vasodilators, such as NO, endothelium-derived hyperpolarizing factor (EDHF), and prostaglandins, contribute to nicorandil-induced vasodilation in the vasculature in humans. We evaluated forearm blood flow (FBF) response to intraarterial infusion of nicorandil alone and in the presence of glibenclamide, a K-ATP channel inhibitor, N(G)-monomethyl-L-arginine, an NO synthase inhibitor, indomethacin, a cyclooxygenase inhibitor, or miconazol, a cytochrome P-450 inhibitor, in 24 healthy male subjects. FBF was measured using strain-gauge plethysmography. Infusion of nicorandil significantly increased the FBF response in a dose-dependent manner. Intraarterial infusion of glibenclamide attenuated nicorandil-induced vasodilation (160.9 +/- 21.2% versus 90.2 +/- 19.4%, P < 0.01), and miconazole also attenuated the FBF response to nicorandil (160.9 +/- 21.2% versus 66.1 +/- 9.2%, P < 0.001). N-monomethyl-L-arginine or indomethacin did not alter the FBF response to nicorandil. These findings suggest that nicorandil causes vasodilation in forearm circulation in humans, at least in part through a pathway that is dependent on K-ATP channels and cytochrome P-450, but not on endogenous NO and prostaglandins. EDHF may contribute to nicorandil-induced vasodilation in humans.

Adult↗
PubMed2005

Adrenomedullin causes coronary vasodilation in humans: effects of inhibition of nitric oxide synthesis.

Experimental studies have shown that adrenomedullin (AM) causes vasodilation, in part, mediated by endothelium-derived nitric oxide (NO). However, it remains to be clarified how NO is involved in AM-induced coronary vasoreactivity in humans. We examined whether NO contributes to the vasodilatory effects of adrenomedullin on human coronary arteries. In 10 patients with angiographically normal coronary arteries, adrenomedullin (low dose: 1 ng/kg/min; high dose: 10 ng/kg/min) was infused into the left coronary ostium before and after an infusion of N-monomethyl-L-arginine (L-NMMA, 40 micromol/min for 5 min), an NO synthase inhibitor. Coronary diameter and coronary blood flow (CBF) were evaluated by quantitative angiography and Doppler flow velocity measurements. Changes in these parameters in response to adrenomedullin were expressed as percent changes from baseline values. Adrenomedullin at a high dose dilated coronary arteries (3.7+/-0.5%, P<0.001). Adrenomedullin increased the coronary blood flow at both doses (low: 55.7+/-13.9%, P<0.01; high: 48.8+/-9.8%, P<0.001). After the infusion of L-NMMA, adrenomedullin-induced coronary vasodilation and increase in coronary blood flow were attenuated. These findings suggest that adrenomedullin dilates human coronary arteries through an increase in NO production, at least in part.

Adrenomedullin↗
PubMed2005

Beneficial effect of T-type calcium channel blockers on endothelial function in patients with essential hypertension.

Endothelial function is impaired in essential hypertension. T-type but not L-type voltage-gated Ca2+ channels were detected in the vascular endothelium. The purpose of the present study was to clarify the role of T-type Ca2+ channels in endothelial function. We studied flow-mediated vasodilation (FMD) and sublingual nitroglycerin (NTG)-induced vasodilation in the brachial artery. Forty patients with essential hypertension were randomly assigned to treatment with efonidipine, a T- and L-type Ca2+ channel blocker, or with nifedipine, an L-type Ca2+ channel blocker. Twenty healthy normotensive individuals were included as a control group. In patients with essential hypertension, FMD was attenuated and NTG was similar that of compared to healthy controls. After 12 weeks, the decrease in mean blood pressure in the efonidipine and nifedipine groups were similar. The endothelial function index, a ratio of FMD/NTG, was significantly increased by efonidipine (73 +/- 24 to 94 +/- 20%) but unchanged by nifedipine. Urinary excretion 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde-modified low-density lipoprotein (LDL) were decreased by efonidipine but unchanged by nifedipine. These results suggest that a T-type Ca2+ channel blocker, but not an L-type Ca2+ channel blocker, may improve vascular endothelial dysfunction in patients with essential hypertension via a reduction in oxidative stress.

Adult↗
PubMed2004

Effect of edaravone, a novel free radical scavenger, on endothelium-dependent vasodilation in smokers.

The forearm blood flow (FBF) responses to acetylcholine and to sodium nitroprusside were evaluated before and after administration of edaravone in 10 smokers and 10 nonsmokers. FBF response to acetylcholine was lower in smokers than in nonsmokers. The vasodilatory effects of sodium nitroprusside were similar in both groups. Co-infusion of edaravone increased the FBF response to acetylcholine in smokers, but did not affect the FBF response to acetylcholine in nonsmokers. The administration of N(G)-monomethyl-l-arginine abolished edaravone-induced augmentation of the FBF response to acetylcholine in smokers. The antioxidative agent edaravone increases nitric oxide mediated vasodilation through a decrease in oxidative stress.

Acetylcholine↗
PubMed2004

Autologous bone-marrow mononuclear cell implantation improves endothelium-dependent vasodilation in patients with limb ischemia.

BACKGROUND: Patients with limb ischemia were associated with endothelial dysfunction. The purpose of this study was to determine whether autologous bone-marrow mononuclear cell (BM-MNC) implantation improves endothelial dysfunction in patients with limb ischemia. METHODS AND RESULTS: We evaluated the leg blood flow (LBF) response to acetylcholine (ACh), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator, before and after BM-MNC implantation in 7 patients with limb ischemia. LBF was measured with a mercury-filled Silastic strain-gauge plethysmograph. The number of BM-MNCs implanted into ischemic limbs was 1.6x10(9)+/-0.3x10(9). The number of CD34+ cells included in the implanted BM-MNCs was 3.8x10(7)+/-1.6x10(7). BM-MNC implantation improved the ankle-brachial pressure index (0.33+/-0.21 to 0.39+/-0.17, P=0.06), transcutaneous oxygen pressure (28.4+/-11.5 to 36.6+/-5.2 mm Hg, P=0.03), and pain-free walking time (0.8+/-0.6 to 2.9+/-2.2 minutes, P=0.02). After BM-MNC implantation, LBF response to ACh was enhanced (19.3+/-6.8 versus 29.6+/-7.1 mL/min per 100 mL; P=0.002). The vasodilatory effect of SNP was similar before and after BM-MNC implantation. CONCLUSIONS: These findings suggest that BM-MNC implantation augments endothelium-dependent vasodilation in patients with limb ischemia.

Acetylcholine↗
PubMed2004

Telomere attrition in white blood cell correlating with cardiovascular damage.

Aging is a major risk factor for cardiovascular disease. Chronological aging does not always parallel biological aging, but there is no reliable biomarker for the latter. In the present study, we tested the hypothesis that telomere attrition in white blood cells is related to endothelial dysfunction and the extent of atherosclerosis, and thus may serve as a useful marker for biological aging. We evaluated telomere lengths in white blood cells by measuring the mean telomere restriction fragment length (mTRFL), as well as endothelial function by flow mediated dilatation (FMD) in the brachial artery, in patients with various degrees of cardiovascular damage and in normal subjects. Cardiovascular damage was assessed by a cardiovascular damage (CVD) score, with 1 point being given for the presence of each cardiovascular risk factor (hypertension, hyperlipidemia and diabetes) and for each event (angina, myocardial infarction, cerebrovascular event and peripheral vascular disease). Subset analysis of CVD score groups revealed that mTRFL and FMD decreased in the rank order of CVD score. Although mTRFL was inversely correlated with age, telomere index, defined as the ratio of TRFL to TRFL predicted by age, also decreased with increase in CVD score. These results indicate that telomere attrition in white blood cells is more closely associated with endothelial damage and atherosclerosis than is chronological aging, supporting the hypothesis that mTRFL in white blood cells is a useful marker for biological aging of the cardiovascular system.

Adult↗
PubMed2004

[Establishment of a clinical method for evaluating flow-mediated vasodilation(FMD) in brachial artery].

We have established a clinical routine method for evaluating the endothelial function in forearm circulation in humans. Flow-mediated vasodilation(FMD) was used as the endothelium-dependent and the response to nitroglycerin(NTG) as the endothelium-independent vasodilation. Diameter of the brachial artery was measured by high-frequency ultrasonographic imaging before and after hyperemia following artery occlusion. Because vasodilation reached the maximal level when the artery was occluded for 5 min, this time was selected as the occlusion time. FMD was greater (12 vs 9%) after upper-arm occlusion than after forearm occlusion. The peak time to maximal vasodilation was 50 sec after forearm occlusion and 70 sec after upper-arm occlusion. During NO synthesis inhibitor infusion, vasodilation after forearm occlusion was abolished, whereas that after upper-arm occlusion was attenuated by half. Therefore, the mechanisms for FMD may differ by occlusion position. The response to NTG was attenuated by aging. FMD was significantly decreased by coronary artery disease and coronary risk factors such as hypertension, hyperlipidemia and diabetes, but the response to NTG was not changed by these diseases. These measurements may offer useful tools for assessment of endothelial function.

Arteriosclerosis↗
PubMed2003

Mnk1 is required for angiotensin II-induced protein synthesis in vascular smooth muscle cells.

Angiotensin II (Ang II) stimulates protein synthesis in vascular smooth muscle cells (VSMCs), possibly secondary to regulatory changes at the initiation of mRNA translation. Mitogen-activated protein (MAP) kinase signal-integrating kinase-1 (Mnk1), a substrate of ERK and p38 MAP kinase, phosphorylates eukaryotic initiation factor 4E (eIF4E), an important factor in translation. The goal of the present study was to investigate the role of Mnk1 in Ang II-induced protein synthesis and to characterize the molecular mechanisms by which Mnk1 and eIF4E is activated in rat VSMCs. Ang II treatment resulted in increased Mnk1 activity and eIF4E phosphorylation. Expression of a dominant-negative Mnk1 mutant abolished Ang II-induced eIF4E phosphorylation. PD98059 or introduction of kinase-inactive MEK1/MKK1, but not SB202190 or kinase-inactive p38 MAP kinase, inhibited Ang II-induced Mnk1 activation and eIF4E phosphorylation, suggesting that ERK, but not p38 MAP kinase, is required for Ang II-induced Mnk1-eIF4E activation. Further, dominant-negative constructs for Ras, but not for Rho, Rac, or Cdc42, abolished Ang II-induced Mnk1 activation. Finally, treatment of VSMCs with CGP57380, a novel specific kinase inhibitor of Mnk1, resulted in dose-dependent decreases in Ang II-stimulated phosphorylation of eIF4E, protein synthesis, and VSMC hypertrophy. In summary, these data demonstrated that (1) Ang II-induced Mnk1 activation is mediated by the Ras-ERK cascade in VSMCs, and (2) Mnk1 is involved in Ang II-mediated protein synthesis and hypertrophy, presumably through the activation of translation-initiation. The Mnk1-eIF4E pathway may provide new insights into molecular mechanisms involved in vascular hypertrophy and other Ang II-mediated pathological states.

Angiotensin II↗
PubMed2003

Low body mass index is a risk factor for impaired endothelium-dependent vasodilation in humans: role of nitric oxide and oxidative stress.

OBJECTIVES: The purpose of this study was to evaluate the relationship between body mass index (BMI), including low BMIs, and endothelial function. BACKGROUND: Epidemiologic study has demonstrated that not only obesity but also a low BMI may be a risk factor for cardiovascular disease. METHODS: The forearm blood flow (FBF) response to acetylcholine (ACh) and isosorbide dinitrate (ISDN) was measured in 87 healthy young men (15 low BMI, 51 normal, 14 obese, and 7 extremely obese). RESULTS: Plasma concentrations of 8-hydroxy-2'-deoxyguanosine and serum concentrations of malondialdehyde-modified low-density lipoprotein were higher in low BMI, obese, and extremely obese subjects than in normal subjects and were similar among the low BMI, obese, and extremely obese groups. The FBF response to ACh was greater in the normal group than in the other groups (p < 0.001), and was lower in the extremely obese group as compared with the other groups (p < 0.001). The ACh-stimulated vasodilation was similar between the low BMI group and the obese group. The ISDN-stimulated vasodilation was similar in all four groups. There were no significant differences in ACh-stimulated vasodilation between the four groups after the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine infusion. Co-infusion of vitamin C augmented the FBF response to ACh in low BMI, obese, and extremely obese groups--but not in normal BMI group. CONCLUSIONS: These findings suggest that not only obesity but also a low BMI may be a risk factor for impaired endothelium-dependent vasodilation through the increased oxidative stress, leading to the reduced bioavailability of NO.

Acetylcholine↗