Although Alzheimer's disease (AD) is associated with an increased risk of intracerebral hemorrhage (ICH) caused by hypertension and cerebral amyloid angiopathy, the precise clinical course after ...hypertensive ICH in AD patients is still unknown. In this study, we investigated how striatal ICH, a frequent site for hypertensive ICH, affected the prognosis of AD. We employed 17‐ and 18‐month‐old male 5XFAD (5X) mice and littermate (LT) controls, and striatal ICH was induced by collagenase injection. First, to address the acute effects of ICH on 5X mice, hemorrhagic volume and brain edema were evaluated 3 days after ICH. Next, to address the long‐term effects of ICH on 5X mice, morbidity, mortality, neurological function (beam‐walking and rotarod tests), and cognitive function (Y‐maze and nest‐building tests) were monitored. Twenty‐eight days later, the animals were euthanized, their brains were isolated, and the cytotoxic alterations were investigated. The results revealed that the acute effects of ICH were not significantly different between 5X and LT mice. In contrast, 5X mice showed significantly higher morbidity and mortality in response to ICH, as well as delayed neurological function recovery, compared to LT mice through 28 days. ICH did not affect cognitive function in either group. Infiltrated macrophages in the perihemorrhagic cortex, gp91phox, p67phox, and COX‐2 were significantly increased in 5X mice in response to ICH. We demonstrated that striatal ICH deteriorated prognosis and delayed neurofunctional recovery in 5X mice, which might be associated with enhanced oxidative stress in the presence of AD‐like pathology.
We explored how intracerebral hemorrhage (ICH) affected the prognosis of 5XFAD mice. Striatal ICH worsened prognosis and delayed neurofunctional recovery in the mice, and infiltrated macrophages in peri‐hemorrhagic cortex and oxidative stress related proteins were increased at 28 days after ICH. The study suggest that additive oxidative stress in the presence of AD‐like pathology is induced by ICH and primarily associated with poor prognosis in 5XFAD mice.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Background:Sirt7 is a recently identified sirtuin and has important roles in various pathological conditions, including cancer progression and metabolic disorders. It has previously been reported ...that Sirt7 is a key molecule in acute myocardial wound healing and pressure overload-induced cardiac hypertrophy. In this study, the role of Sirt7 in neointimal formation after vascular injury is investigated.Methods and Results:Systemic (Sirt7−/−) and smooth muscle cell-specific Sirt7-deficient mice were subjected to femoral artery wire injury. Primary vascular smooth muscle cells (VSMCs) were isolated from the aorta of wild type (WT) and Sirt7−/−mice and their capacity for cell proliferation and migration was compared. Sirt7 expression was increased in vascular tissue at the sites of injury. Sirt7−/−mice demonstrated significant reduction in neointimal formation compared to WT mice. In vitro, Sirt7 deficiency attenuated the proliferation of serum-induced VSMCs. Serum stimulation-induced upregulation of cyclins and cyclin-dependent-kinase 2 (CDK2) was significantly attenuated in VSMCs of Sirt7−/−compared with WT mice. These changes were accompanied by enhanced expression of the microRNA 290-295 cluster, the translational negative regulator of CDK2, in VSMCs of Sirt7−/−mice. It was confirmed that smooth muscle cell-specific Sirt7-deficient mice showed significant reduction in neointima compared with control mice.Conclusions:Sirt7 deficiency attenuates neointimal formation after vascular injury. Given the predominant role in vascular neointimal formation, Sirt7 is a potentially suitable target for treatment of vascular diseases.
ABSTRACT
The purpose of this work was to test whether brain‐penetrating angiotensin‐converting enzyme (ACE) inhibitors (e.g., perindopril), as opposed to non‐brain‐penetrating ACE inhibitors (e.g., ...enalapril and imidapril), may reduce the cognitive decline and brain injury in Alzheimer's disease (AD). We first compared the effect of perindopril, enalapril, and imidapril on cognitive impairment and brain injury in a mouse model of AD induced by intracerebroventricular (i.c.v.) injection of amyloid‐β (Aβ)1–40. Perindopril, with significant inhibition of hippocampal ACE, significantly prevented cognitive impairment in this AD mouse model. This beneficial effect was attributed to the suppression of microglia/astrocyte activation and the attenuation of oxidative stress caused by iNOS induction and extracellular superoxide dismutase down‐regulation. In contrast, neither enalapril nor imidapril prevented cognitive impairment and brain injury in this AD mouse. We next examined the protective effects of perindopril on cognitive impairment in PS2APP‐transgenic mice overexpressing Aβ in the brain. Perindopril, without affecting brain Aβ deposition, significantly suppressed the increase in hippocampal ACE activity and improved cognition in PS2APP‐transgenic mice, being associated with the suppression of hippocampal astrocyte activation and attenuation of superoxide. Our data demonstrated that the brain‐penetrating ACE inhibitor perindopril, as compared to non‐brain‐penetrating ACE inhibitors, protected against cognitive impairment and brain injury in experimental AD models.—Dong, Y. ‐F., Kataoka, K., Tokutomi, Y., Nako, H., Nakamura, T., Toyama, K., Sueta, D., Koibuchi, N., Yamamoto, E., Ogawa, H., Kim‐Mitsuyama, S. Perindopril, a centrally active angiotensin‐converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer's disease. FASEB J. 25, 2911–2920 (2011). www.fasebj.org
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background & Aims:
Interleukin (IL)-22, a member of the IL-10 subfamily, is a recently identified T-cell-derived cytokine. We investigated IL-22 expression in the inflamed mucosa of patients with ...inflammatory bowel disease (IBD) and analyzed its biologic activities in human colonic subepithelial myofibroblasts (SEMFs).
Methods:
Mucosal IL-22 expression was evaluated by immunohistochemical procedures. The effects of IL-22 on colonic SEMFs were investigated by cDNA microarrays, Northern blots, enzyme-linked immunosorbent assay, and electrophoretic gel mobility shift assays (EMSAs).
Results:
IL-22 was not detectable in normal colonic mucosa. In IBD mucosa, IL-22 expression was detectable in CD4-positive T cells. IL-22-positive cells were increased in ulcerative colitis and even more so in Crohn’s disease. IL-22 receptor expression colocalized with a marker of SEMFs. IL-22 did not modulate SEMF proliferation and collagen synthesis. cDNA microarray analyses demonstrated that, in colonic SEMFs, IL-22 increased the messenger RNA (mRNA) expression of inflammatory cytokines (IL-6, IL-8, IL-11, and leukemia inhibitory factor LIF), chemokines, and matrix metalloproteinases. IL-22 induced an activation of nuclear factor (NF)-κB and activating protein (AP)-1 within 1 hour, and a blockade of NF-κB and AP-1 activation markedly reduced IL-22 induction of IL-6, IL-8, IL-11, and LIF mRNA. MAP-kinase inhibitors (PD98059, U0216, and SB202190) significantly reduced IL-22 induction of cytokine secretion. The combination of either IL-17 plus IL-22 or IL-19 plus IL-22 additively up-regulated cytokine secretion.
Conclusions:
IL-22 derived from activated T cells acts on SEMFs to elicit expression of proinflammatory cytokines and matrix-degrading molecules indicating proinflammatory/remodeling roles in IBD.
To investigate whether anemia is an independent risk factor for cardiovascular and renal events in hypertensive outpatients, we performed a subgroup analysis of the ATTEMPT-CVD study based on ...baseline hemoglobin. The ATTEMPT-CVD study was a multicenter, prospective, randomized study of hypertensive outpatients that compared the efficacy of angiotensin receptor blocker (ARB)-based antihypertensive treatment with non-ARB antihypertensive treatment over 3 years. In the present subanalysis, ATTEMPT-CVD study participants (n = 1213) were categorized into the anemic group and nonanemic group according to their baseline hemoglobin. We compared the anemic and nonanemic groups mainly in regard to the incidence of cardiovascular and renal events and blood pressure. We also performed a multivariable Cox proportional hazards analysis to determine the prognostic factors that were independently associated with cardiovascular and renal events. Of the 1213 patients enrolled in the ATTEMPT-CVD, 194 patients had anemia (mostly mild anemia) and 1019 patients did not. Blood pressure was well-controlled during the 3 years of antihypertensive therapy in both the anemic and nonanemic groups. However, the incidence of cardiovascular and renal events was significantly greater in the anemic group than in the nonanemic group (HR = 1.945: 95%CI 1.208-3.130; P = 0.0062). Even after adjustment, anemia was independently associated with cardiovascular and renal events (HR = 1.816: 95%CI 1.116-2.955; P = 0.0163) in overall hypertensive patients with well-controlled blood pressure. Anemia, even mild anemia, is an independent risk factor for cardiovascular and renal events in hypertensive outpatients whose blood pressure is well-controlled. Thus, anemia may be a novel therapeutic target for cardiovascular and renal diseases in hypertensive outpatients with anemia.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objectives The aim of this study was to investigate the antiatherogenic effects of the dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin (DFS). Background The new class of anti–type 2 diabetes ...drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon-like peptide (GLP)-1. Methods Endothelial function was examined by acetylcholine-induced endothelium-dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein E–deficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease. Results DFS significantly improved endothelial dysfunction (89.9 ± 3.9% vs. 79.2 ± 4.3% relaxation at 10−4 mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% 15.6% to 25.8% vs. 24.6% 19.3% to 34.6%, p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l 2.40 to 3.62 pmol/l vs. 4.00 pmol/l 3.10 to 5.90 pmol/l, p < 0.001). Conclusions A DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker + calcium channel blocker combination therapy is better in elderly ...hypertensive patients with high cardiovascular risk. The objective of the study was to compare the efficacy of these treatments in elderly, high-risk Japanese hypertensive patients. Methods The OlmeSartan and Calcium Antagonists Randomized (OSCAR) study was a multicenter, prospective, randomized, open-label, blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease. Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were randomly assigned to receive 40 mg/d olmesartan (high-dose angiotensin II receptor blocker) or a calcium channel blocker + 20 mg/d olmesartan (angiotensin II receptor blocker + calcium channel blocker). The primary end point was a composite of cardiovascular events and noncardiovascular death. Results During a 3-year follow-up, blood pressure was significantly lower in the angiotensin II receptor blocker + calcium channel blocker group than in the high-dose angiotensin II receptor blocker group. Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker + calcium channel blocker group. More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker + calcium channel blocker group (58 vs 48 events, hazard ratio HR, 1.31, 95% confidence interval, 0.89-1.92; P =. 17). In patients with cardiovascular disease at baseline, more primary events occurred in the high-dose angiotensin II receptor blocker group (HR, 1.63, P =. 03); in contrast, fewer events were observed in the subgroup without cardiovascular disease (HR, 0.52, P =. 14). This treatment-by-subgroup interaction was significant ( P =. 02). Conclusion The angiotensin II receptor blocker and calcium channel blocker combination lowered blood pressure more than the high-dose angiotensin II receptor blocker and reduced the incidence of primary end points more than the high-dose angiotensin II receptor blocker in patients with cardiovascular disease. The addition of a second antihypertensive agent is more effective at lowering blood pressure than simply doubling the dose of an existing agent.
Objectives This study investigated the clinical significance of plasma pentraxin 3 (PTX3) levels in patients with heart failure with normal ejection fraction (HFNEF) and whether PTX3 is produced from ...coronary circulation. Background Pentraxin 3 is a novel inflammatory marker and a member of pentraxin superfamily including C-reactive protein (CRP). The relationship between inflammatory markers and HFNEF remains unclear. Methods We measured peripheral blood levels of PTX3, high-sensitivity CRP, tumor necrosis factor-alpha, and interleukin-6 in 323 patients comprising 82 HFNEF, 70 heart failure (HF) with reduced EF, and 171 non-HF patients. Levels of PTX3 were also measured at the aortic root and the coronary sinus in 75 patients. Results The levels of PTX3, tumor necrosis factor-alpha, and interleukin-6, but not high-sensitivity CRP, were significantly higher in HFNEF patients than in non-HF patients. Multivariate logistic regression analysis identified only high levels of PTX3 as the independent inflammatory marker correlated with the presence of HFNEF in patients with normal left ventricular (LV) EF (odds ratio OR: 1.49, 95% confidence interval CI: 1.11 to 1.98, p < 0.01) and with the presence of left ventricular diastolic dysfunction (LVDD) in non-HF patients (OR: 1.23, 95% CI: 1.02 to 1.50, p < 0.05). Levels of PTX3 at the coronary sinus were significantly higher than at the aortic root in HFNEF patients (p < 0.05) and in non-HF patients with LVDD (p < 0.01), but not different in non-HF patients without LVDD (p = 0.33). Conclusions Pentraxin 3 is significantly elevated in HFNEF patients and produced in the coronary circulation in patients with LVDD. Pentraxin 3, but not high-sensitivity CRP, is an independent inflammatory marker correlated with the presence of LVDD and HFNEF. (The Clinical Significance of Plasma Pentraxin 3 levels for Patients with Diastolic Heart Failure; UMIN000002170 )
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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