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This study investigated the relationship between the degree of atherosclerotic changes in the descending thoracic aorta (TA) and the coronary artery using angioscopy. Twenty-five consecutive patients undergoing angioscopy of the TA and coronary angiography were enrolled in this study. Participants were divided into three groups according to the angioscopic grading of the TA: white plaque group (W-group), yellow plaque group (Y-group) and intensive yellow, ruptured plaque with ulceration and/or thrombus group (RP-group). The maximum plaque grade, plaque score, number of yellow plaques, frequency of yellow-plaque grades by coronary angioscopy, and SYNTAX score by coronary angiography were evaluated. Brachial-artery pulse wave velocity and high-sensitivity C-reactive protein level tended to be higher in the RP-group than in the other groups, although the differences were not statistically significant. The SYNTAX score was significantly higher in the RP-group than in the W-group (W-group 4.0 ± 3.6 vs. RP-group 17.5 ± 10.0, P = 0.045). In addition, the angioscopic maximum plaque grade, plaque score, and number of yellow plaques in the RP-group were significantly higher than in the W-group (maximum plaque grade W-group 0.8 ± 0.4 vs. RP-group 1.8 ± 0.8, P = 0.026; plaque score W-group 1.0 ± 1.2 vs. RP-group 4.0 ± 1.4, P = 0.014; and number of yellow plaques W-group 1.0 ± 1.2 vs. RP-group 2.5 ± 0.5, P = 0.023). The yellow-plaque grade in the coronary artery was correlated significantly with the plaque grading of TA (P = 0.043). Our study suggests that the angioscopic progression of aortic atherosclerosis is closely associated with vulnerability to and the extent of coronary stenosis, indicating that vulnerability toward atherosclerotic plaque development occurs simultaneously in the coronary tree and systemic arteries. Electronic supplementary material The online version of this article (doi:10.1007/s10554-015-0669-z) contains supplementary material, which is available to authorized users.

The possible counteracting effect of angiotensin (Ang)-converting enzyme (ACE)2/Ang-(1-7)/Mas axis against the ACE/Ang II/Ang II type 1 (AT1) receptor axis in blood pressure control has been previously described. We examined the possibility that this pathway might be involved in the anti-hypertensive effect of a newly developed AT1 receptor blocker (ARB), azilsartan, and compared azilsartan's effects with those of another ARB, olmesartan. Transgenic mice carrying the human renin and angiotensinogen genes (hRN/hANG-Tg) were given azilsartan or olmesartan. Systolic and diastolic blood pressure, as determined by radiotelemetry, were significantly higher in hRN/hANG-Tg mice than in wild-type (WT) mice. Treatment with azilsartan or olmesartan (1 or 5 mg kg(-1) per day) significantly decreased systolic and diastolic blood pressure, and the blood pressure-lowering effect of azilsartan was more marked than that of olmesartan. The urinary Na concentration decreased in an age-dependent manner in hRN/hANG-Tg mice. Administration of azilsartan or olmesartan increased urinary Na concentration, and this effect was weaker with olmesartan than with azilsartan. Azilsartan decreased ENaC-α mRNA expression in the kidney and decreased the ratio of heart to body weight. Olmesartan had a similar but less-marked effect. ACE2 mRNA expression was lower in the kidneys and hearts of hRN/hANG-Tg mice than in WT mice. This decrease in ACE2 mRNA expression was attenuated by azilsartan, but not by olmesartan. These results suggest that the hypotensive and anti-hypertrophic effects of azilsartan may involve activation of the ACE2/Ang-(1-7)/Mas axis with AT1 receptor blockade.

Background Stroke is a leading cause of death and disability; however, meta-analysis of randomized controlled trials of blood pressure-lowering drugs in acute stroke has shown no definite evidence of a beneficial effect on functional outcome. Accumulating evidence suggests that angiotensin II type 1 receptor blockade with angiotensin II type 2 (AT2) receptor stimulation could contribute to protection against ischemic brain damage. We examined the possibility that direct AT2 receptor stimulation by compound 21 (C21) initiated even after stroke can prevent ischemic brain damage. Methods Stroke was induced by middle cerebral artery (MCA) occlusion, and the area of cerebral infarction was measured by magnetic resonant imaging. C21 (10 µg/kg/day) treatment was initiated immediately after MCA occlusion by intraperitoneal injection followed by treatment with C21 once daily. Results We observed that ischemic area was enlarged in a time dependent fashion and decreased on day 5 after MCA occlusion. Treatment with C21 initiated after MCA occlusion significantly reduced the ischemic area, with improvement of neurological deficit in a time-dependent manner without affecting blood pressure. The decrease of cerebral blood flow after MCA occlusion was also ameliorated by C21 treatment. Moreover, treatment with C21 significantly attenuated superoxide anion production and expression of proinflammatory cytokines, monocyte chemoattractant protein 1, and tumor necrosis factor α. Interestingly, C21 administration significantly decreased blood-brain barrier permeability and cerebral edema on the ischemic side. Conclusions These results provide new evidence that direct AT2 receptor stimulation with C21 is a novel therapeutic approach to prevent ischemic brain damage after acute stroke.

Type 2 diabetes mellitus (T2DM) is known to be associated with increased risk of cognitive impairment including Alzheimer disease. Recent studies have suggested an interaction between angiotensin II and N-methyl-d-aspartic acid (NMDA) glutamate receptors. We previously reported that stimulation of the angiotensin II type 2 (AT2) receptor exerts brain protective effects. A newly developed AT2 receptor agonist, compound 21 (C21), has enabled examination of the direct effect of AT2 receptor stimulation in vivo. Accordingly, we examined the possible synergistic effect of C21 and memantine on cognitive impairment in T2DM mice, KKAy. KKAy were divided into four groups; (1) control, (2) treatment with C21 (10 μg/kg/day), (3) treatment with memantine (20mg/kg/day), and (4) treatment with both for 4 weeks, and subjected to Morris water maze tasks. Treatment with C21 or memantine alone at these doses tended to shorten escape latency compared to that in the control group. C21 treatment increased cerebral blood flow (CBF), but memantine did not influence CBF. Treatment with C21 or C21 plus memantine increased hippocampal field-excitatory postsynaptic potential (f-EPSP). Moreover, treatment with memantine or C21 increased acetylcholine level, which was lower in KKAy than in wild-type mice, and C21 plus memantine treatment enhanced memantine or C21-induced acetylcholine secretion. This study provides an insight into new approaches to understand the interaction of angiotensin II and neurotransmitters. We can anticipate a new therapeutic approach against cognitive decline using C21 and memantine.

An impaired myocardial perfusion state after primary angioplasty is a strong predictor of long-term adverse outcomes in patients with STEMI. We assessed the relationship between culprit plaque characteristics and myocardial perfusion state after primary angioplasty in patients with ST-segment elevation myocardial infarction (STEMI).A total of 101 consecutive patients with de novo STEMI were divided into 3 groups according to the state of myocardial perfusion assessed by ST-segment elevation resolution (STR): Group A (complete: STR ≥ 70%, n=26), Group B (partial: STR70% but ≥ 30%, n=55) and Group C (none: STR30%, n=20). We analyzed plaque features by virtual histology intravascular ultrasound (VH-IVUS) and assessed the relationship between culprit plaque characteristics and STR after primary angioplasty.Total plaque volume was significantly higher in Group C than in Groups A and B (146.4 ± 38.0 mm(3)vs. 93.3 ± 29.1 mm(3) and 105.8 ± 31.5 mm(3), p0.001, respectively). Necrotic core (NC) volume was also significantly higher in Group C than in Groups A and B (25.4 ± 8.0m m(3), vs. 11.9 ± 6.3 mm(3) and 17.3 ± 9.7 mm(3), p0.001, respectively). Analysis of receiver-operating characteristic curves revealed that total plaque volume and NC volume had the best diagnostic accuracy of all the VH-IVUS parameters to predict STR30%. The optimal cutoff values (sensitivity/specificity) were 123.4 mm(3) (75.0%/75.3%) for total plaque volume and 20.3mm(3) (75.0%/74.1%) for NC volume.Culprit plaque with large plaque burden and high NC volume is closely associated with poor STR after revascularization.

The renin-angiotensin system (RAS) has been postulated to regulate not only systemic hemodynamic and hydromineral homeostasis but also individualorgan function in the normal condition. On the other hand, its systemic and localactivationleads to hypertension and diabetes mellitus,resulting intarget end organ damage.RAS in the brain is also well known to be involved in the pathogenesis and progression of neuronal disease, as well as regulating blood pressure, sympathetic activity, vasopressin secretion, thirst and sodium appetite.There is increasing evidence that RAS may contribute to neuroinflammation associated with many neuronal diseases in several animal models. Moreover, recent clinical evidence indicates that RAS blockade, including that byangiotensin converting enzyme inhibitors and angiotensin II receptor blockers, has beneficial effects in treating stroke, cognitive dysfunction, Alzheimer disease and other neuronal diseases, suggesting the potential of RAS as a new therapeutic target in neuronal diseases. This article reviews the recent findings ofbrain RAS involvement and thetherapeutic potential of regulating RAS in neuronal disease.

Angiotensin II type 2 (AT(2)) receptor-interacting protein (ATIP), which interacts with the C-terminal tail of the AT(2) receptor, regulates the functions of the AT(2) receptor. We have reported that AT(2) receptor stimulation attenuated vascular senescence. Therefore, we examined the possible negative role of ATIP in regulating vascular senescence. We generated ATIP-transgenic (Tg) mice, and cultured vascular smooth muscle cells (VSMCs). Persistent angiotensin II stimulation induced increases in SA-β-gal-positive cells and the level of a DNA damage marker, 8-OHdG in VSMC, whereas these effects of angiotensin II were attenuated in VSMC prepared from ATIP-Tg mice. Angiotensin II treatment also upregulated the expression of methyl methanesulfonate-sensitive 2 (MMS2), a DNA repair factor, and Src homology 2 domain-containing protein-tyrosine phosphatase 1 (SHP-1) activity, whereas these effects of angiotensin II were further enhanced in ATIP-Tg VSMC. In vivo, x-ray irradiation to mice caused increases in SA-β-gal-positive area and 8-OHdG level in the thoracic aorta; however, these effects were reduced in ATIP-Tg mice, with a significant increase in MMS2 expression. These results suggest that ATIP could inhibit VSMC senescence, involving MMS2 expression and SHP-1 activity. ATIP might be a new therapeutic molecule to treat vascular aging and age-related vascular diseases.

The contribution of the renin-angiotensin-aldosterone system (RAAS) to central nervous system (CNS) disorders is not yet fully understood. RAAS has been shown to be involved in the proliferation of astrocytes, which have a role in neuronal damage contributing to neurodegenerative diseases. However, the direct relationship between RAAS and neuronal damage is still unclear. We therefore examined the effect of angiotensin (Ang) II and aldosterone (Aldo) on damage to spinal ganglion neurons (SGNs) by regulating astrocytes. Ang II stimulation significantly increased DNA damage in SGNs in a time-dependent manner. This increase in DNA damage was further enhanced when SGNs were co-cultured with astrocytes. On the other hand, no significant increase was observed in SGNs co-cultured with astrocytes without Ang II stimulation. Moreover, the addition of conditioned medium from Ang II-treated astrocytes exacerbated SGN DNA damage. An Ang II type 1 receptor blocker, valsartan, inhibited Ang II-stimulated DNA damage but not DNA damage induced by conditioned medium prepared from astrocyte cultures. In contrast, an Aldo antagonist, eplerenone, significantly inhibited DNA damage induced by the culture medium from Ang II-treated astrocytes. Ang II-stimulated Aldo secretion in the conditioned medium from astrocytes. Furthermore, the administration of Aldo alone also enhanced DNA damage in SGNs. Finally, flow cytometric analysis showed that Ang II or Aldo treatment markedly increased the percentage of dead SGNs. In conclusion, Ang II- and Aldo-induced neuronal damage in SGNs through astrocytes regulation. Blocking Ang II and Aldo to target astrocytes might be useful for the treatment of CNS disorders.

Type 2 diabetes can impair the outcome of stroke as well as increase stroke risk; however, the sex difference in ischemic brain damage is not well known, and even less is known about the difference in diabetes. We therefore investigated the possible gender difference in brain damage after stroke associated with type 2 diabetes using a mouse model, KKAy. Female KKAy showed a much larger ischemic area compared with male KKAy. NADPH oxidase activity in the brain was also increased more in female than in male mice. Ovariectomy enhanced the ischemic area, and treatment with estradiol markedly attenuated the ischemic area to that in female KKAy, with a reduction of NADPH oxidase activity. Female and OVX mice showed improvement of cerebral blood flow (CBF) at 1 hour after middle cerebral artery (MCA) occlusion, but no significant difference in CBF of the ipsilateral penumbra and ipsilateral core 24 hours after MCA occlusion was observed among each group. Severe ischemic brain damage was observed in female KKAy compared with male KKAy. Estrogen showed a protective effect on the brain, at least partly from attenuation of oxidative stress in the female brain. These findings suggest that brain damage in diabetes mellitus might be more marked in women than in men.

Summary Background The angiographic no-reflow phenomenon after primary percutaneous coronary intervention (PCI) carries a poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI). However, the type of plaque composition that associates with the angiographic no-reflow phenomenon remains unclear. Methods A total of 44 patients with STEMI were enrolled in this study. After thrombectomy with an aspiration catheter, virtual histology intravascular ultrasound (VH-IVUS) of the infarct-related vessel was performed. Patients were divided into two groups according to final thrombolysis in myocardial infarction (TIMI) flow grade at the completion of PCI procedure. Complete reperfusion group (CR-group) was defined as final TIMI flow grade 3, and no-reflow group (NR-group) was defined as final TIMI flow ≦2. The relationship between plaque composition and angiographic no-reflow phenomenon was analyzed. Results The angiographic no-reflow phenomenon was observed in 20 individuals. The summation of the percentage of fibrofatty + necrotic core and fibrofatty + dense calcium was significantly higher in the NR-group. Receiver-operating characteristics analysis revealed that the summation of the volume and percentage of fibrofatty + necrotic core (>20.1 mm 3 , 26.2%) and fibrofatty + dense calcium (>20.0 mm 3 , 22.6%) predict the angiographic no-flow phenomenon. Conclusion The fibrofatty-rich component with necrotic core or dense calcium derived from VH-IVUS is closely related to the angiographic no-reflow phenomenon observed in primary PCI.

Wnt signaling has diverse actions in cardiovascular development and disease processes. Secreted frizzled-related protein 5 (Sfrp5) has been shown to function as an extracellular inhibitor of non-canonical Wnt signaling that is expressed at relatively high levels in white adipose tissue. The aim of this study was to investigate the role of Sfrp5 in the heart under ischemic stress. Sfrp5 KO and WT mice were subjected to ischemia/reperfusion (I/R). Although Sfrp5-KO mice exhibited no detectable phenotype when compared with WT control at baseline, they displayed larger infarct sizes, enhanced cardiac myocyte apoptosis, and diminished cardiac function following I/R. The ischemic lesions of Sfrp5-KO mice had greater infiltration of Wnt5a-positive macrophages and greater inflammatory cytokine and chemokine gene expression when compared with WT mice. In bone marrow-derived macrophages, Wnt5a promoted JNK activation and increased inflammatory gene expression, whereas treatment with Sfrp5 blocked these effects. These results indicate that Sfrp5 functions to antagonize inflammatory responses after I/R in the heart, possibly through a mechanism involving non-canonical Wnt5a/JNK signaling.

BACKGROUND Angiotensin II type 2 (AT2) receptor stimulation could exert beneficial effects on vascular remodeling. Previously, we reported that AT2 receptor stimulation ameliorated insulin resistance in diabetic mice accompanied by PPARγ activation which also plays a variety of crucial roles in the vasculature. Therefore, this study aimed to investigate the vascular protective effect of the AT2 receptor with activation of PPARγ involving AT2 receptor-interacting protein (ATIP). METHODS AND RESULTS Vascular injury was induced by polyethylene-cuff placement around the femoral artery in C57BL/6J mice. Treatment with compound 21 (C21), an AT2 receptor agonist, decreased neointimal formation, cell proliferation, and the mRNA levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-α, and interleukin-1β, and phosphorylation of nuclear factor-kappa B, and increased PPARγ DNA-binding activity in the injured artery, whereas these inhibitory effects of C21 were attenuated by co-treatment with a PPARγ antagonist, GW9662. Treatment of vascular smooth muscle cells (VSMC) with C21 prepared from smAT2 transgenic mice, which highly express the AT2 receptor in VSMC, increased both PPARγ activity and its DNA-binding activity determined by dual-luciferase assay and electrophoresis mobility shift assay (EMSA), respectively. We observed that ATIP was involved in PPARγ complex formation, and that transfection of siRNA of ATIP1 attenuated the AT2 receptor-mediated increase in PPARγ activity in VSMC. In response to AT2 receptor stimulation, ATIP was translocated from the plasma membrane to the nucleus. CONCLUSIONS Our results suggest a new mechanism by which AT2 receptor stimulation activates PPARγ, thereby resulting in amelioration of vascular intimal proliferation, and that ATIP plays an important role in AT2 receptor-mediated PPARγ activation.

In the clinical grounds, patients with ≥90 % luminal narrowing during acetylcholine (ACh) testing had variable response. We investigated ischemic findings and chest symptoms in patients with ≥90 % luminal narrowing when performing ACh tests, retrospectively. We performed 763 ACh tests over 13 years (2001-2013). We analyzed chest symptoms and positive ischemic ECG changes during ACh tests. More than 90 % luminal narrowing was found in 441 patients (57.8 %) including 355 patients in the right coronary artery (RCA) and 363 patients in the left coronary artery (LCA). Chest symptom was observed in 386 patients (87.5 %) including 293 patients in the RCA and 304 patients in the LCA. ST elevation was found in 161 patients including 110 in the RCA and 85 patients in the LCA, while ST depression was recognized in 146 patients including 119 patients in the RCA and 117 patients in the LCA. Three quarter of patients with ≥90 % luminal narrowing had significant ischemic ECG changes, whereas two-third of patients with ≥90 % luminal narrowing complained usual chest pain accompanied with significant ischemic ECG changes. Unusual chest symptom was complained in 7.3 % patients with ≥90 % luminal narrowing. Neither chest symptom nor ECG changes were found in 30 patients (6.8 %) with ≥90 % luminal narrowing. A third of these patients had ischemic findings on non-invasive tests before catheterization and six patients had subtotal or total occlusion. We should realize some limitation to define positive coronary spasm based on the ischemic ECG change and chest symptom during ACh tests.

Cross talk between the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 (AT 1 ) receptor axis and the ACE2/Ang-(1–7)/Mas axis plays a role in the pathogenesis of cardiovascular remodeling. Furthermore, possible stimulation of the Ang II type 2 (AT 2 ) receptor by Ang-(1–7) has been highlighted as a new pathway. Therefore, we examined the possibility of whether the ACE2/Ang-(1–7)/Mas axis and Ang-(1–7)/AT 2 receptor axis are involved in the inhibitory effects of AT 1 receptor blockers on vascular remodeling. Wild-type, Mas-knockout, and AT 2 receptor knockout mice were used in this study. Vascular injury was induced by polyethylene-cuff placement around the mouse femoral artery. Some mice were treated with azilsartan, an AT 1 receptor blocker, or Ang-(1–7). Neointimal formation 2 weeks after cuff placement was more marked in Mas-knockout mice compared with wild-type mice. Treatment with azilsartan or Ang-(1–7) attenuated neointimal area, vascular smooth muscle cell proliferation, increases in the mRNA levels of monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and superoxide anion production in the injured artery; however, these inhibitory effects of azilsartan and Ang-(1–7) were less marked in Mas-knockout mice. Administration of azilsartan or Ang-(1–7) attenuated the decrease in ACE2 mRNA and increased AT 2 receptor mRNA but did not affect AT 1 receptor mRNA or the decrease in Mas mRNA. The inhibitory effect of Ang-(1–7) on neointimal formation was less marked in AT 2 receptor knockout mice compared with wild-type mice. These results suggest that blockade of the AT 1 receptor by azilsartan could enhance the activities of the ACE2/Ang-(1–7)/Mas axis and ACE2/Ang-(1–7)/AT 2 receptor axis, thereby inhibiting neointimal formation.

Objective: The possible counteracting effect of angiotensin (Ang)-converting enzyme (ACE)2/Ang (1-7)/Mas axis against the ACE/Ang II/ Ang II type 1 (AT 1 ) receptor axis in blood pressure control has been highlighted. We examined the possibility that this axis might be involved in the anti-hypertensive effect of newly developed Ang II type 1 (AT 1 ) receptor blocker (ARB), azilsartan, in comparison with olmesartan. Methods: Human renin (hRN) and human angiotensinogen (hANG) double transgenic mice (hRN/hANG-Tg) were used. Ten-week-old male hRN/hANG-Tg mice were administrated control chow or three different doses (1, 5 and 10mg/kg/day) of ARBs, azilsartan or olmesartan in chow for 4 weeks. Blood pressure was analyzed by radio telemetry method before drug administration and every two weeks after medication. Four weeks after drug administration, expression of ACE2 mRNA level was assessed by real time RT-PCR method. Results: Blood pressure was significantly higher in hRN/hANG-Tg mice compared with that in wild type (WT) mice. Treatment with all doses of azilsartan decreased blood pressure to the level of WT mice. Treatment with olmesartan (1 mg/kg/day) decreased blood pressure; however, this decrease was weaker than that with azilsartan at the same dose. Olmesartan (5 and 10 mg/kg/day) decreased blood pressure to the WT mice level; however, the reduction of blood pressure in the night-time was stronger in azilsartan group. Expression of ACE2 mRNA was decreased in heart and kidney of hRN/hANG-Tg mice compared with WT mice. This decrease in ACE2 mRNA expression was attenuated by administration of azilsartan, but not by olmesartan treatment. The ratio of heart to body weight ratio was decreased in all azilsartan-treated groups, but this decrease was observed only in 10 mg/kg/day of olmesartan-treated group. Treatment with azilsartan even at lower dose increased the urinary excretion of Na. Conclusion: These results suggested that hypotensive effect of azilsartan may involve the activation of ACE2/Ang(1-7)/Mas axis with AT 1 receptor blockade. Further investigation will reveal the pathophysiological role of ACE2/Ang(1-7)/Mas axis in blood ptessure control and contribute to discuss further the possible drug effect of ARBs beyond class effect.

Objectives: Crosstalk between the angiotensin (Ang)-converting enzyme (ACE)/Ang II/ Ang II type 1 (AT 1 ) receptor axis and ACE2/Ang (1-7)/Mas axis plays a role in the pathogenesis of cardiovascular remodeling. Moreover, possible stimulation of Ang II type 2 (AT 2 ) receptor by Ang-(1-7) has been highlighted as new axis; however, pathophysiological significance of this possibility has to be elucidated in more detail. Therefore, we examined the possibility whether ACE2/Ang (1-7)/Mas axis and Ang (1-7)/AT 2 receptor axis is involved the inhibitory effects of AT 1 receptor blocker (ARB) on vascular remodeling. Methods: Ten-week-old male C57BL/6J (wild type: WT), Mas knockout (MasKO), and AT 2 receptor knockout (AT 2 KO) mice were used in this study. Vascular injury was induced by polyethylene-cuff placement around the mouse femoral artery. After cuff placement, some mice were treated with azilsartan (0.3 mg/kg/day), an ARB, or Ang (1-7) (0.5 mg/kg per day). Two weeks after operation, femoral arteries were removed, fixed and stained by Elastica van Gieson staining for evaluating neointimal formation. Results: Neointima formation induced by cuff placement was further increased in MasKO mice compared with WT mice. Treatment with azilsartan or Ang-(1-7) decreased neointima area and vascular smooth muscle cell proliferation, and attenuated the increases in the mRNA level of MCP-1, TNF-α and IL-1β in the injured artery in WT mice without influencing blood pressure. These inhibitory effects of azilsartan or Ang-(1-7) were less in Mas KO mice. One week after cuff placement, the mRNAs of ACE2 and Mas in the injured artery were markedly decreased in WT mice. Administration of azilsartan or Ang-(1-7) attenuated the decrease in ACE2 mRNA, but not affect the decrease in Mas mRNA. Neointima formation in AT 2 KO mice was more exaggerated compared with that in WT mice. Interestingly, we observed that inhibitory effect of Ang-(1-7) on neointima formation was less in AT 2 KO mice compared with WT mice. Conclusion: These results suggest that blockade of AT 1 receptor by azilsartan could enhance the activities of the ACE2/Ang (1-7)/Mas axis and ACE2/Ang-(1-7)/AT 2 receptor axis, thereby inhibiting the neointima formation.

Background Sarcopenia is the degenerative loss of skeletal muscle mass which impaired quality of life in the elderly. On the other hand, sarcopenic obesity which is a loss of muscle and a concomitant increase in fat is reported to increase in life-style related diseases. Especially the prevalence of sarcopenia is greater in patients with type-2 diabetes mellitus (T2DM) than in non-diabetic subjects. However, the detailed mechanism of such muscle degeneration has not been well established. Here, we investigated muscle regeneration using muscle-injured models in life-style related disease mouse model such as angiotensin II overexpression mice for hypertension and obese diabetic mice for diabetes. Methods Male eight-week-old wild-type mice (C57BL6), Tsukuba hypertensive mice (transgenic mice carrying human renin and angiotensinogen genes) and T2DM mice (KKAy) were undergone intramuscular injection of cardiotoxin (Ctx) (100uL/10uM) into tibia. After two weeks, muscle were removed and stained with hematoxylin and eosin. KKAy replaced by bone marrow prepared from GFP-transgenic mice were generated by 8 Gy whole body X-ray irradiation. Results Treatment with Ctx showed increased muscle satellite cells where nucleuses were observed in the center of cells. In Tsukuba hypertensive mice, inflammatory cells were significantly accumulated in muscle compared with C57BL6, but muscle regeneration was not significantly impaired. KKAy mice exhibited impaired muscle regeneration. Tibia weight was a half in Ctx-injected KKAy compared with Ctx non-injected KKAy, and Ctx-injected and non-injected C57BL6 tibia. Moreover, remarkable fat deposition was observed in Ctx-treated muscle of KKAy. Such change was also observed in another diabetic mouse model, db/db, but not in streptozocin-induced diabetic mice. Fat deposition was remarkably increased in aged KKAy (6-month-old) compared with younger mice (8-week-old). In GFP-chimeric mice, fat tissue showed highly GFP-positive indicating that fat tissue was generated from marrow cells. Conclusion Diabetic mice showed significantly impaired muscle regeneration with fat deposition, suggesting that diabetes enhanced sarcopenic obesity possibly due to inhibitory effect of marrow cell differentiation.

Objective: Diabetes is associated with abnormal regulation of appetite. Dopaminergic activation in food reward induces binge eating disorder (BED) and leads to increase in food intake. On the other hand, recent studies have demonstrated that stimulation of angiotensin II type 2 (AT 2 ) receptor inhibits dopamine (DA) synthesis. In this study, we investigated the relationship between DA level and BED after fasting condition in diabetic mice and the inhibitory effect of AT 2 receptor stimulation on BED and body weight. Methods: Adult male type 2 diabetic mice, KKAy, at 10 weeks of age were treated with an intraperitoneal injection of AT 2 receptor agonist, compound 21 (C21), at the dose of 10 μg/kg/day or saline for 2 weeks. DA level in the striatum was measured by microdialysis. Short-term spatial memory and activity were assessed by Y-maze test. After these tests, brain samples were obtained and the expressions of DA receptor D1 (DRD1), DA receptor D2 (DRD2) and DA transporter (DAT) in the substantia nigra were evaluated by immunohistochemical staining. Results: Food and water intake and DA level in the striatum were significantly increased 48 hours after fasting compared with non-fasting mice. Administration with C21 significantly attenuated these increase without affecting systolic blood pressure. Treatment with C21 remarkably improved short-term cognitive function and increased explore activity. Moreover, C21 treatment did not affect fasting-induced weight loss, but significantly inhibited rebound weight gain after refeeding compared with vehicle-treated group. In KKAy, the expressions of DRD1, DRD2 and DAT in the substantia nigra were markedly decreased compared with wild-type (C57BL/6J strain) mice, whereas these reductions were improved by administration of C21. Interestingly, we demonstrated that fasting decreased DRD1 and DRD2 expression and increased DAT; however, administration of C21 inhibited these reductions of DRD1 and DRD2. Conclusion: Activation of AT 2 receptor could contribute to inhibition of BED and rebound weight gain with modulation of dopamine signaling. These results indicate that stimulation of AT 2 receptor may be a new therapeutic approach to improve the eating disorder associated with dopamine resistance.

We demonstrated that angiotensin II type 2 (AT2) receptor-interacting protein (ATIP) 1 ameliorates inflammation-mediated vascular remodeling independent of the AT2 receptor, leading us to explore the possibility of whether ATIP1 could exert anti-inflammatory effects and play a role in other pathophysiological conditions. We examined the possible anti-inflammatory effects of ATIP1 in adipose tissue associated with amelioration of insulin resistance. In mice fed a high-cholesterol diet, adipose tissue macrophage (ATM) infiltration and M1-to-M2 ratio were decreased in ATIP1 transgenic mice (ATIP1-Tg) compared with wild-type mice (WT), with decreased expression of inflammatory cytokines such as tumor necrosis factor-α and monocyte chemoattractant protein-1 in white adipose tissue (WAT), but an increase in interleukin-10, an anti-inflammatory cytokine. Moreover, 2-[(3)H]deoxy-d-glucose (2-[(3)H]DG) uptake was significantly increased in ATIP1-Tg compared with WT. Next, we examined the roles of ATIP1 in BM-derived hematopoietic cells, employing chimeric mice produced by BM transplantation into irradiated type 2 diabetic mice with obesity, KKAy, as recipients. ATM infiltration and M1-to-M2 ratio were decreased in ATIP1 chimera (ATIP1-tg as BM donor), with improvement of insulin-mediated 2-[(3)H]DG uptake and amelioration of inflammation in WAT. Moreover, serum adiponectin concentration in ATIP1 chimera was significantly higher than that in WT chimera (WT as BM donor) and KKAy chimera (KKAy as BM donor). These results indicate that ATIP1 could exert anti-inflammatory effects in adipose tissue via macrophage polarization associated with improvement of insulin resistance, and ATIP1 in hematopoietic cells may contribute to these beneficial effects on adipose tissue functions in type 2 diabetes.

Objectives: Previous our studies showed that angiotensin II type-2 (AT 2 ) receptor stimulation protects neurons after brain ischemic damage using AT 2 receptor-deficient mice. Recently, Compound 21 (C21) is available to use as a direct AT 2 receptor agonist. We reported that administration of C21 induces vascular dilatation via bradykinin-nitric oxide pathway and maintains cerebral blood flow, resulting in prevention of cognitive impairment. These results inspired us the possibility that administration of C21 could protect ischemic brain damage; therefore, we assessed the effect of C21 on stroke expansion by not only pre-treatment, but also a treatment immediately after stroke. Methods: 10 week-old wild-type male C57BL6 mice were subjected to the middle cerebral artery occlusion (MCAO) by electrocoagulation using a subtemporal approach. Ischemic area after stroke was evaluated by time-course analysis by magnetic resonance imaging (MRI) of the brain. C21 was administrated to mice 2 weeks before MCAO or immediately after MCAO treatment by intraperitoneal injection. Cerebral blood flow was evaluated by using 2D-laser speckle blood flow imaging system. Results: No significant remarkable change was observed in blood pressure in mice with or without C21 treatment. Pretreatment of C21 prevented ischemic brain damage 1 day after MCAO. In contrast, such preventive effect by C21 was not observed in AT 2 receptor-deficient mice. On the other hand, C21 treatment immediately after MCAO did not reduce ischemic area 1 day after MCAO, but remarkably reduced this 3 days after MCAO. Treatment with C21 prevented the reduced cerebral blood flow after MCAO. Conclusions: These findings indicate that AT 2 receptor stimulation by C21 prevents ischemic brain damage at least in part via maintaining cerebral blood flow even after stroke. Therefore, administration of C21 could work as a new therapeutical option in patients with stroke even in acute phase.

ObjectivesThe role of angiotensin II type 2 (AT(2)) receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) might contribute to possible insulin-sensitizing/anti-diabetic effects in type 2 diabetes (T2DM) with PPARγ activation, mainly focusing on adipose tissue.MethodsT2DM mice, KK-Ay, were subjected to intraperitoneal injection of C21 and/or a PPARγ antagonist, GW9662 in drinking water for 2 weeks. Insulin resistance was evaluated by oral glucose tolerance test, insulin tolerance test, and uptake of 2-[(3)H] deoxy-D-glucose in white adipose tissue. Morphological changes of adipose tissues as well as adipocyte differentiation and inflammatory response were examined.ResultsTreatment with C21 ameliorated insulin resistance in KK-Ay mice without influencing blood pressure, at least partially through effects on the PPARγ pathway. C21 treatment increased serum adiponectin concentration and decreased TNF-α concentration; however, these effects were attenuated by PPARγ blockade by co-treatment with GW9662. Moreover, we observed that administration of C21 enhanced adipocyte differentiation and PPARγ DNA-binding activity, with a decrease in inflammation in white adipose tissue, whereas these effects of C21 were attenuated by co-treatment with GW9662. We also observed that administration of C21 restored β cell damage in diabetic pancreatic tissue.ConclusionThe present study demonstrated that direct AT(2) receptor stimulation by C21 accompanied with PPARγ activation ameliorated insulin resistance in T2DM mice, at least partially due to improvement of adipocyte dysfunction and protection of pancreatic β cells.

Additional beneficial effects of angiotensin II type 1 (AT 1 ) receptor blockers beyond AT 1 receptor blockade have been highlighted. Irbesartan is reported to act as an antagonist of the monocyte chemoattractant protein-1 (MCP-1) receptor, C-C chemokine receptor 2 (CCR2). We examined the possible synergistic effects of the combination of irbesartan with rosuvastatin on preventing vascular remodeling focusing on the MCP-1/CCR2 pathway. We observed that administration of irbesartan and CCR2 antagonist, propagermanium, at noneffective doses, decreased the neointima with a decrease in PCNA labeling index in the injured mouse femoral artery induced by cuff placement. We also observed that administration of a noneffective dose of rosuvastatin with propagermanium decreased the neointima area, suggesting that the inhibitory effect of rosuvastatin on neointima formation is at least partly attributable to blockade of the MCP-1/CCR2 pathway. Moreover, we demonstrated that the combination of irbesartan with rosuvastatin decreased neointima formation. MCP-1 mRNA level was significantly increased in injured femoral arteries, and administration of irbesartan with rosuvastatin decreased the mRNA levels of MCP-1, TNFα, and IL-1β, and increased PPARγ mRNA expression. These results suggest that the synergistic inhibitory effects of irbesartan with rosuvastatin on neointima formation may involve attenuation of MCP-1/CCR2 signaling.

An adverse relationship between suboptimal fetal environments and the development of adult diseases, such as hypertension, type II diabetes, and cardiovascular disease, has been reported in numerous studies. The purpose of this study was to investigate the strain difference of offspring's response to maternal malnutrition during pregnancy and the involvement of the renin-angiotensin system (RAS) in the development of adult hypertension using C57BL/6J (C57) mice and angiotensin II (Ang II) type 1 receptor-associated protein-transgenic (ATRAP-Tg) mice. Pregnant dams were fed an isocaloric diet containing either 20% (normal protein; NP) or 8% (low protein; LP) protein. Birth weight was significantly reduced in C57-LP offspring, but not in ATRAP-Tg-LP offspring. Arterial blood pressure was higher in C57-LP offspring than in the other groups. In contrast, ATRAP-Tg-LP offspring did not show an increase in blood pressure compared with NP offspring. Renal angiotensin II type 1 (AT(1)) receptor expression was not altered by maternal malnutrition, whereas angiotensin II type 2 receptor expression was significantly decreased in C57-LP offspring. In conclusion, these findings suggest that a suboptimal intrauterine environment induces adult hypertension because of an alteration of expression of RAS components, which was partly suppressed by sustained ATRAP overexpression via attenuation of the AT(1) receptor-mediated pathological response.

We reported previously that an angiotensin II type 1 receptor blocker, telmisartan, improved cognitive decline with peroxisome proliferator-activated receptor-γ activation; however, the detailed mechanisms are unclear. Enhanced blood-brain barrier (BBB) permeability with alteration of tight junctions is suggested to be related to diabetes mellitus. Therefore, we examined the possibility that telmisartan could attenuate BBB impairment with peroxisome proliferator-activated receptor-γ activation to improve diabetes mellitus–induced cognitive decline. Type 2 diabetic mice KKA y exhibited impairment of cognitive function, and telmisartan treatment attenuated this. Cotreatment with GW9662, a peroxisome proliferator-activated receptor-γ antagonist, interfered with these protective effects of telmisartan against cognitive function. BBB permeability was increased in both the cortex and hippocampus in KKA y mice. Administration of telmisartan attenuated this increased BBB permeability. Coadministration of GW9662 reduced this effect of telmisartan. Significant decreases in expression of tight junction proteins and increases in matrix metalloproteinase expression, oxidative stress, and proinflammatory cytokine production were observed in the brain, and treatment with telmisartan restored these changes. Swollen astroglial end-feet in BBB were observed in KKA y mice, and this change in BBB ultrastructure was decreased in telmisartan. These effects of telmisartan were weakened by cotreatment with GW9662. In contrast, administration of another angiotensin II type 1 receptor blocker, losartan, was less effective compared with telmisartan in terms of preventing BBB permeability and astroglial end-foot swelling, and coadministration of GW9662 did not affect the effects of losartan. These findings are consistent with the possibility that, in type 2 diabetic mice, angiotensin II type 1 receptor blockade with peroxisome proliferator-activated receptor-γ activation by telmisartan may help with protection against cognitive decline by preserving the integrity of the BBB.

Patients with type 2 diabetes mellitus (T2DM) exhibit more severe cognitive decline in females compared with males; however, the preventive approach to this gender-specific cognitive decline is still an enigma. Spironolactone is a potassium-sparing diuretic that also acts as an androgen receptor antagonist. Here, we investigated whether spironolactone attenuates cognitive impairment observed in female T2DM mice. Adult wild-type (WT) mice and an obese T2DM model, KKAy mice, were employed in this study. Cognitive function was evaluated by the shuttle avoidance test and Morris water maze test. Administration of spironolactone (50 mg/kg per day in chow) had no significant effect on blood pressure, glucose tolerance or insulin resistance. In WT mice, no significant sex difference in cognitive function was observed; however, treatment with spironolactone improved spatial memory in the water maze, especially in female WT mice. Administration of spironolactone markedly improved the cognitive decline in female KKAy mice up to the level in male KKAy mice. Spironolactone treatment also improved cognitive function in ovariectomized-KKAy mice, but failed to improve it in those with administration of estradiol (200 µg/kg per day). In diabetic mice, spironolactone improved impaired cognitive function observed in female mice, suggesting that spironolactone may prevent cognitive impairment associated with diabetes in females clinically.

Interleukin 17 (IL-17) is known to contribute to the pathogenesis of hypertension, atherosclerosis, and adipocyte differentiation; however, the roles of IL-17 in glucose metabolism remain to be elucidated. Angiotensin II type 1 receptor blockers improve insulin resistance at least in part because of the amelioration of inflammation. Therefore, we examined the possible roles of IL-17 in the pathogenesis of insulin resistance in type 2 diabetes mellitus using a mouse model, KK-Ay, and angiotensin II type 1 receptor–mediated insulin resistance. KK-Ay mice were administered control-IgG 2A or anti-IL-17 antibody 5 times at a dose of 100 μg every second day by IP injection. KK-Ay mice were administered telmisartan for 2 weeks. C57BL/6J mice treated with angiotensin II infusion for 2 weeks were administered telmisartan or hydralazine. Insulin resistance was evaluated by oral glucose tolerance test, insulin tolerance test, and uptake of 2-[ 3 H]deoxy- d -glucose in peripheral tissues. Serum IL-17 concentration in KK-Ay mice was significantly higher than that in C57BL/6J mice. Treatment of KK-Ay mice with anti–IL-17 antibody significantly increased 2-[ 3 H]deoxy- d -glucose uptake in skeletal muscle but not in white adipose tissue and attenuated the increase in blood glucose level after a glucose load. Blockade of IL-17 enhanced the expression of adipocyte differentiation markers and adiponectin. Treatment with telmisartan decreased serum IL-17 concentration in KK-Ay and ameliorated angiotensin II–induced insulin resistance with a decrease in serum IL-17 level in C57BL/6J. In conclusion, IL-17 could play an important role in the pathogenesis of angiotensin II type 1 receptor–induced insulin resistance.

The angiotensin II type 2 (AT 2 ) receptor is expressed in bone marrow cells and may affect cell differentiation. We previously reported a beneficial role of the AT 2 receptor in ischemic brain damage. Here, we investigated the effect of AT 2 receptor stimulation in hematopoietic cells on ischemic brain injury using chimeric mice. Chimeric mice were generated by bone marrow transplantation into wild-type mice after irradiation. Bone marrow cells were prepared from wild-type ( Agtr2 + ) or AT 2 receptor-deficient mice ( Agtr2 − ). Six weeks after bone marrow transplantation, these chimeric mice were subjected to ischemia/reperfusion injury. Both Agtr2 + and Agtr2 − chimeric mice did not show a significant change in systolic and diastolic blood pressures, whereas body weight decreased in Agtr2 − chimera. Twenty-four hours after ischemia/reperfusion injury, ischemic brain damage in Agtr2 − chimera was exaggerated compared with that in Agtr2 + chimera. Moreover, cerebral blood flow in the peripheral region before and after ischemia/reperfusion injury was decreased in Agtr2 − chimera. The inflammatory response in the ipsilateral hemisphere was not significantly different, whereas tumor necrosis factor-α and monocyte chemoattractant protein 1 expressions tended to increase in the Agtr2 − chimeric brain. Expression of methylmethane sulfonate 2, which has a neuroprotective effect, was lower in the brain of Agtr2 − chimera. These results indicate that deletion of AT 2 receptor in blood cells has a harmful effect on ischemic brain injury.

SummaryBackgroundPlaque rupture plays a critical role for the development of acute myocardial infarction. However, whether quantitative parameters with regard to the cavity size of ruptured plaque are associated with no-reflow (NR) phenomenon following primary angioplasty remains to be elucidated.Methods and resultsA total of 53 patients with de novo ST-elevation myocardial infarction (STEMI) who had plaque rupture at the culprit lesion defined by pre-intervention virtual histology intravascular ultrasound (VH-IVUS) were enrolled. Patients were divided into two groups according to the presence of NR phenomenon: NR group (n=19) and non-NR group (n=34). By VH-IVUS, we evaluated cavity length, maximum area, and volume of ruptured plaque in culprit lesions. The cavity length, maximum area, and volume were significantly higher in the NR group than those of the non-NR group (4.8±2.1mm vs. 2.9±4.8mm, p

Uterine artery embolization (UAE) has become widely employed in Japan. Although several methods of anesthesia and analgesia are performed for UAE, pain control does not appear to be satisfactory. We report a series of UAE, successfully managed using thoracic epidural analgesia.Before UAE an epidural analgesic catheter was inserted at T 10-11. Local anesthetic and morphine sulfate were administered through the catheter. After the UAE patients received patient-controlled epidural analgesia (PCEA) for 24 hours. The next day, patients were treated with diclofenac sodium 25 mg suppository every 8 hours.In all cases, early pain was controlled well by epidural analgesia. Late pain was controlled by combining epidural analgesia with diclofenac sodium. Nausea and pruritus due to morphine sulfate occurred in some cases, but disappeared after discontinuation of PCEA.Several phases of severe pain are seen perioperatively in UAE. Because thoracic epidural analgesia is easily administered and the dosage of the drugs used effectively controlled, it is a practical method for perioperative pain control for UAE.

'Coronary steal' is frequently observed in the recipient artery supplied from collaterals. Coronary steal during stress may have an adverse effect on myocardial function even in a 'well-collateralized' territory. We experienced one case with functional occlusion in which the coronary steal phenomenon was demonstrated non-invasively using transthoracic Doppler echocardiography. The non-invasive assessment of coronary flow measurement might allow us to obtain useful information for understanding the pathophysiology of coronary steal.