Yutaka Kagaya

Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1

AIMSnMobilization of stem cells/progenitors is regulated by the interaction between stromal cell-derived factor-1 (SDF-1) and its ligand, CXC chemokine receptor 4 (CXCR4). Statins have been suggested to ameliorate pulmonary arterial hypertension (PAH); however, the mechanisms involved, especially their effects on progenitors, are largely unknown. Therefore, we examined whether pravastatin ameliorates hypoxia-induced PAH in mice, and if so, which type of progenitors and what mechanism(s) are involved.nnnMETHODS AND RESULTSnChronic hypoxia (10% O(2) for 5 weeks) increased the plasma levels of SDF-1 and mobilization of CXCR4(+)/vascular endothelial growth factor receptor (VEGFR)2(+)/c-kit(+) cells from bone marrow (BM) to pulmonary artery adventitia in Balb/c mice in vivo, both of which were significantly suppressed by simultaneous oral treatment with pravastatin (2 mg/kg/day). Furthermore, in vitro experiments demonstrated that hypoxia enhances differentiation of VEGFR2(+)/c-kit(+) cells into alpha-smooth muscle actin(+) cells. Importantly, pravastatin ameliorated hypoxia-induced PAH associated with a decrease in the number of BM-derived progenitors accumulating in the pulmonary artery adventitia. The expression of intercellular adhesion molecule-1 (ICAM-1) and its ligand, CD18 (beta2-integrin), were enhanced by hypoxia and were again suppressed by pravastatin.nnnCONCLUSIONSnThese results suggest that pravastatin ameliorates hypoxia-induced PAH through suppression of SDF-1/CXCR4 and ICAM-1/CD18 pathways with a resultant reduction in the mobilization and homing of BM-derived progenitor cells.

Long-term inhibition of Rho-kinase ameliorates diastolic heart failure in hypertensive rats.

Diastolic heart failure (DHF) is a major cardiovascular disorder with poor prognosis; however, its molecular mechanism still remains to be fully elucidated. We have previously demonstrated the important roles of Rho-kinase pathway in the molecular mechanisms of cardiovascular fibrosis/hypertrophy and oxidative stress, but not examined in the development of heart failure. Therefore, we examined in this study whether Rho-kinase pathway is also involved in the pathogenesis of DHF in Dahl salt-sensitive rats, an established animal model of DHF. They were maintained with or without fasudil, a Rho-kinase inhibitor (30 or 100 mg/kg/day, PO) for 10 weeks. Untreated DHF group exhibited overt heart failure associated with diastolic dysfunction but with preserved systolic function, characterized by increased myocardial stiffness, cardiomyocyte hypertrophy, and enhanced cardiac fibrosis and superoxide production. Fasudil treatment significantly ameliorated those DHF-related myocardial changes. Western blot analysis showed that cardiac Rho-kinase activity was significantly increased in the untreated DHF group and was dose-dependently inhibited by fasudil. Importantly, there was a significant correlation between the extent of myocardial stiffness and that of cardiac Rho-kinase activity. These results indicate that Rho-kinase pathway plays an important role in the pathogenesis of DHF and thus could be an important therapeutic target for the disorder.

Total Entrance Skin Dose: An Effective Indicator of Maximum Radiation Dose to the Skin During Percutaneous Coronary Intervention

OBJECTIVEnA number of cases of radiation-associated patient skin injury during percutaneous coronary intervention (PCI) have been reported. To protect against this complication, maximum skin dose to the patient should be monitored in real time. Unfortunately, in most cardiac intervention procedures, real-time monitoring of maximum skin dose is not possible. Angiographic X-ray units, however, display the patients total entrance skin dose in real time. We therefore investigated the relation between maximum skin dose and total entrance skin dose to determine whether total entrance skin dose can be used to estimate maximum skin dose during PCI.nnnMATERIALS AND METHODSnThe dose-area product was measured, and maximum skin dose and total entrance skin dose were calculated with a skin-dose-mapping software program. The target vessels of 194 PCI procedures were divided into four groups according to the American Heart Association (AHA) segment system.nnnRESULTSnThe maximum skin dose constituted 48%, 52%, 50%, and 52% of the total entrance skin dose during PCI on AHA segments 1-3, 4, 5-10, and 11-15, respectively. There were significant correlations between maximum skin dose and total entrance skin dose during PCI (r = 0.894, 0.935, 0.859, and 0.898 for segments 1-3, 4, 5-10, and 11-15, respectively; p < 0.001).nnnCONCLUSIONnMaximum skin dose during PCI is approximately 50% of the total entrance skin dose for each target vessel. Correlation between the two doses was very good. Total entrance skin dose is an effective predictor of maximum skin dose during PCI when the formula used is maximum skin dose = 0.5 x total entrance skin dose. Our results provide useful information for avoiding deterministic radiation skin injury to patients undergoing PCI.

Enhanced [18F]fluorodeoxyglucose accumulation in the right ventricular free wall predicts long-term prognosis of patients with pulmonary hypertension: a preliminary observational study.

AIMSnWe have previously demonstrated that [(18)F]fluorodeoxyglucose (FDG) accumulation is increased in the right ventricular (RV) free wall of patients with pulmonary hypertension (PH), and that this accumulation is ameliorated after the treatment with epoprostenol associated with improvement of haemodynamic overload. The aim of this study was to examine whether enhanced RV FDG accumulation by gated positron emission tomography (PET) has a prognostic impact in patients with PH.nnnMETHODS AND RESULTSnWe examined the prognostic impact of the RV standardized uptake value (SUV) of FDG-PET corrected for the partial volume effect (cRV-SUV) in 27 patients with PH who underwent gated FDG-PET from March 2001 to June 2004. During the follow-up period of 69 ± 49 (mean ± SD) months, among the 27 patients, 15 showed clinical worsening (CW) and 11 died. FDG-PET examination showed that cRV-SUV was significantly higher in the CW group compared with the non-CW group (10.1 vs. 7.6, P = 0.02). Univariate Cox hazard analysis showed that cRV-SUV was significantly correlated with the time to CW (hazard ratio 1.25, 95% confidence interval 1.04-1.51, P = 0.02), which remained significant even after adjustment of World Health Organization functional class. Kaplan-Meier analysis showed that the patients with cRV-SUV ≥8.3 had poor prognosis compared with those with cRV-SUV <8.3 (log-rank P = 0.005 for time to CW and P = 0.07 for mortality).nnnCONCLUSIONnThese results indicate that enhanced FDG accumulation in the RV free wall may be a novel prognostic factor in patients with PH.

OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization

AIMSnAtherosclerosis is characterized by infiltration of inflammatory cells and enhanced vasa vasorum formation, for which immunological mechanisms may be involved. OX40, a membrane-bound molecule of the tumour necrosis factor-receptor superfamily, is expressed by activated T-cells, while OX40 ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we thus examined whether the OX40/OX40L system is involved in the pathogenesis of atherosclerosis.nnnMETHODS AND RESULTSnWe examined apolipoprotein E-deficient (ApoE(-/-)) mice and ApoE(-/-)/OX40L-double-deficient (ApoE(-/-)/OX40L(-/-)) mice fed on a high-fat diet for 8 weeks. The extent of aortic atheroma was significantly less in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. We also treated high-fat-fed ApoE(-/-) mice with or without MGP34 antibody (OX40L-specific neutralizing antibody) for 10 weeks. After the treatment, the extent of aortic atheroma was again significantly less in MGP34-treated mice compared with controls. Importantly, both vascular density in the aortic adventitia and vascular endothelial growth factor-induced angiogenesis in the Matrigel assay in vivo were significantly reduced in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. Finally, when high-fat-fed ApoE(-/-) mice were transplanted with bone marrow cells from either wild-type or OX40L(-/-) mice, the extent of aortic atheroma was comparable between the two groups.nnnCONCLUSIONnThese results indicate that the vascular OX40/OX40L system plays an important role in the formation of vasa vasorum and subsequent atherosclerosis, suggesting that the vascular OX40/OX40L system might be a new therapeutic target of atherosclerosis.

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

Diabetes mellitus (DM) is a major risk factor for heart failure, independent of coronary artery disease or hypertension (HT). Therefore, our study was designed to examine the mechanisms of DM-induced left ventricular (LV) diastolic dysfunction. In this study, we made five different 10-week treatment groups of Dahl salt-sensitive rats as follows: Control; a low-salt (0.5% NaCl) diet, HT; a high-salt (5% NaCl) diet, DM; a low-salt diet with streptozotocin (STZ) injection (30u2009mgu2009kg−1 i.p.), HT+DM; a high-salt diet with STZ injection, and the Olmesartan group; a high-salt diet with STZ treated with an angiotensin receptor blocker, olmesartan (1u2009mgu2009kg−1u2009day−1). Cardiac diastolic dysfunction with a preserved systolic function was noted in the HT group, and was most prominently noted in the HT+DM group, characterized by enhanced cardiac fibrosis, whereas the extent of HT and myocardial hypertrophy was comparable between the two groups. Myocardial expressions of collagen III, transforming growth factor-β2, angiotensin-converting enzyme (ACE), angiotensin II type-1 receptor and myocardial oxidative stress (evaluated by 4-hydroxy-2-nonenal-modified protein) were mostly enhanced in the HT+DM group. Importantly, there was a positive correlation between the extent of diastolic dysfunction and that of myocardial ACE expression. All these cardiac abnormalities induced by DM and HT were ameliorated in the olmesartan group. These results indicate that DM accelerates diastolic dysfunction in hypertensive heart disease through activation of the renin–angiotensin system, with subsequent inflammatory and oxidative stresses and myocardial fibrosis, suggesting that an inhibition of the system is effective for the treatment of diastolic dysfunction in this combined disorder.

Evaluation of Patient Radiation Dose during Cardiac Interventional Procedures: What Is the Most Effective Method?

Cardiac interventional radiology has lower risks than surgical procedures. This is despite the fact that radiation doses from cardiac intervention procedures are the highest of any commonly performed general X-ray examination. Maximum radiation skin doses (MSDs) should be determined to avoid radiation-associated skin injuries in patients undergoing cardiac intervention procedures. However, real-time evaluation of MSD is unavailable for many cardiac intervention procedures. This review describes methods of determining MSD during cardiac intervention procedures. Currently, in most cardiac intervention procedures, real-time measuring of MSD is not feasible. Thus, we recommend that physicians record the patients total entrance skin dose, such as the dose at the interventional reference point when it can be monitored, in order to estimate MSD in intervention procedures.

Thyroid hormone and chronically unloaded hearts.

The heart is subjected to chronic mechanical unloading during prolonged spaceflight and microgravity. The heart in patients with end-stage heart failure is also unloaded in prolonged duration after left ventricular assist devices (LVAD) are implanted. Heterotopic heart transplantation in rats is an established model of chronic cardiac unloading, and has been used to investigate the effects of chronic cardiac unloading on the heart. Observations that have been found using this experimental model are as follow. Chronic cardiac unloading induces time-dependent depressions of Ca2+ handling and myocyte contractility, which are associated with the shift of myosin heavy chain (MHC) isozymes and altered expressions of Ca2+ cycling-related proteins. Treatment with the physiological treatment dose of thyroid hormone restores the expression levels of Ca2+ cycling-related proteins, Ca2+ handling, and contractile function of cardiac myocytes in chronically unloaded hearts. Although future studies are required to determine precise mechanisms of the beneficial effects of thyroid hormone on chronically unloaded hearts, these observations may have clinical implications in the future for chronic cardiac unloading in the space industry as well as in the treatment of patients with end-stage heart failure supported by LVAD.

Emergence of the erythropoietin/erythropoietin receptor system as a novel cardiovascular therapeutic target.

Abstract Although hypoxia and ischemia are known to be involved in the pathogenesis of cardiovascular disease, specific therapeutic targets still remain elusive. To address this important issue, we have performed 2 series of experimental studies, aiming at erythropoietin (Epo)/Epo receptor (EpoR) based on the following backgrounds. Epo has long been regarded as a hematopoietic hormone that acts exclusively in the proliferation and differentiation of erythroid progenitors. Although recent studies have demonstrated that EpoR is expressed in the cardiovascular system, the potential protective role of the vascular Epo/EpoR system in vivo remains to be examined. We hypothesized that the vascular Epo/EpoR system plays an important protective role against the development of cardiovascular disease. Using vascular EpoR-deficient mouse, we demonstrated that the vascular Epo/EpoR system plays a crucial role for endothelial function and vascular homeostasis. The vascular Epo/EpoR system is important for the activation of the vascular endothelial growth factor/vascular endothelial growth factor receptor-2 system, inhibits hypoxia-induced pulmonary endothelial damage and promotes ischemia-induced angiogenesis in vivo. These results indicate that the vascular Epo/EpoR system plays an important protective role against hypoxia/ischemia, demonstrating that this system is a novel therapeutic target in cardiovascular medicine.

Mitsugumin 53-mediated maintenance of K+ currents in cardiac myocytes.

Mitsugumin 53 (MG53) is a muscle-specific RBCC/TRIM family member predominantly localized on small vesicles underneath the plasma membrane. Upon cell-surface lesion MG53 recruits the vesicles to the repair site in an oxidation-dependent manner and MG53-knockout mice develop progressive myopathy associated with defective membrane repair. In this report, we focus on MG53-knockout cardiomyocytes showing abnormal action potential profile and a reduced K+ current density. In cDNA expression experiments using cultured cells, KV2.1-mediated currents were remarkably increased by MG53 without affecting the total and cell-surface levels of channel expression. In imaging analysis MG53 seemed to facilitate the mobility of KV2.1-containing endocytic vesicles with acidic pH. However, similar effects on the current density and vesicular mobility were not observed in the putative dominant-negative form of MG53. Our data suggest that MG53 is involved in a constitutive cycle of certain cell-surface proteins between the plasma membrane and endosome-like vesicles in striated muscle, and also imply that the vesicular dynamics are essential for the quality control of KV2.1 in cardiomyocytes.