Emerin plays a crucial role in nuclear invagination and in the nuclear calcium transient

13301甲第4595号博士（医学）金沢大学博士論文本文Full 以下に掲載：Scientific Reports 44312(7) pp.1-16 2017. Nature. 共著者：Masaya Shimojima, Shinsuke Yuasa, Chikaaki Motoda, Gakuto Yozu, Toshihiro Nagai, Shogo Ito, Mark Lachmann, Shin Kashimura, Makoto Takei, Dai Kusumoto, Akira Kunitomi, Nozomi Hayashiji, Tomohisa Seki, Shugo Tohyama, Hisayuki Hashimoto, Masaki Kodaira, Toru Egashira, Kenshi Hayashi, Chiaki Nakanishi, Kenji Sakata, Masakazu Yamagishi, Keiichi Fukud

エメリンが核膜陥入層及び，核内カルシウム動態に重要な役割を果たす

第16回　高安賞優秀論文賞受賞Scientific Reports 2017 Mar 14; 7: 44312 2017年3月掲載　　 Masaya Shimojima, Shinsuke Yuasa, Chikaaki Motoda, Gakuto Yozu,　　 Toshihiro Nagai, Shogo Ito, Mark Lachmann, Shin Kashimura,　　 Makoto Takei, Dai Kusumoto, Akira Kunitomi, Nozomi Hayashiji,　　 Tomohisa Seki, Shugo Tohyama, Hisayuki Hashimoto,　　 Masaki Kodaira, Toru Egashira, Kenshi Hayashi, Chiaki Nakanishi,　　 Kenji Sakata, Masakazu Yamagishi & Keiichi Fukud

Diagnostic Intravascular Imaging Modalities for Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV) is one of the major factors limiting long-term survival after heart transplantation (HTX). Typically, concentric vascular thickening and fibrosis with marked intimal proliferation are found in CAV. Most of HTX patients often remain free from symptoms of typical angina. Therefore, surveillance diagnostic exams are often performed. The gold standard of diagnosing CAV is coronary angiography (CAG). However, CAG can often be a less sensitive modality for the detection of diffuse concentric lesions. Intravascular ultrasound (IVUS) is helpful for direct imaging of vessel walls and provides useful information about coronary intimal thickening; however, it is difficult to evaluate plaque morphology in detail. Optimal coherence tomography (OCT), which delivers high resolution of 10 μm, can provide more details on plaque morphology than conventional imaging modalities. Recently, OCT imaging revealed new insight in CAV such as the development of atherosclerotic lesions and complicated coronary lesions. We review the pathogenesis, clinical features, diagnosis of CAV, with a particular focus on diagnostic intravascular imaging modalities

Induction Therapy in the Current Immunosuppressive Therapy

The current immunosuppressive therapy including calcineurin inhibitors, mycophenolate mofetil, and steroids, has substantially suppress rejections and improved clinical outcomes in heart transplant (HTx) recipients. Nevertheless, the management of drug-related nephrotoxicity, fatal acute cellular rejection (ACR), antibody-mediated rejection and infections remains challenging. Although previous some studies suggested that perioperative induction immunosuppressive therapy may be effective for the suppressing ACR and deterioration of renal function, increased incidence of infection and malignancy was concerned in recipients with induction immunosuppressive therapy. The international society of heart and lung transplantation (ISHLT) guidelines for the care of heart transplant recipients do not recommend routine use of induction immunosuppressive therapy, except for the patients with high risk of acute rejection or renal dysfunction, however, appropriate therapeutic regimen and indication of induction immunosuppressive therapy remains unclear in HTx recipients. We review current evidence of induction immunosuppressive therapy in HTx recipients, and discuss the appropriate therapeutic regimen and indication of induction therapy

Rapid changes in plaque composition and morphology after intensive lipid lowering therapy: study with serial coronary CT angiography.

Although intensive lipid lowering by statins can enhance plaque stability, few data exist regarding how early statins change plaque composition and morphology in clinical setting. Therefore, to examine early changes in plaque composition and morphology by intensive lipid lowering with statins, we evaluate coronary plaques from acute coronary syndrome (ACS) before and 3 weeks after lipid lowering by coronary CT angiography. We enrolled 110 patients with suspected ACS and underwent coronary CT. We defined plaque as unstable when CT number of plaque1.10. Rosuvastatin (5 mg/day) or atorvastatin (20 mg/day) were introduced to reduce low density lipoprotein cholesterol (LDL-C). Then, CT was again performed by the same condition 3 weeks after lipid lowering therapy. Total 10 patients (8 men, mean age 72.0 years), in whom informed consent regarding serial CT examination was obtained, were analyzed. Among them, 4 patients who denied to have intensive lipid lowering were served as controls. In remaining 6 patients, LDL-C reduced from 129.5±26.9 mg/dl to 68.5±11.1 mg/dl after statin treatment. Under these conditions, CT number of the targeted plaque significantly increased from 16.0±15.9 to 50.8±35.0 HU (p<0.05) and remodeling index decreased from 1.22±0.11 to 1.11±0.06 (p<0.05), although these values substantially unchanged in controls. These results demonstrate that MDCT-determined plaque composition as well as volume could be changed within 3 weeks after intensive lipid lowering. This may explain acute effects of statins in treatment of acute coronary syndrome

Emerin plays a crucial role in nuclear invagination and in the nuclear calcium transient.

Alteration of the nuclear Ca2+ transient is an early event in cardiac remodeling. Regulation of the nuclear Ca2+ transient is partly independent of the cytosolic Ca2+ transient in cardiomyocytes. One nuclear membrane protein, emerin, is encoded by EMD, and an EMD mutation causes Emery-Dreifuss muscular dystrophy (EDMD). It remains unclear whether emerin is involved in nuclear Ca2+ homeostasis. The aim of this study is to elucidate the role of emerin in rat cardiomyocytes by means of hypertrophic stimuli and in EDMD induced pluripotent stem (iPS) cell-derived cardiomyocytes in terms of nuclear structure and the Ca2+ transient. The cardiac hypertrophic stimuli increased the nuclear area, decreased nuclear invagination, and increased the half-decay time of the nuclear Ca2+ transient in cardiomyocytes. Emd knockdown cardiomyocytes showed similar properties after hypertrophic stimuli. The EDMD-iPS cell-derived cardiomyocytes showed increased nuclear area, decreased nuclear invagination, and increased half-decay time of the nuclear Ca2+ transient. An autopsied heart from a patient with EDMD also showed increased nuclear area and decreased nuclear invagination. These data suggest that Emerin plays a crucial role in nuclear structure and in the nuclear Ca2+ transient. Thus, emerin and the nuclear Ca2+ transient are possible therapeutic targets in heart failure and EDMD. © The Author(s) 2017

Determination of Early and Late Endothelial Progenitor Cells in Peripheral Circulation and Their Clinical Association with Coronary Artery Disease

金沢大学医薬保健研究域医学系The clinical implications of early and late endothelial progenitor cells (EPCs) in coronary artery disease (CAD) remain unclear. We investigated endothelial dysfunction in CAD by simultaneously examining early and late EPC colony formation and gene expression of specific surface markers in EPCs. EPCs were extracted from a total of 83 subjects with (n=47) and without (n=36) CAD. Early and late EPC colonies were formed from mononuclear cells extracted from peripheral blood. We found that fewer early EPC colonies were produced in the CAD group (7.2 ± 3.l/well) than those in the control group (12.4 ± 1.4/well, p<0.05), and more late EPC colonies were produced in the CAD group (0.8 ± 0.2/well) than those in the control group (0.25 ± 0.02/well, p<0.05). In the CAD group, the relative expression of CD31 and KDR of early and late EPCs was lower than in the control group. These results demonstrate that CAD patients could have increased late EPC density and that early and late EPCs in CAD patients exhibited immature endothelial characteristics. We suggest that changes in EPC colony count and gene expression of endothelial markers may have relation with development of CAD. © 2015 Shotoku Tagawa et al

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements