| 研究課題/領域番号 |
19H03405
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| 研究機関 | 国立研究開発法人国立循環器病研究センター |
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研究代表者 |
Pearson James 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (30261390)
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| 研究分担者 |
土持 裕胤 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (60379948)
曽野部 崇 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (70548289)
杜 成坤 国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (90590646)
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| 研究期間 (年度) |
2019-04-01 – 2023-03-31
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| キーワード | coronary vessels / diabetes / aging / oxidative stress / vasodilators |
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| 研究実績の概要 |
We performed the study 1 utilising senescence accelerated mice (SAMP8) and resistant mice (SAMR1) to investigate the effect of aging in non-diabetic model. Mice were maintained on either a high fat diet (HFD, 56% fat) or normal fat diet (NFD) for 16 weeks with 1% NaCl drinking water. Some of the SAMP8 mice were concurrently treated with Nox inhibitor (apocynin 5mg/kg/d) or monoamine oxidase-A inhibitor (clorgyline 1mg/kg/d) through subcutaneous osmotic pumps. Cardiac function was assessed by echocardiography before terminal synchrotron microangiography assessment of coronary function. SAMP8 mice treated with apocynin gained less body weight than clorgyline or vehicle treated SAMP8 mice on HFD. Furthermore, aponcynin treated HFD SAMP8 mice showed lower levels of plasma catecholamines, comparable to NFD SAMR1 mice. Ongoing analyses suggest that nitric oxide bioavailability was variable among mice on HFD irrespective of drug treatment relative to NFD. Acetylcholine stimulation of coronary vessels during blockade of calcium-activated K channels and prostanoids revealed segmental and focal vasoconstriction in all HFD mouse groups. These findings suggest that senescence accelerated mice show reduced NO biovailability and endothelial-smooth muscle dysfunction following HFD exposure and that blockade of individual sources of ROS does not ameliorate this dysfunction; that is there is redundancy in the sources of oxidative stress in the heart. Western blotting for eNOS and big calcium activated K channels suggest that protein expression was most reduced in vehicle HFD SAMP8 mice.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
The first study was completed as planned while there was an extended period of interruption to animal experiments due to relocation of our institute. Six groups of mice were prepared and evaluated for cardiac and coronary function in vivo with echocardiography and high-resolution angiography. Following these experiments we commenced image analysis, immunohistochemistry and western blotting assays to establish the mechanisms of vascular dysfunction involving the major vasodilator and constrictor pathways as well as oxidative stress.
The findings to date are complex, but they are clear cut and we anticipate preparing the first publication within 2020.
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| 今後の研究の推進方策 |
We had started preparations to perform the next part of study 1, which involved exercise treatment of HFD SAMP8 mice and preparing study 2 utilising diet-induced diabetic mice. However, COVID-19 pandemic and the suspension of our animal facility and the synchrotron facility will delay the planned experiments until the last half of 2020 FY. Nevertheless, we will next compare coronary and cardiac function in high intensity exercise treated diabetic mice with sedentary diabetic mice using the same protocols as study 1. During the continued interruption we will continue molecular analyses of samples collected to assess changes in MAO-A and Nox proteins and complete assays of oxidant-antioxidant status and quantitative assessment of coronary vascular changes in study 1.
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