심혈관질환에 대한 유자의 효능 검증 및 기전 연구
Protective Effects of Yuzu and Its Component against Cardiovascular Disease
- 주제(키워드) yuzu , hesperidin , platelet aggregation , cardiomyocyte , ischemic heart disease , left ventricular remodeling , apoptosis , fibrosis , inflammation , heart failure
- 발행기관 아주대학교
- 지도교수 이수환, 정이숙
- 발행년도 2015
- 학위수여년월 2015. 2
- 학위명 박사
- 학과 및 전공 일반대학원 의생명과학과
- 실제URI http://www.dcollection.net/handler/ajou/000000018830
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Left ventricular (LV) remodeling, which includes ventricular dilatation and increased interstitial fibrosis after myocardial infarction (MI), is the critical process underlying the progression to heart failure (HF). Therefore, a novel approach for preventing LV remodeling after MI is highly desirable. Yuzu is a citrus plant originating in East Asia, and has a number of cardioprotective ingredients such as hesperidin. However, no study has proved whether yuzu can prevent LV remodeling. The aim of this study was to determine the effects of yuzu on HF and its potential impact on the LV remodeling process after MI and platelet aggregation. In this study, it was investigated whether yuzu and its components hesperidin and naringin, have anti-platelet activities. Yuzu and hesperidin inhibited collagen-, arachidonic acid (AA)-, ADP- and thrombin-induced rat platelet aggregation in vitro and ex vivo. Naringin also inhibited platelet aggregation induced by collagen, AA, or thrombin, but not by ADP. The oral administration of yuzu or hesperidin prolonged mouse tail vein bleeding time in a dose-dependent manner. LV remodeling in vivo study using the permanent left anterior descending coronary artery (LAD) occlusion model demonstrated that one week pretreatment with yuzu or its major metabolite hesperidin before LAD occlusion significantly attenuated cardiac dysfunction, myocyte apoptosis and inflammation. Not only yuzu but also hesperidin inhibited caspase-3 activity, myeloperoxidase expression, α-smooth muscle actin expression, and matrix metalloproteinase-2 activity in a permanent LAD occlusion rat model. These results suggest that yuzu and hesperidin have anti-platelet activity, and that intake of yuzu, which contains various flavonoids such as hesperidin, may be beneficial for individuals at high risk of cardiovascular diseases. These findings provide the first evidence that yuzu and hesperidin prevent MI-induced ventricular dysfunction and structural remodeling of myocardium.
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ABSTRACT i
TABLE OF CONTENTS iii
LIST OF FIGURES vii
LIST OF TABLES ix
ABBREVIATION x
I. INTRODUCTION 1
A. Antiplatelet therapy in cardiovascular diseases 1
B. Left ventricular (LV) remodeling and heart failure (HF) 1
C. Yuzu and its components 3
D. Aims of study 4
II. MATERIALS AND METHODS 5
A. Materials 5
1. Materials 5
B. Methods 5
1. Plant material and preparation of samples 5
2. Experimental protocol 6
3. Animals 7
4. Preparation of platelets 7
5. In vitro platelet aggregation study 8
6. Determination of cytotoxicity 8
7. Ex vivo platelet aggregation study 9
8. In vivo mice tail bleeding times 9
9. Measurement of thromboxane A2 (TXA2) formation 10
10. Echocardiography 10
11. Histological analysis 11
12. Immunohistochemistry 11
13. Gelatin zymography 11
14. Western blot analysis 12
15. Terminal dUTP nick end-labeling (TUNEL) staining 12
16. Statistical analysis 13
III. RESULTS 14
A. PART I. Anti-platelet effects of yuzu extract and its component 14
1. Effects of yuzu on platelet aggregations in vitro 14
2. Contents of hesperidin and naringin in yuzu extracts 17
3. Effects of hesperidin and naringin on platelet aggregations in vitro 20
4. Cytotoxic effects of yuzu, hesperidin, and naringin on platelets 23
5. Effects of yuzu, hesperidin, and naringin on TXB2 formation 25
6. Effects of yuzu and hesperidin on platelet aggregation ex vivo 27
7. Effects of yuzu and hesperidin on tail bleeding times in mice 29
B. PART II. Preventive effect of yuzu and hesperidin on LV remodeling and dysfunction in rat permanent LAD occlusion model 31
1. Yuzu and hesperidin prevented LV remodeling and functional deterioration following MI 31
2. Yuzu and hesperidin prevented myocardial fibrosis during LV remodeling after chronic MI 35
3. Yuzu and hesperidin reduced the inflammatory reaction and MPO expression during LV remodeling after chronic MI 38
4. Yuzu and hesperidin block myocardial apoptosis through inhibition of caspase-3 activation during LV remodeling after chronic MI 41
5. Yuzu and hesperidin block LV wall thinning through inhibition of MMP-2 activation during LV remodeling after chronic MI 44
IV. DISCUSSION 47
A. PART I. Anti-platelet effects of yuzu extract and its component 47
B. PART II. Preventive effect of yuzu and hesperidin on LV remodeling and dysfunction in rat permanent LAD occlusion model 51
V. CONCLUSION 55
REFERENCES 56
국문요약 65
