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研究生:陳其宇
研究生(外文):Chen, Chi-Yu
論文名稱:血管再塑形在心血管疾病之角色-從飲食到基因調控之研究
論文名稱(外文):Vascular Remodeling in Cardiovascular Disease-Dietary Intake to Gene Regulation
指導教授:林幸榮林幸榮引用關係黃柏勳黃柏勳引用關係
指導教授(外文):Lin, Shing-JongHuang, Po-Hsun
學位類別:博士
校院名稱:國立陽明交通大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2022
畢業學年度:110
語文別:英文
論文頁數:80
中文關鍵詞:動脈粥狀硬化血管內膜新生血管再塑型血管平滑肌細胞四個半LIM的結構蛋白2氧化三甲胺33-二甲基-1-丁醇內質網壓力
外文關鍵詞:AtherosclerosisNeointimal formationVascular remodelingVascular smooth muscle cellfour and a half LIM domain protein 2trimethylamine‐N‐oxide33-Dimethyl-1-butanolEndoplasmic reticulum stressFHL2TMAODMB
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血管重塑是一個複雜的病生理過程,在心血管疾病的臨床表現中有著重要作用。重塑的一個重要概念是保持恆定血流。實驗和臨床觀察顯示,血管重塑與內膜中層增厚(intima-media thickening, IMT)和動脈粥狀硬化斑塊形成有關。受動脈粥狀硬化影響,血管壁上維持穩定環境的生理需求增加。為應對不斷增長的斑塊,血管壁會發生重塑以補償血流的變化。血管平滑肌細胞(vascular smooth muscle cells, VSMC)在動脈粥狀硬化發展過程中調節血管壁重塑具有重要作用。我們希望通過這一系列研究,了解血管平滑肌細胞在心血管疾病中的作用。
在研究的第一部分,我們研究了四個半LIM的結構蛋白2 (four and a half LIM domain protein 2, FHL2)在血管重塑中的機制。FHL2是FHL基因家族的成員,它與富含膽固醇的飲食促進動脈粥狀硬化有關。然而,FHL2 蛋白對受到血流動力學改變之血管重塑的影響仍不清楚。在這裡,我們研究FHL2在受限血流誘導的動脈粥狀硬化模型中的作用。為了誘發體內血管內膜增生,我們對 FHL2+/+和FHL2-/-小鼠執行左頸動脈(left carotid artery, LCA) 部分結紮。在 FHL2-/-小鼠中p-ERK和p-AKT的表現下降。FHL2與AKT結合作用調節AKT磷酸化並導致Rac1-GTP失去活性。在人類主動脈平滑肌細胞中降低FHL2表現能減少血小板衍生生長因子(platelet-derived growth factor, PDGF)誘導的ERK和AKT磷酸化。此外,FHL2表現量降低減少細胞骨架結構的變化並導致細胞週期停滯。我們認為FHL2 對於調節動脈平滑肌細胞功能至關重要,FHL2通過有絲分裂原活化蛋白(Mitogen-activated protein kinase, MAPK) 和 PI3K-AKT 機轉調節細胞增生和遷移,導致動脈壁增厚造成血管內膜增生。
在研究的第二部分,我們探討攝入過多的氧化三甲胺(trimethylamine‐N‐oxide, TMAO)是否會造成血管發炎而促進血管重塑。近來研究顯示,由於TMAO刺激血管發炎,因此被認定為是造成動脈粥狀硬化的危險因素。然而,TMAO對血管損傷後內膜增生的影響仍不清楚。我們在小鼠模型上,藉由餵食高含量的TMAO飲食,以更深入地了解TMAO在血管損傷中的機制。本研究是在小鼠模型上利用左頸動脈部分結紮以模擬急性血流改變。3,3-二甲基-1-丁醇(3,3-Dimethyl-1-butanol, DMB) 是膽鹼的一種結構類似物,用於競爭性結合以降低體內TMAO的濃度。將野生型(wild-type, WT)小鼠分為四組[常規飲食、高 含量TMAO飲食、高含量膽鹼飲食和高含量膽鹼飲食+ DMB] 以研究TMAO 升高及DMB抑制效果對血管病變的影響。與對照組相比,餵食高含量TMAO 和高含量膽鹼飲食的小鼠顯著增加了血管內膜增生和晚期斑塊,而DMB治療減少了血管內膜和中層增生。此外,高含量TMAO和高含量膽鹼飲食造成結紮誘導的動脈彈性蛋白碎裂、增加巨噬細胞浸潤、細胞發炎因子分泌,並活化核因子活化B細胞κ輕鏈增強子(nuclear factor kappa-light-chain-enhancer of activated B cells, NF-κB)和NLRP3發炎體。給予TMAO抑制劑DMB治療可以顯著減少了血管損傷、發炎體、內質網壓力和活性氧的表現。我們的研究結果顯示,TMAO升高會促進血管病變,而給予DMB可以減緩血管重塑,在此說明了TMAO可以做為治療標的,來減緩動脈粥狀硬化與避免血管內膜再狹窄的理論基礎。
調控血管重塑的過程涵蓋了內在的基因表達到外在的攝取物的影響,基因表達的調控協調重要的細胞過程,包括細胞增生、分化和發炎。血管滑肌細胞中的轉錄因子表達和細胞週期調節受FHL2的調節,且會隨著血管損傷而變化。 FHL2是否可以作為疾病生物標誌物將取決於更多不同疾病患者上的發現。微生物群的代謝物與疾病的危險因素之間存在相關性,除了腸道微生物群外,宿主遺傳、共同代謝和飲食也會對產生TMA和TMAO有影響。如果可以研究微生物群在調節TMAO濃度的具體作用及其飲食調節機制,將能夠成為改善患者預後的新治療目標。
Vascular remodeling plays an essential part in the clinical performance of cardiovascular diseases, which includes a complex pathophysiological process. The maintenance of constant flow is a critical concept for vascular remodeling. Recent observations from experimental and clinical consequences intimate that vascular remodeling is related to the formation of atherosclerotic plaque and intima-media thickening (IMT). Maintaining the homeostatic environment for the physiological requirement on the vessel wall is a significant increase in response to atherosclerosis. The remodeling of the vascular wall compensates for the alterations in blood flow in response to the growing plaque. Vascular smooth muscle cells (VSMCs) play a vital role in regulating vascular remodeling during atherosclerosis development. Through a series of studies, we hope to clarify the role of VSMC in cardiovascular diseases.
In the first part of the study, we investigated the mechanism of four and a half LIM domain protein 2 (FHL2) in vascular remodeling. FHL2 is a member of the four and a half LIM domain (FHL) gene family, which is associated with high-cholesterol diet-promoted atherosclerosis. However, the relationship between the influence of FHL2 protein and hemodynamic-altered vascular remodeling remains unknown. In this study, we demonstrate the role of FHL2 in a restricted blood flow‐induced atherosclerosis model. We performed a partial ligation of the left carotid artery (LCA) on FHL2+/+ and FHL2−/− mice to establish neointimal formation in vivo. The results showed that the expression of p‐ERK and p‐AKT declined in FHL2−/− mice. FHL2 inhibited Rac1‐GTP activation by binding to AKT and reduced its phosphorylation. Moreover, PDGF-induced ERK and AKT phosphorylation were reduced by silence of FHL2 in human aortic smooth muscle cells (HASMCs). Knockdown of FHL2 decreased cytoskeleton conformational changes and brought about cell cycle arrest. We concluded that FHL2 is necessary for regulating the function of arterial smooth muscle cells and modulates neointimal formation by regulating proliferation and migration through mitogen‐activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)‐AKT signaling.
In the second part of the study, we investigated whether moderate intake of high TMAO would enhance vascular remodeling through vascular inflammation. Trimethylamine‐N‐oxide (TMAO) has recently been identified as a novel independent risk factor for atherosclerosis through the induction of vascular inflammation. However, the effect of TMAO on neointimal formation in response to vascular injury remains unclear. We applied a murine model supplemented with high-TMAO diets to gain deeper insights into the mechanism of TMAO in vascular injury. This study was conducted using a murine model of acutely disturbed flow-induced atherosclerosis by partial carotid-artery ligation. 3,3-Dimethyl-1-butanol (DMB), a structural analog of choline, was used to reduce TMAO concentrations. Wild-type (WT) mice were divided into four groups [regular diet, high-TMAO diet, high-choline diet, and high-choline diet + DMB] to investigate the effects of TMAO elevation and its inhibition by DMB on disturbed flow-induced atherosclerosis. Mice fed high-TMAO, and high-choline diets had significantly enhanced neointimal hyperplasia and advanced plaques relative to the control group, whereas DMB treatment attenuated neointimal and medial hyperplasia. Additionally, the high-TMAO and high-choline diets promoted ligation-induced arterial elastin fragmentation, increased macrophage infiltration, inflammatory cytokine secretion, and enhanced activation of nuclear factor-κB and the NLRP3 inflammasome. DMB treatment substantially reduced disturbed flow-induced atherosclerosis, inflammasome expression, endoplasmic reticulum stress, and reactive oxygen species expression. Our findings demonstrate that TMAO elevation promotes disturbed flow-induced atherosclerosis and that DMB administration mitigates vascular remodeling, suggesting a rationale for a TMAO-targeting strategy for the treatment of atherosclerosis.
The regulation of vascular remodeling relies on the influence of internal gene expression and external uptake. Regulation of gene expression orchestrates important cellular processes, including proliferation, differentiation, and inflammation. Transcription factor expression and cell cycle regulation in vascular SMCs are regulated by patterns of FHL2 that change in response to injury. Whether FHL2 can serve as disease biomarkers will depend on findings in more diverse patient populations. Recent studies suggest that there is a correlation between the metabolites by microbiota and the risk factors for diseases. Besides intestinal microbiota, host genetics, co-metabolism, and diet also respond to the production of TMA and TMAO. If it was possible to investigate the specific role of microbiota in regulating the levels of TMAO concentration and their mechanism of dietary modulation, it could become a new therapeutic target for improving the outcomes of patients.
致謝 i
中文摘要 ii
English Abstract iv
目錄 vii
List of the abbreviations x
1. INTRODUCTION 1
1.1. Neointimal formation 1
1.2. The role of vascular smooth muscle cells and endothelial cells in vascular remodeling 1
1.3. FHL2 3
1.4. TMAO and DMB 4
1.5. Aim and design of the study 6
2. MATERIALS AND METHODS 7
2.1. Experimental animals 7
2.1.1. FHL2 KO mice 7
2.1.2. TMAO administration mice 7
2.2. Ethics 8
2.3. Partial carotid artery ligation model 8
2.4. Vascular morphometric analysis 8
2.5. Elastic fragmentation measurement 9
2.6. Measurement of plasma TMAO levels 9
2.7. Measurement of IL-1β, IL-6, IL-10, and TNF-α 10
2.8. Measurement of mitochondrial membrane potential 10
2.9. Reactive oxygen species measurement 11
2.10. Oxygen consumption assay and ATP generation assay 11
2.11. HASMC cultivation 11
2.12. Cell viability and proliferation assay 12
2.13. Cell migration assay 12
2.14. Transfection of siRNA 12
2.15. Cell cycle analysis 13
2.16. Lamellipodia formation assay 13
2.17. Co-immunoprecipitation 13
2.18. Rac1 activity assay 13
2.19. Western blotting 14
2.20. Immunofluorescence 15
2.21. Statistical analysis 16
3. RESULTS 17
3.1. FHL2 deficiency attenuates neointimal formation in mice 17
3.2. FHL2 deficiency inhibits proliferation signals and cytokine secretion in vivo 17
3.3. PDGF regulates FHL2 expression 18
3.4. Knockdown of FHL2 expression inhibits cell proliferation and signaling in HASMCs 18
3.5. Knockdown of FHL2 expression regulates cell cycle arrest 18
3.6. Knockdown of FHL2 expression inhibits cell migration and eliminates cytoskeleton conformational changes 19
3.7. FHL2 interacts with AKT as a scaffold protein and regulates phosphorylation 19
3.8. Effect of high-TMAO and high-choline diets on plasma TMAO levels 20
3.9. Effect of high-TMAO and high-choline diets on vascular remodeling after carotid artery ligation 20
3.10. Effects of TMAO elevation on vascular inflammation after carotid artery ligation 21
3.11. Effects of TMAO on mitochondrial function, endoplasmic reticulum stress, and ROS production after carotid artery ligation 22
3.12. TMAO increases the activation of NLRP3 inflammasome in vitro 22
3.13. TMAO attenuates mitochondria function and increases ER stress in vitro 23
4. DISCUSSION 25
5. CONCLUSIONS 34
6. PERSPECTIVES 35
7. REFERENCES 36
8. FIGURES 48
9. SUPPLEMENTARY FIGURES 79
10. PUBLICATIONS 80
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