资源简介

(共74张PPT)
Cardiovascular system
心血管系统疾病
动脉粥样硬化
冠状动脉粥样硬化和冠心病
高血压病
风湿病
感染性心内膜炎
心瓣膜病
心肌病和心肌炎
Section 1
动脉粥样硬化
Atherosclerosis
大动脉（弹力型）… 主a，肺a
中动脉（肌型）…冠状a，肾a
小动脉（直径 2mm）
细动脉（直径20-100 m）
…组织器官中
波及大中动脉
动脉内膜的病变
粥样纤维脂质斑块
动脉粥样硬化 概述
Blockage
(preceded by narrowing)
2) Rupture
Preceded by weakening)
心绞痛 Angina
心肌梗死 Myocardial infarct
缺血性纤维化 Ischemic scarring of the myocardium
动脉硬化性痴呆 Atherosclerotic dementia
跛行 Leg claudication
动脉硬化性中风 Atherosclerotic stroke
肠坏疽 Gangrene of the bowel
kidney
冠状动脉血栓形成
粥瘤性动脉瘤
流行病学
地区（Japan, French）
年龄 ( MI…40-60岁）
性别
遗传
ApoA1-HDL
ApoB100-LDL
Lp(a)
Exercise habit
高水平 LDL cholesterol
吸烟 Cigaret smoking
高血压 High blood pressure
糖尿病 Diabetes from any cause
缺乏锻炼 Lack of exercise
Manageable risk factors
Heredity
Diet
慢性内皮细胞损伤
LDL, Cholesterol 沉积于动脉壁
脂蛋白氧化
单核细胞迁移 endothelium *
血小板黏附和激活
SMC从中膜迁移进入内膜，活化巨噬细胞 (foam cells)
SMC增殖和分泌ECM
细胞内和ECM间脂质贮存
内皮功能失调
单核细胞黏附浸润
脂质浸润
SMC proliferation
ECM沉积
thrombosis
Atherogenesis
(Circulation. 2009;119:3133-3141.)
Cells …M ，SMCs，other leukocytes
ECM …胶原纤维，弹力纤维和多糖蛋白
Lipids
动脉内膜上形成粥样斑块 Atheroma
病理
The innocent precursors：脂纹 Fatty streaks
The time bombs: 纤维斑块 Fibrous plaques
The killers: 复合斑块 Complicated plaques
* 不同斑块各成分比例不同
Fatty streaks
FATTY
STREAKS
泡沫细胞
泡沫细胞
泡沫细胞
Foam cells
泡沫细胞
( foam cell ）
纤维斑块 Fibrous plaques
纤维斑块早期
纤维斑块
粥样斑块 （粥瘤）
粥样斑块或粥肿
胆固醇裂隙
1
2
3
斑块破裂、遗留溃疡
Superimposed thrombosis
Embolization
斑块内出血
钙化
动脉瘤Aneurysmal dilation
粥样斑块继发性病变
冠脉粥样硬化—斑块出血
主动脉粥样硬化---溃疡、附壁血栓
钙化
夹层动脉瘤
腹主动脉多见 ，后壁及分支开口
在脑，广泛分布在Willis动脉环
在心冠状动脉，呈偏心分布
粥样斑块分布
腹主动脉ATH
脑动脉ATH
动脉粥样硬化之肾脏
冠状动脉ATH
Reversing Atherosclerosis
（n engl j med 360;11 march 12, 2009）
Atherosclerosis is reversible and involves the removal of trapped cholesterol-loaded foam-cell macrophages from the arterial intima. A recent study by Park and colleagues showed that these foam cells are trapped by interaction with oxidized low-density lipoprotein (LDL) and can be remobilized by dynamic exposure to key antioxidants such as resveratrol白藜芦醇, a polyphenolic多酚类compound found in grapes and red wine and having potential antiatherogenic properties.
It was once thought that atherosclerosis was a lipid-storage disease and that its pathology — a lesion or plaque causing arterial obstruction — resulted from the accumulation of lipid within arteries. It is now understood that atherosclerotic lesions are more sophisticated entities.
They are foci of vessel-wall inflammation, which at a local level have many hallmarks of chronic inflammation,including the presence of macrophages,dendritic cells, and lymphocytes. These leukocytes accumulate at specific loci, underneath endothelial cells displaying an activated or inflamed phenotype.
Lesions begin as fatty streaks and progress to pathologic lesions under the influence of both genetic and lifestyle insults. Whereas most plaques are the result of many years of gradual asymptomatic disease progression, the final obstructive event is often sudden and thrombotic.
During the major part of a lifetime that will elapse between fatty-streak formation and overt disease, multiple events will occur to accelerate, retard, and even reverse lesion progression. That a major component of atherosclerosis is chronic inflammation of the arterial wall raises questions about the relationship between inflammatory events and disease severity.
Inflammation is a normal homeostatic response of the body to wounds or infections. Usually, it is self-limiting, and homeostasis is restored. Chronic inflammation occurs when the inflammatory response cannot resolve the initiating event or when self-limiting mechanisms go awry. Some of the factors that contribute to atherosclerosis progression include hyperlipidemia, lipid oxidation, leukocyte accumulation in the arterial wall, and the formation of macrophage foam cells.
The in vivo generation of biologically active oxidized lipids can both initiate and modulate these inflammatory cellular events. The accumulation of cholesterol (in the form of the macrophage foam cell) within lesions is presumably due to insufficient activity of key lipid efflux, catabolic pathways, or both.
On a molecular level, scavenger receptors on the macrophage surface play a central role in foam-cell formation. For example, CD36 mediates the cellular uptake of oxidized LDL through its recognition of specific truncated fatty acid moieties部分and oxidized phosphatidylcholine磷脂酰胆碱. Consistent with this observation is the atheroprotection observed in hyperlipidemic mice that are deficient in CD36
The bioactive lipids from oxidized LDL that are internalized by CD36 activate nuclear receptors such as peroxisome proliferator-activated receptor γ to initiate transcriptional programs to up-regulate CD36 expression, as well as the expression of other genes involved in lipid metabolism. CD36 is also a direct signaling molecule; it initiates key signaling cascades.
In their recent study, Park et al. described a new role for CD36: a regulator of cellular mobility. Intimal macrophage trapping leads to lesion progression, whereas macrophage removal from the intima promotes healing (Fig. 1). Macrophage movement involves the formation of lamellipodia (a cytoskeletal projection of intracellular actin), the breaking of existing cell focal adhesive contacts, and the establishment of new contacts. These processes in turn depend on the dynamic control of both the actin cytoskeleton and focal adhesions. Park et al. found that CD36 signaling by oxidized LDL (but not LDL) promotes cellular actin polymerization and “cements” adhesions, thus trapping foam-cell macrophages within lesions. They found that CD36 signaling triggers this cellular immobilization through the generation of reactive oxygen species (ROS), which indirectly activate a focal adhesion kinase that in turn leads to an increase in the level of actin polymerization.
An imbalance between the synthesis of ROS and antioxidants is described as oxidative stress. The production of ROS in the body is countered by several antioxidative mechanisms. The first mechanism is at the level of production itself. NADPH oxidase is the enzyme responsible for ROS production, and inhibition of this enzyme represents an attractive therapeutic target for the treatment of many diseases. A second approach lies in an armory of antioxidants, albeit one that is sometimes insufficient to counter the effects of ROS.
Park et al. used two NADPH oxidase inhibitors, apocynin and diphenyleneiodonium, and therapeutic doses of the antioxidants N-acetylcysteine and resveratrol to inhibit the production of ROS by macrophages in vitro. A subsequent restoration of cell migration in the presence of oxidized LDL allowed foam cells to break the focal adhesions needed for spreading. The antioxidants used by Park et al., in addition to other antioxidants, may provide a therapeutic strategy for the treatment of atherosclerosis by relieving macrophage foam-cell adhesion and spreading ithin the intima. Such a reversal of macrophage immobility would permit the foam-cell movement necessary for cellular egress and lesion regression.

展开更多......

收起↑