脂代谢紊乱与动脉粥样硬化
Cardiovascular disease is the leading cause of death among adults worldwide (1996)
Coronary disease 7.2 million
Cancer 6.3
Cerebrovascular disease 4.6
Acute lower respiratory tract infections 3.9
Tuberculosis 3.0
COPD (chronic obstructive pulmonary disease) 2.9
Diarrhea (including dysentery) 2.5
Malaria 2.1
AIDS 1.5
Hepatitis B 1.2
Coronary mortality: alarming worldwide forecasts
Atherosclerosis: a multifactorial disease
Main risk factors for coronary heart disease
Global projections for the diabetes epidemic: 1995-2010
Atherosclerosis
Arterial wall: structure and function
Different stages of atherosclerotic plaque development
Vascular endothelium modification in atherosclerosis
Plaque formation 1 — Fatty streak
Plaque formation 2 — Fibrous cap
Plaque formation 3 — Lipid core
From plaque to thrombosis, key event: plaque rupture
Lipid core constitution Activated macrophages accumulate lipids
Lipid core constitution LDL oxidation
Parietal vascular inflammation The activated macrophage produces inflammatory cytokines
Parietal vascular inflammation NFkB action in the inflammation process
Diabetes and atherosclerosis
Tobacco and atherosclerosis
Dyslipidemia and atherosclerosis
HTN, hemodynamic factor and atheroclerosis
How to reduce plaque formation Intervention on risk factors
How to reduce the risk of plaque rupture
How to reduce the risk of thrombosis
~10% Weight loss = ~30% Visceral adipose tissue loss
Characteristics of an unstable plaque
Plaque vulnerability factors Intrinsic factors
Modification of extrinsic vulnerability factors
Plaque rupture The main releasing factors
Classification of lipids and lipoproteins
Characteristics of lipoproteins
Triglyceride-rich lipoproteins: size, structure and composition
Digestion and metabolism of dietary fat
HDL metabolism and reverse cholesterol transport
Cholesterol efflux and reverse cholesterol transport is modulated by two receptors
Atherogenicity of small dense LDL
Size and apolipoprotein composition are the main factors determining atherogenicity of triglyceride-rich particles
Size and apolipoprotein composition are the main factors determining atherogenicity of triglyceride-rich particles
Apo C-III modulates VLDL
Apo C-III in apo B particles is atherogenic
Relationship between apo C-III in apo B containing lipoproteins and atherogenicity
PROCAM Study MI-Incidence according to LDL-cholesterol and triglycerides
PROCAM Study CHD risk according to LDL-C and TG increased TG confers raised CHD risk at all levels of LDL-C
HDL: an anti-atherogenic lipoprotein
HDL metabolism: 5 key genes
HDL: apo AI-rich particles
Apo A-I protects against atherosclerosis
Apo A-II protects against atherosclerosis The human apo A-II transgenic mouse model
Genes and environment in type 2 diabetes and atherosclerosis
Pima Indians Thrifty genes
Aboriginal Canadians Oji-Cree
Obesity, type 2 diabetes, atherosclerosis
The Metabolic Syndrome
Visceral obesity is associated with a cluster of metabolic abnormalities
The atherogenic triad
PROCAM Study: MI-Incidence according to LDL-cholesterol and triglycerides
70% of men with CHD had a low HDL ≤44mg/dL Framingham Male Offspring 35-54
Obesity, type 2 diabetes, lipid metabolism The key role of the transcriptional factors PPARs
PPARa discovery elucidates mechanism of action of fibrates
The different PPAR subtypes
PPARa: a transcription factor
PPARa: transcriptional activation in two stages
PPARa: transcriptional activation in two stages
Transcriptional activation by PPARa
PPARs: regulation of lipoprotein metabolism by PPARa
PPARa activators lower small dense LDL
An apolipoprotein identified
Plasma triglyceride and cholesterol levels for human apo A-V transgenic mice
Plasma triglyceride and cholesterol levels for apo A-V knockout mice
Allele frequencies for SNP 3 according to plasma triglyceride levels
PPARa activators induce apo A-V gene expression
PPARa activates human apo A-V transcription through two PPREs
PPARa: apo A-l, apo A-ll, LPL, ABCA-1 and SR-BI expression
PPARa activators induce ABCA-1 gene expression in human macrophages
PPARa activators induce cholesterol efflux from human macrophages
CLA-1/SR-BI protein may promote cholesterol removal from peripheral cells
CLA-1 expression is regulated by PPARa activators in differentiated human macrophages
PPARa activators induce cholesterol efflux and reverse cholesterol transport
PPARs in the vascular wall
Mechanisms of transrepression by PPARa
The transcription factor NFkB: a key role in the inflammatory response
Model of NFkB signal pathway inhibition by PPARa activators
PPARa activated by fibrates inhibits IL-1b induced expression of COX-2 in SMC
Fenofibrate reduces plasma IL-6 in patients with CAD
Fenofibrate lowers plasma CRP in patients with CAD
PPARa activators reduce adhesion molecule production by interfering with NFkB
PPAR activators reduce endothelin-1 production by interfering with AP-1 transcription factor
PPARa activators inhibit thrombin induced ET-1 secretion in human macro- and microvascular endothelial cells
PPARa activators reduce tissue factor production by interfering with NFkB and AP-1 transcription factors
PPARa activated by fibrates negatively regulates fibrinogen-b expression
Statins Molecular mechanisms of action SREBP feedback control
SREBP* regulates the LDL receptor Three-step activation process
Common properties of PPARa activators and statins Parietal vascular effects
Statins and PPARa activators, similar effects Similar effector, PPARa?
Statins induce PPARa activity
Human apo A-I mRNA is induced by statins in a dose-dependent manner
Statins act on apo A-I mRNA expression at the transcriptional level Inhibition by actinomycin D
Statin effect on apo A-I synthesis is related to its mode of action Inhibition by mevalonate
Statins and PPARa activators increase human apo A-I gene expression
Simvastatic acid reduces induced LPS MMP9 secretion
Parietal vascular effects of statins (1) Endothelial cells
Parietal vascular effects of statins (2) Monocytes, macrophages
PPARa activators act on the main factors involved in the onset of atherosclerosis
VA-HIT
VA-HIT cont
DAIS
DAIS cont
HHS
HHS cont
4S
4S cont
CARE
CARE cont
WOSCOPS
WOSCOPS cont
LIPID
LIPID cont
AFCAPS/TexCAPS
AFCAPS/TexCAPS cont
AVERT
AVERT cont
HPS
HPS cont
NCEP guidelines
NCEP guidelines cont
NCEP guidelines cont
NCEP guidelines cont
AHA/ACC guidelines
ADA guidelines
ADA guidelines cont
Lipid management for primary prevention of CHD in adults – ILIB recommendations
Lipid management for secondary prevention of CHD in adults – ILIB recommendations
Lipid management for secondary prevention of CHD in adults with diabetes mellitus – ILIB recommendations
Abbreviations list
AS Atherosclerosis
BL Baseline
BMI Body Mass Index
BP Blood Pressure
CABG Coronary Artery Bypass Graft
CAD Coronary Artery Disease
CARE Cholesterol and Recurrent Events
CE Cholesterol Ester
CERP Cholesterol Efflux Regulatory Protein
CETP Cholesterol Ester Transfer Protein
CHD Coronary Heart Disease
CHF Congestive Heart Failure
Chol Cholesterol
COX-2 Cyclo-oxygenase-2
C