Lecture 37: Pathogenesis of Atherosclerosis Flashcards
What is atherosclerosis?
Arterial INTIMAL disease of large-medium arteries characterized by lipid accumulation and inflammation
Space between endothelium and smooth muscle cell layer
Driven by lipid antigens and lipids
What is the time course of atherosclerosis?
Chronic Progressive Disease
Acute clinical manifestations
20 yo can have atherosclerosis present but doesn’t present until later on in life
What is the natural history of atherosclerosis?
- Fatty streaks
- Lipid rich
- Internal rupture that leads to accumulation of WBCs and RBCs
- Formation of calcified shell over lipid rich plaque
- formation of a SCAR, fibrous cap, calcified plaque
- Vulnerable to rupture if plaque is thin
- Rupture of fibrous cap
- After rupture, you get thrombus (platelets and fibrin come by to clot the rupture0
- Myocardial infarction if platelet and fibrin occludes the artery
- Obstructive where lipid/fibrin/SMC accumulation is so much that it obstructs the arteries
What is the first indication of atherosclerosis?
Fatty streaks
What are the clinical consequences of atherosclerosis?
- Coronary heart disease
- MI
- sudden death/heart failure
- Cerebro vascular disease like stroke and vascular dementia
- Peripheral artery disease
- Renal artery stenosis
What are the steps towards thrombosis and plaque rupture in atherosclerosis?
- Enothelial inflammation and dysfunction
- Oxidized modified lipoproteins
- Monocytes, macrophages, foam cells, T-cells
- Paracrine and endocrine signals
- Smooth muscle cells (ECM)
- Matrix proteolysis (MMPs/TIMPs) (plaque rupture
- Platelets driven thrombosis
How do monocytes contribute to atherosclerosis?
They differentiate into inflammatory macrophage once it travels to activated endothelium
Macrophages take up modified lipoproteins to form foam cells
How do SMCs contribute to atherosclerosis?
Migrate into intimal space and secrete ECM
Contributes to the BULK of the atherosclerotic lesion
Provides framework for cellular interactions
SMCs form the FIBROUS cap over the inflammatory sub-endothelial intimal lesion
As plaque evolves, it outgrows nutrient supply and induces neovascularization of the plaque from advential surface of disease vessel
How does MMPs and TIMPs contribute to atherosclerosis?
MMPs degrade the protective cap
The TIMPs are downregulated and thus cant inhibit MMP activity
Degradation of cap = more likely to rupture
What are the factors that leads to endothelial injury and dysfunction?
- Shear stress (HTN)
- Oxidant stress (smoking)
- diet and physical inactivity
- excess and modified lipoproteins
- diabetes (glycation)
- Adipocytokines (endocrine and paracrine)
- Infection (CMV, HSV, Chlamydia, gut flora)
- Genes can lead to injury susceptibility
What are the consequences of mechanosignal transduction and hypercholesterolemia for the endothelium?
They induce endothelial cell dysfunction that promotes inflammation and fatty streak formation
Occurs in the intimal stage
Turbulent flow is more likely during a state of HTN
What does turbulent flow do the endothelium?
Activates ICAM-1 and VCAM receptors
Leads to growth factors and chemokine secretion
Recruits monocytes into the vascular wall (via selectins and integrin ligands)
Monocytes then differentiate into inflamed macrophages that will turn into foam cells once it takes up oxidized LDL
What are the hallmarks of dysfunctional endothelium?
- increase of superoxide and peroxynitrite
- Increased adhesion molecules and cytokines
- reduced NO and prostacyclin
- Reduced endothelium dependent vasodilation
What are the endothelial adhesion molecules?
- VCAM-1
- ICAM-1
- E-selectin
What is responsible for chemotaxis of monocytes?
- CCR2/MCP-1 receptor/chemokine
- CX3CR1/CX3CL1
- CCR5/CCL5
What is the significance of lipid entry into vascular wall?
As VLDL and LDL migrates through endothelium
Gets MODIFIED
-oxidized by iNOS, NADPH, 15-LO
-or acetylated
Activates macrophages which lead to inflammation
Oxidation/aggregation of modified lipids
What is the first step in atherosclerosis?
- infiltration of LDL from arterial lumen into the arterial wall and its entrapment therein
- Modification of LDL through
i. oxidation
ii. chemical derivation - Scavenger receptors on arterial wall macrophages recognized MOFIDIFIED LDL and internalize oxidized LDL through engulfment
- Uptake of LDL by macrophages leads to foam cell formation, the HALLMARK of the atherosclerotic lesion
How do you form the fatty streak?
Fatty streak = cholesterol rich foam cells and T cells
You form fatty streak when you get macrophages engulfing activated LDL (acetylated or oxidized)
T-cells are prominent in fatty streaks as wells
What is the hallmark of the atherosclerotic lesion?
Foam cell formation
What is scary about the scavenger receptors in relation to LDL uptake?
Molecules that induce atherosclerosis
Example: LDL, VLDL (especially beta-VLDL)
What is the importance of LDL modification in foam cell formation?
Native LDLreceptor is downregulated and doesn’t get taken up fast
However, modified LDL through
i. acetylation
ii. Oxidation
Get taken up much faster by scavenger receptors on macrophages which are NOT downregualted
Examples of scavenger receptors that take up acetylated and oxidated LDL:
i. SRA
ii. CD36
What is the significance of foam cell formation?
Foam cells are the cellular lipid reservoir responsible for chronically driving inflammation while accelerating atherosclerosis progression
What are the athrogenic actions of oxidized LDL and oxidized phospholipids?
- Induce monocyte/T-cell binding to endothelial cells
- Increase tissue factor activity
- Increase expression of MCSF and MCP-1
- Increase expression of VCAM-1
- Induce Fas-mediated apoptosis
- Alter NO release or function
- Increase collagen synthesis of SMCs
- Activate nuclear factor kappabeta
- Induce expression of type 1 metalloproteinase
- Activate gene expression for PPARgamma, CD36 and ABCA1
How are fatty streaks induced?
- Hypercholesterolemia and mechanosignal transduction in EC
- Adherence of monocytes and Tcells to arterial endothelium
- Monocyte and T cell transendothelial migration
- Phenotypic modulation of scavenger receptor expression and modified LDL
- Fatty streak rich in cholesterol-rich foam cells and T cells
How do LDLs get modified?
Inflammatory enzymes are present in endothelium
Enzymes like myeloperoxidase will modify LDL (modified lipids)
What is the role of T lymphocytes in the atherosclerotic lesions?
Are present in atherosclerotic lesions
CD3, CD4 and AbTCR T cells are prominent in lesiosn
Moderate numbers of CD8 and some NK cells
TH1 cells are dominant, expressing high levels of IFN
What is the role of TH1 lymphcytes in atherosclerosis?
Lesion initiation, progression and instability plaque rupture
Releases IFNgamma to stimulate macrophages
Macrophages then release IL-12 to produce TH1 cells
Positive feedback
What are the proposed roles of HDL on atherosclerosis?
Anti-athrogenic
May inhibit oxidation of LDL
Reverse cholesterol transport
What is the role of MPO in atheroscler?
Oxidizes LDL to modify it
What is responsible for lesion progression?
- smooth muscle cells
- macrophages
- Endothelial cells
- fibrous cap
- T-cells
How do macrophages contribute to intermediate athero lesions?
Macrophages die and release lipids into necrotic core
They also secrete growth factors that lead to cell proliferation and metalloproteinases
What role do smooth muscle cells in the progression of the intermediate lesion?
Migrate and replicate to increase bulk of lesion
Secrete connective tissue matrix proteins
Secretes chemokines, cytokines and metalloproteinases that modulate dynamic remodeling of the lesion
Leads to:
i. switch from contractile to synthetic phenotype
ii. migrate into the neointima
iii. undergo limited proliferation
iv. secrete large amount of matrix
v. secrete cytokines, chemokines, growth factors and inflammatory prostaglandins
vi. migrate to subendothelial location at site of greatest hemodynamic stress
vii. encapsulates lesion by fibrous cap
viii. synthetic smooth muscle cells express scavenger receptors and can take up oxidized lipids to form subpopulation of non-macrophage foam cells
What is the significance of calcification in atherosclerotic lesions?
Useful screening test for prognosis
Calcium doesn’t do shit but is just formed
What is the role of T cells in progression of the intermediate lesion?
TH1 cells increase macrophage inflammation and increase metalloproteinases that degrade matrix and fibrous cap
-Reduces SmC proliferation
What is Glagov’s coronary remodeling hypothesis?
Plaque development is extraluminal until lesion occupies 40% of area
Only then does the lumen begin to shrink
Starts with compensatory expansion to maintain constant lumen (minimal/moderate CAD)
At severe CAD, compensatory expansion of the lumen is overcome and lumen narrows
What are the key characteristics of the intermediate lesion?
Subclinical and asymptomatic
Stage at which you are at risk for plaque rupture
Shoulder region
Less T-lymphocytes and more foam cells
What are the characteristics of a stable lesion?
Smooth muscle cells Fibrotic TGF-beta Thick cap around the lipid core (won’t release Lipids to lumen)
What are the characteristics of an unstable lesion?
Foam cells predominate
IFN-gamma
IL-18
IL-12 present
What are the characteristics of a “vulnerable plaque”?
Thin fibrous cap Low VSMC count Large lipid pool High oxLDL content and high macrophage count High T cell count Thin shoulder region Greater neovascularization Not related to degree of vessel stenosis
What are the overlapping mechanisms that may contribute to plaque instability?
- thrombus formation
- impaired endothelial function
- Inflammation
- Impaired plaque stabilization
(just having high BP one of these days)
How does the thombus form?
If the plaque ruptures
Platelets will aggregate at place
of the plaque lesion
What are the characteristic of obstructive disease?
Resolution of the thrombus then leads to obstructed artery
Healed prior plaque rupture is often silent
What may leads to the regression of atherosclerosis?
- Lower LDL-atherogenic lipoproteins (decrease influx)
- Increased HDL or HDL function (lipid efflux)
- Regulation of macrophages and plaque inflammation (macrophage egress)
What is atherosclerosis?
A. A mechanical disorder characterized by endothelial injury and hemodynamic stress
B. A lipoprotein disorder characterized by excess atherogenic lipoproteins, their modification and uptake into macrophage-foam cells
C. An inflammatory disorder of monocytes, macrophages, T cells and others
D. A vascular SMC disorder of migration, matrix secretion and fibrous cap
E. A thrombotic disorder of endothelial injury, tissue factor expression and platelet activation
