Download Role of acute-phase response in atherosclerosis

Ch 8, Inflammation, Cardiovascular Disease
and the Metabolism Syndrome
Geng-Ruei Chang
2006.12.14
Cardiovascular
complication
Metabolism
syndrome
Type 2 diabetes
Relationships between obesity, diabetes and atherosclerosis.
Introduction
Atherosclerosis is now understood to be a disease
characterized by inflammation that results in a host of
complications, including ischemia, acute coronary
syndromes (unstable angina pectoris and myocardial
infarction), and stroke.
The chronic inflammatory process involving the arterial
endothelium that ultimately results in the complications of
atherosclerosis may be caused by a response to the
oxidative components of modified low-density lipoprotein
(LDL), or to chronic infection, free radicals, or other
factors.
The association of inflammation with the initiation and
progression of atherosclerosis suggests that markers of
inflammation, eg, acute phase reactants such as C-reactive
protein (CRP), may be useful in predicting an increased
risk of coronary heart disease (CHD).
Introduction
There is accumulating evidence that inflammation is
an important risk factor in cardiovascular disease
(CVD).
The metabolic syndrome as a cluster of risk factors
for CVD, characterized by insulin resistance, visceral
adiposity, low high-density lipoprotein (HDL)cholesterol and a systemic pro-inflammatory state, is
a major cause of premature death.
Atherosclerosis is to a large extent driven by the
cytokine/growth factor crosstalk between endothelial
cells, macrophages and vascular smooth muscle cells..
Introduction
In the USA the meatbolic syndrome affects roughly
25 per cent of adults over the age of 20 years and up
to 45 per cent of the population aged over 50 years.
Drugs exerting anti-inflammatory and vascular
effects have future potential to be used within an
array of interventions aimed at reducing the
enormous cardiovascular burden associated with the
metabolic syndrome.
Introduction
Mortality from coronary heart disease (CHD), CVD and other
causes is greater in persons with diabetes and pre-existing
CVD. (Table 8.1)
Chronic inflammation results in endothelial dysfunction and
facilitates the interactions between modified lipoproteins,
monocyte-derived macrophages, T cells and normal cellular
elements of the arterial wall, inciting early and late
atherosclerotic processes (It is initiated by endothelial
dysfunction in which a particularly important role is played by
the nitric oxide (the bioavailability of NO is impaired by the
superoxide radical).
Evaluating inflammatory markers of atherosclerosis, of which
high-sensitivity C-reactive protein (CRP) has emerged as one
of the most important.
Metabolic syndrome is associated with an
increased risk of death from CHD, CVD or other
causes in US adults.
Role of inflammation in atherosclerosis
High plasma concentrations of cholesterol, particularly
those of low-density lipoprotein (LDL)-cholesterol, are
one of the principal risk factors for atherosclerosis.
The process of atherosclerosis previously has been
considered largely to reflect an accumulation of lipids
within the artery wall.
The current notion that inflammation and immune
response contribute to atherosclerosis.
Inflammation and the initiation of
atherosclerosis
Panel A shows a cross-sectioned coronary artery from a patient who died of a
massive myocardial infarction.
Panel B is a high-power micrograph of the area in Panel A indicated by the
asterisk and shows that the contents of the atheromatous plaque have seeped
through the gap in the cap into the lumen, suggesting that plaque rupture preceded
thrombosis
(Hansson , 2005)
Activating Effect of LDL Infiltration on
Inflammation in the Artery.
(Hansson , 2005)
Inflammation and the initiation of atherosclerosis.
Panel C illustrates the consequences of the activation of immune cells in a
coronary plaque.
Inflammation and the initiation of atherosclerosis.
Oxidized LDL stimulates the vascular endothelial cells to produce
adhesion molecules (i.e., E-selectin, P-selectin, VCAM-1, and ICAM-1)
and chemotactic proteins such as MCP-1.
Inflammation and the initiation of atherosclerosis.
Role of monocytes in atherogenesis after
inflammatory activation of endothelial cells
Endogenous anti-inflammation pathways and
atherosclerosis.
Many such atheroprotective genes may modulate
inflammation, for example, superoxide dismutase,
expressed in regions of laminar flow, may combat
oxidative stress and hence limit VCAM-1 expression
and other inflammatory pathways.
NO can inhibit VCAM gene expression through a
novel pathway involving inhibition of the activation
of NF-kB.
Endogenous anti-inflammation pathways and
atherosclerosis.
Endogenous anti-inflammation pathways and
atherosclerosis.
Mechanism of leucocyte chemoattraction
MCP-1, can recruit the monocyte that
characteristically accumulate in the nascent atheroma.
Mice lacking MCP-1 or its receptor CCR2, and
susceptible to atherosclerosis owing to the absence of
genes encoding apoE or the LDL receptor, has shown
decreases in mononuclear phagocyte accumulation
and local lipid levels.
Mechanism of leucocyte chemoattraction
Chemoattractants include IFN-γ-inducible
chemokines of the CXC family, including inducible
protein-10 (IP-10) , monokike induced by IFN-r
(Mig) and IFN-inducible T-cell a-chemoattractant
(I-TAC) that bind to chemokine receptor CXCR3
expressed by T cells in the atherosclerotic lesion.
Within the atheroma, as in other tissues, the T
helper cells can polarize into those secreting
generally pro-inflammatory cytokines (TH1 cells)
and/or those secreting predominantly anti- proinflammatory cytokines (TH2).
Mechanism of leucocyte activation in the intima
Once resident in the arterial intima, monocyte
acquire the morphological characteristics of
macrophage, undergoing a series of changes that
lead ultimately to foam cell formation.
The monocytes increase expression of scavenger
receptors such as SRA and CD36, and then
internalize modified lipoproteins so that cholesteryl
esters accumulate in cytoplasmic droplets.
Foam cells is known as the early atherosclerotic
lesion.
Inflammation in atheroma progression and
complication
After formation of the initial lesion of atherosclerosis
(fatty streak), the nascent atheroma typically evolves
into a more complex lesion that eventually leads to
clinical manifestations.
Many coronary arterial lesions in humans develop
stenoses discontinously.
Plaque disruption and discontinuous progression
of atheroma
Current evidence suggests that physical disruption of
plaques may trigger thrombosis and thus promote sudden
expansion of atheromatous lesion.
Three types of physical disruption may occur: superficial
erosion, or microscopic areas of desquamation of
endothelial cells that form the monolayer covering the
intima; disruption of the microvessels that form in
atherosclerotic plaques; and fracture of the plaque’s
fibrous cap (most common mechanism causing about
three-quarters of the acute myocardial infarctions) .
Relation between inflammation and endothelial
function in humans
The vascular endothelium contributes to inflammatory
responses in the pathogenesis of atherosclerosis.
The Framingham Offspring Study tested the hypothesis
that inflammation impairs endothelial function by
assessing brachial artery flow-mediated dilation as a
measure of conduit artery vasodilator function, and
reactive hyperaemia as a measure of foream
microvascular vasodilator function, as well as serum
levels of CRP, IL-6, sICAM-1 and MCP-1.
Risk factors induce a state of inflammation that impairs
vascular function.
Role of acute-phase response in atherosclerosis
The acute-phase response is pro-coagulate, an innate body
defense seen during acute illness and involves the increased
production of certain blood proteins termed acute-phase
protein, such as CRP, that are produced by cells in the liver
and promote inflammation.
Activated macrophages and other leucocytes release
pro-inflammatory cytokines such as TNF-a, IL-1 and
IL-6 when their toll-like receptors bind pathogen-associated
molecular patterns.
Clotting is required for the formation of abscesses, for
walling-off invading microbes and delayed hepersensitivity .
Role of acute-phase response in atherosclerosis
Acute-phase mediators include fibrinogen, PAI-1 and
CRP, which stimulate the expression of tissue factor on
monocyte.
Two views of the role of acute-phase response in
atherothrombosis:
First holds that acute-phase response is activated by
ongoing intra-arterial inflammation. Oxidized LDLcholesterol and LDL-phospholipids provokes macrophages
and smooth-muscle cells within atheromas to make CRP
and to release IL-6 and other mediators, which induce the
production by the liver of CRP and others.
Role of acute-phase response in atherosclerosis
Two views of the role of acute-phase response in
atherothrombosis:
Second, extravascular stimuli induce a chronic, lowlevel activation of the acute-phase response, which, over a
long period, contributes to atherothromosis in persons
predisposed to the formation of atheromas. Chronic, lowlevel activators of the acute-phase response include smoking,
smouldering mucosal infections such as bronchitis, gastritis
or periodontitis, and non- inflammatory conditions such as
aging and obesity.
Is CRP mechanistically linked to atherosclerosis?
Recent clinical trials showed that C-reactive protein (CRP) is
a powerful independent predictor of future cardiovascular
events. Moreover, CRP accelerates the progression of
atherosclerosis in apolipoprotein E-deficient mice.
CRP, the major acute-phase reactant in humans, is mainly
produced by hepatocytes in response to interleukin-6 (IL-6)
Proposed signaling pathways leading to statininduced reduction of CRP release in hepatocytes
Is CRP mechanistically linked to atherosclerosis?
Evidence for the pro-atherogenic role of CRP is further
provided by in vitro studies reporting that CRP modulates
the activity and expression of multiple factors implicated in
atherogenesis.
CRP downregulates endothelial nitric oxide synthase (eNOS),
resulting in decreased release of NO, and thus facilitation of
endothelial cells apoptosis and inhibition of angiogenesis .
In addition, CRP stimulates the production of the
vasoconstrictor endothelin-1 (ET-1) and the inflammatory
marker IL-6 by endothelial cells.
Is CRP mechanistically linked to atherosclerosis?
Furthermore, CRP increases the expression of NF-kB,
vascular cell adhesion molecule-1 (VCAM-1), intercellular
adhesion molecule-1 (ICAM-1), E-selectin and monocyte
chemoattractant protein-1 (MCP-1). Moreover, it has been
shown that CRP itself is a potent chemoattractant for
monocytes and facilitates the uptake of LDL by macrophages.
In smooth muscle cells (SMCs), CRP upregulates
angiotensin type 1 receptor and stimulates SMCs migration,
proliferation and reactive oxygen species production.
CRP Physiology
Is CRP mechanistically linked to
atherosclerosis?
CRP augmented ANGⅡ-induced vascular smooth
muscle (VSM) cell migration and proliferation. In
VSM cells, CRP increased basal ROS production
and potentiated the effects of ANGⅡon ROS
formation.
Endothelial progenitor cells (EPCs, for
neovascularization) incubated with human
recombinant (hr) CRP inhibit EPC differentiation.
Inflammatory markers as predictors of
cardiovascular disease
Traditionally, CVD risk prediction algorithms have
primarily focused on diabetes, hypertension,
smoking, and hyperlipidaemia.
Framingham Heart Study………… Levels of CRP
of <1, 1-3 and >3 mg/l have been defined as lower,
moderate and higher CVD risk.
Available inflammatory markers CRP appears to be
the strongest and most consistent predictor of CHD.
Predictive value of CRP in relation to
Framingham Risk Score
Five major prospective studies have demonstrated that
hsCRP adds prognostic information on cardiovascular
risk beyond that available using the Framingham Risk
Score aloe : Physicians’ Health Study, Women’s Health
Study, Atherosclerosis Risk in Communities
Study. ……………………..
Predictive value of CRP in relation to
Framingham Risk Score
Novel circulating markers of low-grade vascular
inflammation, high-sensitivity CRP (hsCRP) has attained
most attraction and has been evaluated most extensively.
However, a predictor of CVD, hsCRP levels do not track
closely with subclinical atherosclerosis, as measured by
cardiac catheterization, intimal-mediated thickness, the
ankle-brachial index or coronary calcification.
Predictive value of CRP in relation to the
metabolic syndrome
Measuring CRP would also add prognostic
information as an additional clinical criterion in the
context of the metabolic syndrome. Data to
support………………….
In WOSCOPS, CRP levels above and below 3 mg/l
at basekine were predictive of incident vascular
events after stratification by the presence or absence
of the CRP and the metabolic syndrome.
Predictive value of CRP in relation to the
metabolic syndrome
In the Framingham Offspring Study, both CRP and
the metabolic syndrome were independent predictors
of new CVD events.
CRP and the metabolic syndrome havesimilar
discriminatory ability with respect to subsequent CVD
risk, combining these variables adds little to overall
risk prediction and therefore further research should
aim at establishing whether such combinations could
be useful in the risk assessment of individual patients.
The American Heart Foundation/Centers for Disease
Control and Prevention (AHA/DOC) recommendation
Against screening of the entire adult population for CRP as a
public health measure and an adjunct to the major risk factors to
assess further the absolute risk for CHD primary prevention.
A high relative risk levels of CRP ( > 3 mg/l ) may allow for
intensification of medical therapy to reduce further the risk and
to motivate some patients to improve their lifestyle or comply
with medications prescribed in order to reduce their risk.
CRP may be useful as an independent marker for assessing the
likelihood of recurrent events, including death, myocardial
infarction or re-stenosis after percutaneous coronary
intervention.
Inflammation and insulin resistance
Positive associations between components of the
metabolic syndrome and markers of inflammation and
endothelial dysfunction, including CRP, fibrinogen,
PAI-1, TNF-a, IL-6 and white blood cell count.
The CRP levels are associated with BMI, serum lipids,
fasting glucose and impaired glucose tolerance (IGT).
Mechanisms linking insulin resistance
and inflammation
Inflammatory cytokine, TNF-α was able to induce
insulin resistance via induced suppression of hepatic
glucose production, enhance hepatic production of
triglycerides and free fatty acids and inhibit insulinstimulated glucose uptake.
Insulin resistance may also promote chronic
inflammation. Insulin itself has potent acute antiinflammatory effects, including reductions in ROS
generation, MCP-1 and PAI-1, and also has effects on
hepatic protein synthesis, increasing albumin production
but suppressing acute-phase proteins.
Mechanisms linking insulin resistance
and inflammation
Thus, insulin resistance may result in increased
production of CRP, fibrinogen, other acute-phase
proteins and may lead directly to impaired endothelialdependent vasodilatation in response to acetylcholine,
and hyperinsulinaemia can increase the expression of
ICAM-1 and thereby facilitate macrophage
recrumitment into the endothelium.
Potential cellular mechanisms for activating
inflammatory signaling.
Obesity and high-fat diet activate IKKβ/NF-κB and JNK pathways
in adipocytes, hepatocytes, and associated macrophages.
Local, portal, and systemic effects of inflammation in
insulin resistance and antherogenesis.
Role of adiponectin
Adiponectin, also termed adipose most abundant gene
transcript 1(apM1), adipocyte complement related protein
of 30 kDa (Acrp30) , AdipoQ, or gelatine binding protein
28 kDa (GBP28).
Adiponectin is composed of an N-terminal signal sequence,
a variable domain, a collagen-like domain and C-terminal
globular domain, which structurally, adiponectin belongs to
the collagen superfamily sharing homologies with collagens
(type Ⅷ and Ⅹ), complement factors (C1 q)and TNFa.
Adiponectin levels correlate negatively with percentage
body fat, central fat distribution, fasting plasma insulin and
oral glucose tolerance and positively with glucose disposal
during euglycaemic in insulin clamp.
Role of adiponectin
Adiponectin exists in the circulation as a full-length
protein (fAD) as well as a putative proteolytic cleavage
fragment consisting of the globular C-terminal domain
(gAD), which may have enhanced potency.
Adiponectin on the vasculature have been
hypothesized to be associated with enhanced eNO
generation by endothelial cells. Consistent with this,
fAD similar to those found in the circulation have been
shown to enhanced NO production in cultured aortic
endothelial cess.
Furthermore, gAD enhanced NO production by
ameliorating the suppression of eNOS activity by
oxidized.
Structure of adiponectin receptors.
AdipoR1 and AdipoR2 (66.7% amino acid identity with AdipoR1) are predicted to
contain 7 transmembrane domains but are structurally and topologically distinct
from GPCRs.
Adiponectin for insulin resistance, the metabolic
syndrome, and atherosclerosis.
Anti-inflammatory effects of adiponectin
Adiponectin (fAD) inhibited TNF-a-induced
expression of VCAM-1, E-selectin, and ICAM-1 and
suppressed the effect of TNF-a to induce the
adhesion of monocytic THP-1 cells to cultured
endothelial cells.
The reduced circulating levels of adiponection in
visceral adiposity are now known to contribute not
only to insulin resistance and dysglycaemia but also
to the endothelial vascular dysfunction that is
characteristic of the metabolic syndrome.
Role of PPAR
PPAR-γ is expressed in the vascular endothelium, macrophages,
vascular smooth muscle cells and atherosclerotic lesions.
C/EBPs enhance the transcription of various inflammatory
cytokines, including IL-1, IL-6 and TNF-α. The promoter region of
the PPAR-γgene contains repeated C/EBP binding motifs and the
interaction of PPAR—γ and C/EBP is know to be important in
regulating adipocyte differentiation but also appears to be involved
in the control of vascular inflammation.
Thus, PPAR-r appears to provide a feedback mechanism in
vascular tissue through which inflammatory process can be downregulated.
PPAR-γsignaling.
Inflammatory markers as predictors of the
metabolic syndrome and its components
To date at least 15 studies have been published (Table
8.3).
Low adiponectin levels predict an increase incidence of
type 2 diabetes (Table 8.4).
Table 8.3 (cont.)
Inflammatory markers as predictors of the
metabolic syndrome and its components
In the KIHD study, men with CRP concentrations of >
3 mg/l vs those with < 1.0 mg/l had an increased ageadjusted risk of developing the metabolic
syndrome……
Thus, elevated CRP levels may increase the risk of the
metabolic syndrome in men but some of the risk is
mediated through obesity and factors related to insulin
resistance.
Lifestyle and drug interventions
The interaction between inflammation, insulin
resistance and atherosclerosis open up novel therapeutic
perspectives.
Lifestyle changes including weight loss, dietary
changes and increased leisure-time physical activity,
reduce the risk of type 2 diabetes by 58 per cent in
persons with IGT (Table 8.5).
Aspirin, Thiazolidinediones (TZDs), lifestyle
intervention (DPP, FDPS), ACE inhibitors (CAPPP,
HOPE, SOLVD), AT1 receptor blockers (LIFE,
SCOPE), statins (WOSCOPES) and glitazones
(TRIPOD)…………………
Q &A
Atherosclerosis的形成過程暨與
metabolic syndrome的關係？
Thanks for your attention！