ch 8, inflammation, cardiovascular disease and the metabolism syndrome

Ch 8, Inflammation, Cardiovascular Disease and the Metabolism Syndrome

Geng-Ruei Chang 2006.12.14

Metabolismsyndrome

Type 2 diabetes

Cardiovascular complication

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

(Hansson , 2005)

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

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.


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.

Role of monocytes in atherogenesis after inflammatory activation of endothelial cells

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.

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- pro-inflammatory cytokines (TH2).

Mechanism of leucocyte chemoattraction

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.

Mechanism of leucocyte activation in the intima

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.

Inflammation in atheroma progression and complication

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) .

Plaque disruption and discontinuous progression of atheroma

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.

Relation between inflammation and endothelial function in humans

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-, 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 LDL-cholesterol 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.


Two views of the role of acute-phase response in atherothrombosis:

Second, extravascular stimuli induce a chronic, low-level activation of the acute-phase response, which, over a long period, contributes to atherothromosis in persons predisposed to the formation of atheromas. Chronic, low-level 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.


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)

Is CRP mechanistically linked to atherosclerosis?

Proposed signaling pathways leading to statin-induced reduction of CRP release in hepatocytes

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.


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


CRP augmented ANG -Ⅱ induced vascular smooth muscle (VSM) cell migration and proliferation. In VSM cells, CRP increased basal ROS production and potentiated the effects of ANG on ROS formation.Ⅱ

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-, 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 insulin-stimulated glucose uptake.

Insulin resistance may also promote chronic inflammation. Insulin itself has potent acute anti-inflammatory 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 endothelial-dependent 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 activatinginflammatory 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 and ), complement factors (C1 q)and TNFa.Ⅷ Ⅹ

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--induced expression of VCAM-1, E-selectin, and ICAM-1 and suppressed the effect of TNF- 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 down-regulated.

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 age-adjusted 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 interventionsThe 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 ！

ch 8, inflammation, cardiovascular disease and the metabolism syndrome

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