Review Article
Cytokine Biomarkers, Endothelial Inflammation, and Atherosclerosis in the Metabolic Syndrome: Emerging Concepts

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Abstract

In recent years, an explosion of research related to the cellular and vascular accompaniments of the metabolic syndrome has generated intense interest and controversy. Attention has focused on the vascular endothelium, where heightened, low-grade inflammatory processes lead to a continuum of vascular insults ranging from early endothelial derangements to advanced atherosclerosis. Inflammatory biocytokines, such as C-reactive protein, have been speculated to be both markers and mediators of oxidative stress and endovascular toxicity. Adipocytokines originating from fatty tissue have reinforced the concept that fat is a metabolically active organ rather than inert tissue. To fully elucidate its complex pathogenetic mechanisms, further inquiry into the inflammatory components of the metabolic syndrome is warranted. Unraveling the role of emerging proinflammatory markers has the promising potential to shed light into the underlying pathophysiology of the epidemic of obesity and the metabolic syndrome and thus help devise effective therapies.

Section snippets

Endothelial Dysfunction and Atherosclerosis

The vascular endothelium is an anatomical barrier that protects the vessel from the potentially harmful consequences of toxic substances, helps to maintain vascular homeostasis and tone, regulates local cellular activity, and modulates hemostatic, inflammatory, and reparative responses to injurious agents. It is also an active interface between the circulating blood and the vessel wall. Heightened inflammation through elevated oxidative stress and endothelial dysfunction is thought to promote

Role of Adipose Tissue in Cardiometabolic Health

Obesity and the metabolic syndrome have greatly impacted the incidence and severity of cardiovascular complications. Central obesity, one of the components of metabolic syndrome, is a cardiometabolic risk factor associated with a state of chronic inflammation and coagulation. Dysregulation of pro- and antiinflammatory adipocytokine function and production is associated with visceral fat obesity and the metabolic syndrome, suggesting that inflammation may contribute to the development of the

Inflammatory Markers in the Metabolic Syndrome: Nontraditional Risk Factors

Inflammation is regarded as a contributor to morbidity in the closely related conditions of CVD, obesity, the metabolic syndrome, and type 2 diabetes and has been the focus of extensive research recently.18., 28. Inflammatory markers CRP, fibrinogen, the ILs, TNF-α, PAI-1, and serum amyloid A (SAA) have been included in the ever-expanding list of emerging or nontraditional risk factors for the atherosclerotic process29 (Table 2). They mirror oxidative stress and generation of free radicals that

To Screen or Not to Screen?

Although the field of emerging risk factors has seen rapid advances, the issue of using them for disease screening is controversial.41., 42. Because CVD and the metabolic syndrome are closely linked, any discussion of cardiac risk factors must necessarily overlap with the criteria designated for the metabolic syndrome. The traditional risk factors for CVD – positive family history, hypertension, diabetes, dyslipidemia, and smoking – explain a preponderant amount of morbidity and mortality,

C-Reactive Protein: Marker or Mediator?

CRP is a member of the pentraxin family, which consists of 5 noncovalently associated peptides surrounding a central core. It is an acute-phase reactant that is synthesized in the liver and activates the classical pathway of complement through the immune system. It is the best-known marker of inflammation and has been touted as an independent risk factor for CVD on the basis of recent studies. Various proinflammatory cytokines, such as TNF and IL-1 derived from vascular endothelium and adipose

Adiponectin

Adiponectin is produced by adipocytes and has remarkable properties that inhibit inflammation and enhance insulin sensitivity, glucose transport, and fatty acid oxidation. Low levels of adiponectin are found in subjects with diabetes and obesity, and correlate with insulin resistance and the future development of glucose intolerance and the metabolic syndrome. It has been shown to suppress endothelial dysfunction, lipid accumulation, smooth muscle proliferation and to inhibit atherosclerotic

Relationship Between CRP and the Adipocytokines

CRP is strongly associated with adipose-derived cytokines, including IL-6 and TNF-α.74., 75. These are likely to be elevated in obese insulin-resistant subjects, especially in those with upper-body fat deposition, but not generally in obese subjects who are insulin sensitive.55 In addition, several other markers of inflammation correlate with both insulin resistance and hyperinsulinemia. Because they are also elevated in obesity and in the presence of cardiovascular risk factors,50 they provide

Interleukin-6

IL-6 is a cytokine that is produced largely in omental fat. It seems to exert its metabolic actions through its actions both in the central nervous system (CNS) and on peripheral organs. It is released in response to stress and stimulation of the sympathetic nervous system. Several studies point to it being a central mediator of the inflammatory response, and it tends to correlate closely with CRP76., 77. and the presence of multiple features of the metabolic syndrome.78 It increases hepatic

Tumor Necrosis Factor-α

TNF-α is produced largely by adipose tissue and also by macrophages and endothelial cells. Its levels correlate with the amount of adipose tissue, and it has a role in modulating insulin sensitivity.80 It has been linked to the increase in insulin resistance seen with obesity,81 although a consistent correlation of TNF-α with BMI has not been conclusively demonstrated. Although it has been implicated in states of increased insulin resistance, passive immunization with antibodies to TNF-α does

Leptin

An important adipocytokine that acts directly on the hypothalamus, and it regulates food intake and energy expenditure. Hypoleptinemia has been linked to weight gain, fat deposition in organs, such as the liver, muscle, and pancreatic islets, clinical features of the metabolic syndrome, and a general proinflammatory state.82 Leptin is secreted by adipocytes and binds to receptors in the CNS, where it suppresses appetite and decreases food intake. In the peripheral tissues, it enhances insulin

Resistin

Additional research has unveiled another adipocyte-derived cytokine, resistin, that is elevated in obesity and impaired glucose tolerance. It seems to be correlated with markers of inflammation and to be predictive of coronary atherosclerosis and type 2 diabetes in humans. However, its role in the genesis and pathophysiology of the metabolic syndrome remains to be fully elucidated. Plasma resistin levels are highly positively correlated with triglycerides, waist circumference, waist/hip ratio,

A Unifying Hypothesis

A mechanistic pathway linking the conventional and nontraditional risk factors in the pathophysiology of the metabolic syndrome is illustrated in Figure 2. On the basis of research done thus far, the inflammatory cytokines are critical in affecting the balance of endothelial health: obesity, insulin resistance, stress, presence of the metabolic syndrome components, and other acute or chronic insults tend to tilt the balance toward a more proinflammatory picture and lead to an environment

Should the Inflammatory Markers Be Used in Screening for Health Risk and as Therapeutic Targets?

There is currently no consensus in using the markers of inflammation as screening tools or as risk factors to be targeted. This area seems to be embroiled in controversy and confusion,41 although some recommendations have been put forth.31 The argument for testing of individuals at moderate risk for CVD is based on further stratifying their risk status and assisting in clinical management. On the other hand, some contend that the role of these acute-phase reactants in disease causation is not

CONCLUSION

The phenomenal increase in the prevalence of obesity and the metabolic syndrome has accentuated the various clinical manifestations and pathopysiologic underpinnings of this epidemic. Although the major pathophysiologic mechanisms are still in the process of being elucidated, the possible role of inflammation, cytokines, and atherogenic markers in the metabolic syndrome has received attention lately. Taken together, these abnormalities shift the balance of endothelial function toward an

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