Biological relevance of inflammation and oxidative stress in the pathogenesis of arterial diseases

Abstract

Over the past three decades, age-adjusted rates of cardiovascular morbidity and mortality have fallen in the United States, but the prevalence of obesity and associated metabolic disorders has risen dramatically. Recent studies have begun to unravel the complex linkages between adipose and vascular tissues that may accelerate the development of atherosclerosis in the context of obesity. Experimental models indicate that inflammation and oxidative stress, which mutually amplify each other within the vasculature and in visceral fat, are key processes that drive the initiation, progression, and subsequent rupture of the atherosclerotic lesion. Emerging research is further elucidating the contributions made by chemokines and their receptors, adipokines, and miRNAs to arterial disease. Translation of these basic science findings to clinical applications represents a tantalizing possibility for reducing the global burden of obesity-associated atherosclerosis and other cardiovascular diseases.

Figure 1

Mechanisms of disease in atherosclerosis and obesity. Pathophysiological processes within the vessel wall lead to the development of atherosclerosis and may be augmented by obesity-associated effects in adipose tissue. Atherosclerosis begins with the retention and oxidative modification of LDL, incorporation of oxidized LDL into burgeoning foam cells, triggering of a proinflammatory cascade, and subsequent proliferation of smooth muscle cells as the plaque progresses. Dendritic cells and T cells are drawn into the lumen by adhesion molecules and are incorporated into the atheroma. In obesity, macrophages are recruited and infiltrate adipose tissue, which can result in the release of adipokines and generation of a proinflammatory state. Under these conditions, lipolysis can lead to increased release of nonesterified fatty acids and possibly also to insulin resistance. The resulting increase in oxidative stress, combined with the action of adipokines, exacerbates the vascular pro-oxidant and proinflammatory environment, worsens endothelial dysfunction and smooth muscle cell proliferation, and accelerates the atherosclerotic process.