Abstract
Metabolic syndrome is associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathy, and elevated inflammatory status. To determine whether metabolic syndrome-associated elevation of the inflammatory cytokine interleukin-18 (IL-18) in serum and cardiac tissue, and its potential sequelae could be attenuated pharmacologically, we studied fructose-fed rats. The fructose-fed rats exhibited increases in systolic blood pressure (SBP), body weight, heart weight, left ventricular weight, and blood insulin. Serum IL-18 levels in these rats were also elevated significantly. These changes were significantly different compared to those in control rats. Perivascular fibrosis around coronary arterioles was evident in the fructose-fed rats, accompanied by a paralleled increase in IL-18 by immunohistochemical analysis and real time polymerase chain reaction. Felodipine attenuated the increased levels in serum IL-18 and cardiac IL-18 mRNA as well as coronary perivascular fibrosis. Thus, augmented IL-18 in serum and cardiac tissue in metabolic syndrome may contribute to the coronary perivascular fibrosis; felodipine administration can attenuate the inflammatory and fibrosis process.
Highlights
Accelerated coronary atherosclerosis contributes to the increased mortality associated with metabolic syndrome [1,2], a cluster of metabolic disorders including central adiposity, insulin resistance, hypertension, dyslipidemia, and proinflammatory state [3,4,5]
Inflammation and activated innate immunity are thought to play an important role in the development of atherosclerosis and diabetes, which may represent a unifying link between metabolic syndrome, type 2 diabetes, and cardiovascular disease [10,11,12]
Several cross-sectional studies have shown that acute-phase reactants such as C-reactive protein (CRP), and cytokines such as IL-6 and tumor necrosis factor-α are associated with features of the metabolic syndrome such as body mass index, measures of insulin resistance, hypertension, and dyslipidemia [35,36,37,38]
Summary
Accelerated coronary atherosclerosis contributes to the increased mortality associated with metabolic syndrome [1,2], a cluster of metabolic disorders including central adiposity, insulin resistance, hypertension, dyslipidemia, and proinflammatory state [3,4,5]. These coronary microvascular changes are common, often preceded by obesity and insulin resistance [6], which are considered the most prominent pathogenic changes underlying metabolic syndrome [7,8]. Activated innate immunity and chronic inflammation have been causally implicated in metabolic syndrome-associated atherogenesis [10,11,12]. Interleukin-18 (IL-18), a member of the IL-1 cytokine superfamily, is recognized as an important regulator of innate and acquired immune responses [13,14]. Prospective studies have shown an association of circulating IL-18 levels with cardiovascular death in patients with coronary artery disease [16,17]
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