Felodipine reduces cardiac expression of IL-18 and perivascular fibrosis in fructose-fed rats

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.

Figure 1

Body weight, heart weight, and left ventricular weight in the control (n = 12), fructose (n = 9), and felodipine (n = 9) groups. ^*P < 0.05, ^**P < 0.01 compared with the control group; ^§P < 0.05, ^§§P < 0.01 compared with the fructose group.

Figure 2

Fibrosis-to-lumen and fibrosis-to-wall ratios of coronary arteries in the control (n = 12), fructose (n = 9), and felodipine (n = 9) groups. Top, representative photograph of coronary arteries in control (A), fructose-fed rat (B), and felodipine-treated fructose-fed rat (C). ^*P < 0.05, ^**P < 0.01 compared with the control group; ^§P < 0.05, ^§§P < 0.01 compared with the fructose group. Bar = 50 μm.

Figure 3

Representative photographs of cardiac cross-sections stained immunohisto-chemically for IL-18. Sections were counterstained with hematoxylin to show nuclei in dark blue. A) IL-18 stain of cardiac tissue from control mouse. B) IL-18 stain of cardiac tissue from fructose-fed rat. C) IL-18 stain of cardiac tissue from fructose-fed rat treated with felodipine for 6 wks. D) Isotope IgG stain of cardiac tissue used as the primary antibody and as a control for comparison. Arrows indicate staining for IL-18. Bar = 50 μm. Bottom, results of quantitative image analysis for detection of IL-18 in the control (n = 12), fructose (n = 9), and felodipine (n = 9) groups. ^*P < 0.05, ^**P < 0.01 compared with the control group; ^§P < 0.05, ^§§P < 0.01 compared with the fructose group.

Figure 4

IL-18 mRNA in cardiac tissue in the control (n = 12), fructose (n = 9) and felodipine (n = 9) groups. ^*P < 0.05, ^**P < 0.01 compared with the control group; ^§P < 0.05, ^§§P < 0.01 compared with the fructose group.

Figure 5

The correlation between fibrosis-to-lumen ratio and serum IL-18 level (A) or IL-18 mRNA expression (B) in data taken from the fructose group (n = 9). The correlation between fibrosis-to-wall ratio and serum IL-18 level (C) or IL-18 mRNA expression (D) in data taken from the fructose group (n = 9).