Novel anti-inflammatory properties of the Na +/H + exchange inhibitor ethylisopropylamiloride result in attenuation of atherogenesis in apolipoprotein E-deficient mice

Abstract

Amiloride and related derivatives, such as ethylisopropylamiloride (EIPA), are Na +/H + exchange inhibitors that antagonize urokinase plasminogen activator (uPA) activity; however, their effect on the genesis of complex atherosclerotic lesions is unknown. Therefore, we sought to determine if (and how) EIPA reduces lesion formation in atherosclerosis-prone apoE-deficient (apoE −/−) mice. Eight-week-old male apoE −/− mice were fed an atherogenic diet with ( n=10) or without ( n=9) a continuous infusion of EIPA via a subcutaneous minipump (3 mg/kg/day) for 4 weeks. No significant differences were observed in the serum cholesterol levels, yet there was a 46% reduction in the en face aortic lesion size with EIPA treatment (control: 29.8±5.9% vs. EIPA: 16.1±4.8%; p<0.001), with a 41% reduction in the percentage of subendothelial area occupied by macrophages (control: 45.8±5% vs. EIPA: 27.2±3.2%; p<0.001). Both the number of VCAM-1-expressing aortic endothelial cells and the abundance of adherent monocytes, detected by scanning electron microscopy, were reduced in the EIPA-treated mice. These data demonstrate novel anti-inflammatory properties of EIPA that result in attenuation of atherogenesis.