Blockade of endothelin receptors reduces diet-induced hypercholesterolemiaand atherosclerosis in apolipoprotein E-deficient mice

Objective: Endothelin (ET)-1 has proatherogenic properties, since ET recept or antagonists reduce atherosclerotic lesions in animals. However, we recen tly demonstrated that ET-1 and ETB receptors are increased in atherosclerot ic lesions. To further examine the effects of ETB receptor antagonism on at herogenesis, we investigated the chronic effects of the nonselective ETA/ET B receptor antagonist SB209670 on the development of atherosclerosis in apo lipoprotein E (ApoE)-deficient mice. Methods: Ninety-four male mice (10 weeks of age) were randomly divided into four groups: mice fed a Western-type diet or a chow diet with SB209670 tre atment (10 mg/kg/day) or placebo for 12 weeks. Results: In mice fed the Western-type diet, but not in mice fed the chow di et, treatment with SB209670 significantly attenuated the increase in plasma total cholesterol, predominantly in the very-low-density lipoprotein and i ntermediate-density lipoprotein fractions, without altering the plasma trig lyceride level. Furthermore, treatment with SB209670 significantly reduced the extent of aortic atherosclerosis, by 53% in mice fed the Western-type d iet and by 38% in mice fed the chow diet. Histological analysis revealed th at SB209670 prevented the formation of atheromatous plaque lesions by inhib iting the fibroproliferative process. Conclusion: We found that chronic administration of SB209670 reduced diet-i nduced hypercholesterolemia and atherosclerosis in ApoE-deficient mice. Thu s, nonselective ET receptor antagonists may have a therapeutic potential in the treatment of human atherosclerotic disease. Copyright (C) 2001 S. Karg er AG, Basel.