Enhanced atherosclerosis and kidney dysfunction in eNOS(-)/(-)Apo(-)/(-) mice are ameliorated by enalapril treatment

Hypertension and atherosclerosis are each important causes of morbidity and mortality in the developed world. We have investigated the interaction bet ween these conditions by breeding mice that are atherosclerotic due to lack of apolipoprotein (apo) E with mice that are hypertensive due to lack of e ndothelial nitric oxide synthase (eNOS). The doubly deficient mice (nnee) h ave higher blood pressure (BP) and increased atherosclerotic lesion size bu t no change in plasma lipoprotein profiles compared with normotensive but a therosclerotic (NNee) mice. The nnee mice also develop kidney damage, evide nced by increased plasma creatinine, decreased kidney weight/body weight ra tio, and glomerular lipid deposition and calcification. Enalapril treatment abolishes the deleterious effects of eNOS deficiency on BP, atherosclerosi s, and kidney dysfunction in nnee mice. In striking contrast, a genetic lac k of inducible NOS, which does not affect BP, has no effect on the developm ent of atherosclerotic lesions in Apoe(-/-) mice. We also observed a positi ve relationship between BP and size of atherosclerotic lesions. These resul ts suggest that the atherogenic effects of eNOS deficiency can be partially explained by an increase in BP and reemphasize the importance of controlli ng hypertension in preventing atherosclerosis.