Intravascular hemolysis increases atherogenicity of diet-induced hypercholesterolemia in rabbits in spite of heme oxygenase-1 gene and protein induction.
Free radical mediated oxidation of apoB lipoproteins in the arterial intima appears to contribute to atherogenicity of the entrapped particles. A plausible pathogenic mechanism for oxidation is the one induced by heme leaking from erythrocytes that is then carried into the arterial wall by its high affinity for lipoproteins. In the intima, in the presence of H(2)O(2) secreted by macrophages, heme can be a potent oxidant. To study the role of heme as a promoter of oxidative stress damage in vivo we used a model of intravascular hemolysis (IVH) caused by phenylhydrazine in rabbits with and without diet-induced moderate hypercholesterolemia (MHC). Evaluation of the antioxidant status of plasma indicated that at the end of the treatment period this was compromised by the MHC-IVH. After 10 weeks the animals with combined MHC-IVH showed more of the aorta surface covered by lesions (27%+/-8, mean (SD) than the animals with only MHC (11%+/-7), in spite of having similar plasma levels of VLDL+LDL lipoproteins. The animals with only IVH, as well as the controls, showed minimal lesions (<1%). Heme oxygenase (HO-1) expression in aorta and other tissues was markedly increased in the group with MHC-IVH and it was correlated with the extent of IVH. The data suggest that the oxidative stress associated with IVH potentiates the atherogenicity of moderate hypercholesterolemia and that in spite of a strong induction of HO-1 this is not sufficient to counteract the atherogenicity of the combined condition.
Fernandez
A Z
AZ
Laboratorio de Trombosis Experimental, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela.
López
F
F
Tablante
A
A
Romano
E
E
Hurt-Camejo
E
E
Camejo
G
G
Apitz-Castro
R
R
D000818:Animals; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004036:Diet, Atherogenic; D005786:Gene Expression Regulation; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000502:physiology; D051547:Heme Oxygenase-1; D006454:Hemoglobins / Q000032:analysis; D006461:Hemolysis / Q000187:drug effects / Q000502:physiology*; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications*; D008297:Male; D018384:Oxidative Stress; D010659:Phenylhydrazines / Q000494:pharmacology; D011817:Rabbits
D006454:Hemoglobins; D010659:Phenylhydrazines; C030299:phenylhydrazine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1