RESUMO
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.
Assuntos
Arteriosclerose/fisiopatologia , Heme Oxigenase (Desciclizante)/genética , Hemólise/fisiologia , Hipercolesterolemia/complicações , Animais , Aorta/patologia , Arteriosclerose/etiologia , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Dieta Aterogênica , Regulação da Expressão Gênica , Heme Oxigenase (Desciclizante)/fisiologia , Heme Oxigenase-1 , Hemoglobinas/análise , Hemólise/efeitos dos fármacos , Hipercolesterolemia/sangue , Masculino , Estresse Oxidativo , Fenil-Hidrazinas/farmacologia , CoelhosRESUMO
The development of atherosclerotic lesions can be described as a tissular response to deposition of apoB-100 containing lipoproteins (LpApoB) in the arterial intima. These particles that circulate in blood are the low-density lipoproteins (LDL), the very low and intermediate density lipoproteins (VLDL and IDL) and the Lp(a). To initiate the tissue response is critic that LpApoB are retained in the subendothelial space. This occurs by the interaction of specific positive segments of the apoB-100 with negative glycosaminoglycan chains of the proteoglycans of the intima extracellular matrix. The inflammatory response involve macrophages and other immuno-competent cells, smooth muscle cells and endothelial cells. The direct agents that induce this reaction appear to be products of hydrolytic and oxidative modifications of the phospholipids, triglycerides and sterols of the retained LpApoB. The enzymes that cause these modifications are secreted by arterial cells stimulated by pro-inflammatory cytokines. The sequence of LpApoB retention and modification in the extracellular matrix followed by proliferation and inflammation seems to be a cyclic process that leads to the chronic progress of atherosclerotic lesions. These concepts constitute the base of a new hypothesis to explain atherosclerosis: the "response to retention hypothesis".