N-acetylcysteine inhibits in vivo oxidation of native low-density lipoprotein.

Atherosclerosis is the most common cause of cardiovascular diseases like coronary artery disease (CAD) and stroke1. Hyperlipidemia is a major risk factor for the development of atherosclerosis. Although elevated low-density lipoprotein (LDL) is closely related to atherosclerosis, LDL itself is not atherogenic2,3. It is accepted that LDL oxidative modification with formation of oxidized LDL (ox-LDL) renders LDL atherogenic4,5,6. Indeed, after injection of unmodified human LDL to Sprague-Dawley rats, ox-LDL was detected in arterial endothelium7, suggesting that native LDL was converted to ox-LDL in vivo. Oxidative stress with reactive oxygen species (ROS) formation plays a critical role in atherosclerosis8,9,10,11,12,13. ROS generation in blood monocytes is increased in hyperlipidemic patients with elevated plasma ox-LDL10. Ox-LDL is a potent oxidative agent that produces a significant amount of ROS in vitro8, and increases intracellular ROS formation in cultured endothelial cells8,14,15. ROS formation from ox-LDL is partially responsible for the actions of ox-LDL on bone marrow stem cells8. N-acetylcysteine (NAC) inhibits the progression of atherosclerosis in apolipoprotein E-deficient mice16, decreases ROS generation and suppresses foam cell formation in the presence of ox-LDL17. NAC inhibits in vitro LDL oxidation induced by copper sulfate, 2,2′-azobis(2-amidinopropane) dihydrochloride, and UV light18. However, it is not known if native LDL oxidation to ox-LDL in vivo could be inhibited by NAC. The present study was to test the hypothesis that NAC decreased native LDL in vivo oxidation to ox-LDL and attenuated the progression of atherosclerosis. To achieve the goal, human native LDL was injected into male C57 BL/6 mice intravenously to determine the formation of oxidized human LDL with and without NAC treatment. In vivo ROS formation was determined in the mice injected with native LDL or ox-LDL and hyperlipidemic mice with and without NAC treatment. Our data demonstrated that native LDL was indeed converted to ox-LDL in vivo and generated a significant level of ROS that was effectively inhibited by NAC. NAC treatment did not affect the fate of ox-LDL in vivo. However, NAC effectively prevented the in vivo ROS production from ox-LDL and significantly reduced the progression of atherosclerotic lesions in LDL receptor knock-out (LDLR−/−) hyperlipidemic mice. NAC treatment also significantly decreased serum ox-LDL level in CAD patients with hyperlipidemia.