Institute of Molecular Biosciences, University of Graz, Graz, Austria; Division of General Radiology, Department of Radiology, Medical University of Graz, Graz, Austria.
Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
Biomed Pharmacother. 2024 Sep;178:117244. doi: 10.1016/j.biopha.2024.117244. Epub 2024 Aug 9.
Atherosclerosis, the leading cause of cardiovascular disease, cannot be sufficiently explained by established risk factors, including cholesterol. Elevated plasma homocysteine (Hcy) is an independent risk factor for atherosclerosis and is closely linked to cardiovascular mortality. However, its role in atherosclerosis has not been fully clarified yet. We have previously shown that rabbits fed a diet deficient in B vitamins and choline (VCDD), which are required for Hcy degradation, exhibit an accumulation of macrophages and lipids in the aorta, aortic stiffening and disorganization of aortic collagen in the absence of hypercholesterolemia, and an aggravation of atherosclerosis in its presence. In the current study, plasma Hcy levels were increased by intravenous injections of Hcy into balloon-injured rabbits fed VCDD (VCDD+Hcy) in the absence of hypercholesterolemia. While this treatment did not lead to thickening of aortic wall, intravenous injections of Hcy into rabbits fed VCDD led to massive accumulation of VLDL-triglycerides as well as significant impairment of vascular reactivity of the aorta compared to VCDD alone. In the aorta intravenous Hcy injections into VCDD-fed rabbits led to fragmentation of aortic elastin, accumulation of elastin-specific electron-dense inclusions, collagen disorganization, lipid degradation, and autophagolysosome formation. Furthermore, rabbits from the VCDD+Hcy group exhibited a massive decrease of total protein methylated arginine in blood cells and decreased creatine in blood cells, serum and liver compared to rabbits from the VCDD group. Altogether, we conclude that Hcy contributes to atherogenic transformation of the aorta not only in the presence but also in the absence of hypercholesterolemia.
动脉粥样硬化是心血管疾病的主要病因，不能仅用胆固醇等已确立的危险因素来充分解释。血浆同型半胱氨酸（Hcy）升高是动脉粥样硬化的独立危险因素，与心血管死亡率密切相关。然而，其在动脉粥样硬化中的作用尚未完全阐明。我们之前的研究表明，用缺乏 B 族维生素和胆碱（VCDD）的饮食喂养兔子，这些物质是 Hcy 降解所必需的，会导致主动脉中巨噬细胞和脂质的积累、主动脉僵硬以及没有高胆固醇血症时主动脉胶原的紊乱，并且存在高胆固醇血症时会加重动脉粥样硬化。在目前的研究中，通过静脉注射 Hcy 到喂食 VCDD 的球囊损伤兔子（VCDD+Hcy）中，使血浆 Hcy 水平升高，在没有高胆固醇血症的情况下。虽然这种治疗方法不会导致主动脉壁增厚，但静脉注射 Hcy 到喂食 VCDD 的兔子中会导致 VLDL-甘油三酯大量积累，以及与单独喂食 VCDD 相比，主动脉血管反应性显著受损。在 VCDD 喂养的兔子的主动脉中，静脉注射 Hcy 会导致主动脉弹性蛋白的碎片化、弹性蛋白特异性电子致密内含物的积累、胶原的紊乱、脂质的降解和自噬溶酶体的形成。此外，与 VCDD 组的兔子相比，VCDD+Hcy 组的兔子血液中的总蛋白甲基精氨酸大量减少，血液中的肌酸以及血清和肝脏中的肌酸减少。总之，我们得出结论，Hcy 不仅在存在高胆固醇血症的情况下，而且在不存在高胆固醇血症的情况下，也会促进主动脉的动脉粥样硬化转化。
