Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
Department of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
Biomed Pharmacother. 2024 Nov;180:117527. doi: 10.1016/j.biopha.2024.117527. Epub 2024 Oct 13.
Atherosclerosis is a leading cause of morbidity and mortality in the Western countries. Mounting evidence points to the role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Recently, it has been shown that mitochondrial hydrogen sulfide (HS) can complement the bioenergetic role of Krebs cycle leading to improved mitochondrial function. However, controlled, direct delivery of HS to mitochondria was not investigated as a therapeutic strategy in atherosclerosis. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with mitochondrial HS donor AP39 on the development of atherosclerotic lesions in apolipoprotein E knockout (apoE) mice. Our results indicated that AP39 reduced atherosclerosis in apoE mice and stabilized atherosclerotic lesions through decreased total macrophage content and increased collagen depositions. Moreover, AP39 reduced proinflammatory M1-like macrophages and increased anti-inflammatory M2-like macrophages in atherosclerotic lesions. It also upregulated pathways related to mitochondrial function, such as cellular respiration, fatty acid β-oxidation and thermogenesis while downregulated pathways associated with immune system, platelet aggregation and complement and coagulation cascades in the aorta. Furthermore, treatment with AP39 increased the expression of mitochondrial brown fat uncoupling protein 1 (UCP1) in vascular smooth muscle cells (VSMCs) in atherosclerotic lesions and upregulated mRNA expression of other thermogenesis-related genes in the aorta but not perivascular adipose tissue (PVAT) of apoE mice. Finally, AP39 treatment decreased markers of activated endothelium and increased endothelial nitric oxide synthase (eNOS) expression and activation. Taken together, mitochondrial HS donor AP39 could provide potentially a novel therapeutic approach to the treatment/prevention of atherosclerosis.
动脉粥样硬化是西方国家发病率和死亡率的主要原因。越来越多的证据表明线粒体功能障碍在动脉粥样硬化的发病机制中起作用。最近，已经表明线粒体硫化氢（HS）可以补充三羧酸循环的生物能作用，从而导致线粒体功能的改善。然而，作为动脉粥样硬化的治疗策略，尚未研究控制和直接将 HS 递送到线粒体。因此，我们的研究目的是全面评估长期给予线粒体 HS 供体 AP39 对载脂蛋白 E 敲除（apoE）小鼠动脉粥样硬化病变发展的影响。我们的结果表明，AP39 可减少 apoE 小鼠的动脉粥样硬化，并通过减少总巨噬细胞含量和增加胶原蛋白沉积来稳定动脉粥样硬化病变。此外，AP39 减少了动脉粥样硬化病变中的促炎 M1 样巨噬细胞，增加了抗炎 M2 样巨噬细胞。它还上调了与线粒体功能相关的途径，如细胞呼吸、脂肪酸β-氧化和产热，同时下调了与免疫系统、血小板聚集和补体及凝血级联相关的途径在主动脉中。此外，AP39 治疗增加了血管平滑肌细胞（VSMC）中动脉粥样硬化病变中线粒体棕色脂肪解偶联蛋白 1（UCP1）的表达，并上调了 apoE 小鼠主动脉中其他产热相关基因的 mRNA 表达，但不是血管周围脂肪组织（PVAT）。最后，AP39 治疗降低了激活的内皮标志物的表达，并增加了内皮型一氧化氮合酶（eNOS）的表达和激活。总之，线粒体 HS 供体 AP39 可能为动脉粥样硬化的治疗/预防提供一种新的治疗方法。
