Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India.
Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India.
Pharmacol Ther. 2018 Jul;187:1-12. doi: 10.1016/j.pharmthera.2018.02.002. Epub 2018 Feb 4.
Atherosclerosis is a progressive disease of large arteries and a leading cause of cardiovascular diseases and stroke. Chronic inflammation, aberrant immune response, and disturbances to key enzymes involved with lipid metabolism are characteristic features of atherosclerosis. Apart from targeting the derangements in lipid metabolism, therapeutic modulation to regulate chronic inflammation and the immune system response may prove to be very promising strategies in the management of atherosclerosis. In recent years, various targets have been studied for the treatment of atherosclerosis. PCSK9, a serine protease, actively targets the LDL-R and causes lysosomal degradation, which leads to excessive accumulation of LDL-C. Regulatory T cells (Tregs) and Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) affects the adaptive and innate immune response, respectively, and thus, therapeutic intervention of either of these targets would directly modulate disease progression. Advanced atherosclerotic lesions are characterized by an accumulation of apoptotic cells. Cluster of differentiation-47 (CD47), an anti-phagocytic known as the "don't eat me" signaling molecule, inhibits efferocytosis, which causes accumulation of cell debris in plaque. ADAMTS and Notch signaling potentially affect the formation of neointima by modulation of extracellular matrix components such as macrophages and vascular smooth muscle cells. This review provides insights on the molecular targets for therapeutic intervention of atherosclerosis, their effect at various stages of atherosclerosis development, and the therapies that have been designed and currently being evaluated in clinical trials.
动脉粥样硬化是一种大血管的进行性疾病，也是心血管疾病和中风的主要原因。慢性炎症、异常的免疫反应以及与脂质代谢相关的关键酶的紊乱是动脉粥样硬化的特征。除了针对脂质代谢失调进行靶向治疗外，调节慢性炎症和免疫系统反应的治疗调节可能是动脉粥样硬化治疗中非常有前途的策略。近年来，已经研究了各种针对动脉粥样硬化的治疗靶点。PCSK9 是一种丝氨酸蛋白酶，可主动靶向 LDL-R 并引起溶酶体降解，从而导致 LDL-C 的过度积累。调节性 T 细胞（Tregs）和髓样细胞触发受体 1（TREM-1）分别影响适应性和固有免疫反应，因此，对这些靶点中的任何一个进行治疗干预都将直接调节疾病的进展。晚期动脉粥样硬化病变的特征是凋亡细胞的积累。分化抗原-47（CD47），一种被称为“不要吃我”的信号分子的抗吞噬作用，抑制吞噬作用，导致斑块中细胞碎片的积累。ADAMTS 和 Notch 信号通路可能通过调节巨噬细胞和血管平滑肌细胞等细胞外基质成分来影响新生内膜的形成。本文综述了动脉粥样硬化治疗干预的分子靶点，它们在动脉粥样硬化发展的各个阶段的作用，以及已经设计和正在临床试验中评估的治疗方法。
