Evolving targets for the treatment of atherosclerosis

Abstract

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.

Keywords: ADAMTS; CD47; PCSK9; TMAO; TREM-1; Tregs.