PCSK9 signaling pathways and their potential importance in clinical practice

AbstractIn the following review, authors described the structure and biochemical pathways of PCSK9, its involvement in LDL metabolism, as well as significances of proprotein convertase subtilisin/kexin type 9 targeted treatment. PCSK9 is a proprotein convertase, which plays a crucial role in LDL receptor metabolism. Transcription and translation of PCSK9 is controlled by different nuclear factors, such as, SREBP and HNF1 α. This review focuses on interactions between PCSK9 and LDL receptor, VLDLR, ApoER2, CD36, CD81, and others. The role of PCSK9 in the inflammatory process is presented and its influence on cytokine profile (IL-1, IL-6, IL-10, TNF) in atherosclerotic plaque. Cholesterol metabolism converges also wi th diabetes by mTORC1 pathways. PCSK9 can be altered by oncologic pathways with utilization of kinases, such as Akt, JNK, and JAK/STAT. Finally, the article shows that blocking PCSK9 has proapoptotic capabilities. Administration of monoclonal antibodies against PCSK9 reduced mortality rate and cardi ovascular events in randomized trials. On the other hand, immunogenicity of new drugs may play a crucial role in their efficiency. Bococizumab ended its career following SPIRE-1,2 outcome. PCSK9 inhibitors have enormous potential, which had been reflected by introducing them (as a new class of drugs reducing LDL concentration cholesterol) into New Lipid Guidelines from Rome 2016. Discoveries in drugs development are focused on blocking PCSK9 on different levels. For ex...
Source: EPMA Journal - Category: International Medicine & Public Health Source Type: research