Recent Advances on the Roles of PCSK-9 Inhibitors in the Management of Acute Ischemic Stroke Patients

Figures

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  Figure 1. The main mechanisms of the LDL-C-lowering therapies. Statins directly inhibit the HMG-CoA reductase, thus inhibiting the transformation of HMG-CoA to mevalonate. Those are the precursors of cholesterols in its cascade of biosynthesis. By decreasing the cholesterol availability, more LDL-R will be recycled to the surface of hepatocyte, favoring the bind to LDL-C, thus reducing the LDL-C in the blood circulation. Ezetimibe inhibits the NPC1L1 protein, at the level of jejunal margin, thus the absorption of cholesterol will decrease. The cholesterol transported to the liver will also decrease. This will decrease the storage of cholesterol in the liver. Consequently, more LDL-R will be available to bind with LDL-C, decreasing again its level in the blood circulation. PCSK-9 inhibitors inhibit the binding of PCSK-9 protein to LDL-R. Consequently, the complex PCSK-9 protein-LDL-R will not form, and the LDL-R will not be degraded. Therefore, PCSK-9 inhibitors favor the recirculation of the LDL-R on the hepatocyte surface. Inclisiran prevents the formation of PCSK-9 protein, its mechanism is detailed in Figure 2.

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  Figure 2. The mechanism of inclisiran, the first synthetic siRNA. After conjugation to GalNac, it binds the ASGPR receptor and is internalized into the cell. PCSK-9 mRNA is produced in the nucleus and then released into the cell. The internalized inclisiran binds the PCSK-9 mRNA, which leads to its degradation. Consequently, less PCSK-9 protein is synthesized and less will be available to bind the LDL-R. With an increased LDL-R available the LDL-C uptake will increase and the level of LDL-C in the blood circulation will decrease.