PCSK9 in cholesterol metabolism: from bench to bedside

Abstract

Dyslipidemia, and specifically elevated low-density lipoprotein (LDL) cholesterol, is one of the most important cardiovascular risk factors. Statins are considered first line therapy for the primary and secondary prevention of cardiovascular disease. However, statins may not be adequate treatment for elevated circulating LDL levels and are ineffective in certain familial hypercholesterolemias. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulatory protein that affects LDL receptors, offers a new alternative for these patients. Moreover, gain-of-function mutations were discovered to be the root cause of familial autosomal dominant hypercholesterolemia. Inhibition of PSCK9 reduces plasma LDL levels, even in patients for whom statins are ineffective or not tolerated. Alirocumab and evolocumab, human monoclonal antibodies that inhibit PCSK9, have been approved to lower LDL levels. While there are drawbacks to these treatments, including adverse events, administration by subcutaneous injection, and high cost, these drugs are indicated for the treatment of atherosclerotic cardiovascular disease and familial hypercholesterolemia as adjunct to diet and maximally tolerated statin therapy. PCSK9 inhibitors may work synergistically with statins to lower LDL. Novel approaches to PCSK9 inhibition are currently in development with the aim of providing safe and effective treatment options to decrease cardiovascular event burden, ideally at lower cost and with oral bioavailability.

Aloe-emodin exerts cholesterol-lowering effects by inhibiting proprotein convertase subtilisin/kexin type 9 in hyperlipidemic rats

“…For instance, subcutaneous injection of PCSK9 monoclonal (either alirocumab or evolocumab) may cause certain adverse effects. Moreover, its high cost may aggravate the patients’ economic burden [ 24 ]. Thus, new oral PCSK9 inhibitors with good bioavailability are urgently needed.…”

Di’ao Xinxuekang Capsule, a Chinese Medicinal Product, Decreases Serum Lipids Levels in High-Fat Diet-Fed ApoE–/– Mice by Downregulating PCSK9

“…Nonsense mutations in PCSK9 were relevant with the effect of lowering LDL-C and reducing cardiovascular events ( Cohen et al, 2006 ). Therefore, since its discovery in 2003, PCSK9 has become a research hotspot in the development of new drugs to lower cholesterol and intervene in atherosclerosis ( Reiss et al, 2018 ). Apolipoprotein E (ApoE), which is mainly synthesized in the liver and brain, is a glycoprotein that functions as a ligand for receptors that clear chylomicrons and very low-density lipoprotein (VLDL) remnants ( Meir and Leitersdorf, 2004 ).…”

Fármacos utilizados no tratamento de hipercolesterolemia: uma análise histórica e químico-medicinal

“…Os domínios variáveis das cadeias pesadas e leves foram projetados para a combinação ao local específico de ligação na PCSK9 (Manniello & Pisano, 2016). Um terceiro mAb, denominado bococizumabe, está atualmente em fase III dos estudos clínicos (Reiss et al, 2018).…”