Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

Abstract

Ischemic heart disease is the main cause of death worldwide and is accelerated by increased levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL-C through its ability to induce degradation of the LDL receptor (LDLR) in the lysosome of hepatocytes. Only in the last few years, a number of breakthroughs in the understanding of PCSK9 biology have been reported illustrating how PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Two humanized antibodies directed against the LDLR-binding site in PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics are climbing up the phases of clinical trials. The first outcome data of the PCSK9 inhibitor evolocumab reported a significant reduction in the composite endpoint (cardiovascular death, myocardial infarction, or stroke) and further outcome data are awaited. Meanwhile, it became evident that PCSK9 has (patho)physiological roles in several cardiovascular cells. In this review, we summarize and discuss the recent biological and clinical data on PCSK9, the regulation of PCSK9, its extra-hepatic activities focusing on cardiovascular cells, molecular concepts to target PCSK9, and finally briefly summarize the data of recent clinical studies.

Keywords: LDL; LDL receptor; oxLDL.

Fig. 1

Regulation of PCSK9 promoter region in hepatic cells. Pathways that increase the expression are indicated in green and those that depress expression of PCSK9 are indicated in red. The sterol-regulatory element (SRE) is activated by SREBP1c and SREBP2 that coactive hepatocyte nuclear factor (HNF)-1. The histone H3 is deacetylated by SIRT6/FOXO3 complexes and histone H4 is acetylated by HINPF/NPAT/TRRAP complexes

Fig. 2

Effect of insulin and PPARγ on PCSK9 expression. Insulin activates a classical insulin receptor signaling cascade leading to a depression of HNF1 and thereby PCSK9 expression. PPARγ activates PCSK9 transcription by attenuating MAP-kinase-dependent brake on PCSK9 expression

Fig. 3

Effect of siRNA directed against PCSK9 on load-free cells shortening (ΔL/L) of isolated adult rat ventricular cardiomyocytes exposed to oxLDL. Data are mean ± SD from n = 90 cells (10 culture dishes; 2 preparations)

Fig. 4

Ongoing large cardiovascular outcome trials in secondary prevention with PCSK9-inhibiting antibodies. The drugs are applied subcutaneously. The recruitment of ODYSSEY outcomes and FOURIER has been completed. The studies are event driven. LDL-C values are depicted in mg/dL (mM/L). CV cardiovascular, MI myocardial infarction, UA unstable angina