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Page 2 of 9 Agdamag et al. Vessel Plus 2020;4:42 I http://dx.doi.org/10.20517/2574-1209.2020.60

INTRODUCTION
The association between dyslipidemia and the risk of atherosclerotic cardiovascular diseases (ASCVD)
is well established. Numerous clinical studies have documented the strong correlation of elevated serum
low-density lipoprotein cholesterol (LDL-C) levels with plaque development and progression over the past
[1-3]
decades . This has led to a surge in research aimed at identifying new molecules with more profound
cholesterol lowering effect. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors
were developed in the mid-1980’s, and lovastatin was the first statin approved by the Food and Drug
Administration (FDA) in 1987. Several more potent drugs in this class have been more recently developed
and introduced into clinical practice, as their routine use has been widely endorsed by both the American
College of Cardiology/American Heart Association (ACC/AHA) and European guidelines for many
[4,5]
years . For the past few decades, statins have served as the backbone for LDL-C reduction and have
[1,4]
revolutionized cardiovascular prevention . However, it became evident that medications in this class may
not be well tolerated by many, may be contraindicated, or may provide suboptimal lipid control in some
patients. Therefore, research in the field of cardiovascular prevention continued and several novel agents
in multiple drug classes have been developed with profound lipid lowering effect. Proprotein convertase
subtilisin/kexin type 9 (PCSK9) inhibitors are one of those new classes.

THE BIOLOGY OF PCSK9
LDL-C receptors (LDL-R) are transmembrane proteins that function primarily to attract, bind to, and
remove circulating LDL-C particles from the blood. While a limited number of LDL-R are present on the
[6]
surface of most cells of the human body, their expression is abundant on hepatocytes . After binding to
a target LDL-C particle, the receptor complex enters the hepatocyte through endocytic clathrin-coated
pit formation. Subsequently, the ligand separates, the LDL-R is recycled and is transported back to the
[6]
cell surface to bind additional LDL-C particles . This cycle may repeat several times per hour, up to 150
[7]
times total, which is thought to be the lifecycle of the LDL-R . PCSK9 is a proteolytic enzyme secreted
by the liver that regulates the number of LDL-R expressed on the cellular surface. It interferes with the
release of the LDL-C particle from its receptor following endocytosis, ultimately prompting proteolysis of
[1,6]
the entire complex . Premature degradation leads to the reduced expression of LDL-R on the hepatocyte
surface and therefore decreased LDL-C clearance. On the contrary, inhibiting the PCSK9 enzyme leads to
increased LDL-R recovery and a significant reduction in circulating LDL-C .
[1]
In addition to hepatocytes, PCSK9 is expressed in cardiac myocytes and vascular smooth muscle cells in
response to pro-inflammatory mediators such as lipopolysaccharide, TNF alpha, ox-LDL, reactive oxygen
species (ROS) and damaged mitochondrial DNA [8-12] . In turn, PCSK9 increases the expression of various
scavenger receptors, particularly LOX-1, through a positive feedback loop. This facilitates ox-LDL uptake
[13]
by macrophages promoting the development and progression of atherosclerosis . In addition, it mediates
the further release of pro-inflammatory cytokines from macrophages, hepatocytes and other tissues [9,13] .

Myocardial ischemia and elevated ROS levels during reperfusion promote mitochondrial stress,
cardiomyocyte apoptosis, autophagy, and increase PCSK9 expression in the zone bordering the
infarction [14-16] . Animal models demonstrate that pre-treatment with PCSK9 inhibitors reduces the infarct
size by attenuating mitochondrial dysfunction, mitochondrial fission and the apoptotic process. However,
[17]
administration following the ischemic injury was not protective . Further studies are needed to determine
the possible protective role of PCSK9 inhibitors in reducing infarct size following coronary occlusion.

ESTABLISHED AND EMERGING PCSK9 INHIBITORS
Soon after discovery of the PCSK9 enzyme, inhibiting its function became a target of intense research.
This led to the development of a novel class of agents with prominent cholesterol lowering effect, the