Abstract:
Cardiovascular disease (CDV) represents the major cause of death globally.
Atherosclerosis, as the primary cause of CVD, is a chronic immune-inflammatory disorder
with complex multifactorial pathophysiology encompassing oxidative stress, enhanced
immune-inflammatory cascade, endothelial dysfunction, and thrombosis. An initiating
event in atherosclerosis is the subendothelial accumulation of low-density lipoprotein
(LDL), followed by the localization of macrophages to fatty deposits on blood vessel
walls, forming lipid-laden macrophages (foam cells) that secrete compounds involved
in plaque formation. Given the fact that foam cells are one of the key culprits
that underlie the pathophysiology of atherosclerosis, special attention has been paid to
the investigation of the efficient therapeutic approach to overcome the dysregulation of
metabolism of cholesterol in macrophages, decrease the foam cell formation and/or to
force its degradation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory
serine proteinase that has emerged as a significant regulator of the lipid metabolism
pathway. PCSK9 activation leads to the degradation of LDL receptors (LDLRs), increasing
LDL cholesterol (LDL-C) levels in the circulation. PCSK9 pathway dysregulation
has been identified as one of the mechanisms involved in atherosclerosis. In addition, microRNAs
(miRNAs) are investigated as important epigenetic factors in the pathophysiology
of atherosclerosis and dysregulation of lipid metabolism. This review article summarizes
the recent findings connecting the role of PCSK9 in atherosclerosis and the involvement
of various miRNAs in regulating the expression of PCSK9-related genes. We
also discuss PCSK9 pathway-targeting therapeutic interventions based on PCSK9 inhibition,
miRNA levels manipulation by therapeutic agents, and the most recent advances in
PSCK9 gene editing using CRISPR/Cas9 platform, meganuclease, and base editors.
