The Role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Cardiovascular Homeostasis: A Non-Systematic Literature Review

The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) recently emerged as a crucial component in lipid homeostasis after extensive investigational efforts conducted to unveil the complex mechanisms associated with familial hypercholesterolemia. In 2003, Abifadel et al. were the first to identify mutations in the genes encoding for PCSK9 as a cause of autosomal familial hypercholesterolemia (FH) [1]. Investigating the role of PCSK9 showed its association with low-density lipoprotein (LDL) receptor intracellular degradation [2-5]. The relationship between LDL-cholesterol (LDL-C) serum levels and atherosclerosis has been extensively studied. Higher LDL-C levels are strongly correlated with atherosclerosis and higher cardiovascular comorbidities and mortality [6]. Whereas gain-of-function mutations was associated with increased levels of LDL-C and early onset of atherosclerosis [7], loss-of-function mutations on the other hand was linked to a lower LDL-C and a subsequent decrease in cardiovascular risk [8, 9]. This prompted evaluation of the therapeutic potential of inhibiting PCSK9, where a monoclonal antibody inhibiting PCSK9, when added to conventional therapy (statins), was found to further reduce the incidence of cardiovascular events in the Open Label Study of Long Term Evaluation against LDL-C (OSLER) trials [10], as well as reduce mortality and improve outcomes in the recently published “Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk” (FOURIER) trial [11]. Regarding its physiology, the PCSK9 protein is expressed in significant amounts in the liver, intestine and the kidneys [12]. In addition to its role in lipid metabolism, PCSK9 is also expressed in pancreatic insulin-secreting beta cells and has been shown to play a part in normal insulin homeostasis [13]. Besides, the role of PCSK9 extends to involve regulation of inflammation, blood pressure and carcinogenesis [14-16]. This non-systematic review summarizes the data present to date and pertaining to the emerging role of PCSK9 in the different aspect of cardiovascular homeostasis focusing on dyslipidemia, glomerular proteinuria, insulin secretion, blood pressure regulation and inflammation. In order to compile a comprehensive data for this review, PubMed, EMBASE, Scholar and Scopus databases were searched to identify randomized controlled trials, observational studies, in-vitro trials and reviews about the role of PCSK9 in cardiovascular homeostasis.