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.

Association between proprotein convertase subtilisin/kexin 9 (PCSK9) and lipoprotein subclasses in children with type 1 diabetes mellitus: Effects of glycemic control

“…It has been demonstrated that upon attachment to LDL, PCSK9 has delayed plasma clearance and, more importantly, loses its ability to mediate LDL-R degradation [29]. Our findings fit the conclusion of Glerup and colleagues [30] that plasma LDL-C level (or LDL particles number) may serve as a feedback mechanism that regulates PCSK9 activity. Conversely, there is also the possibility that LDL-bound PCSK9 form has residual activity toward LDL-R [31].…”

“…Expression of circulating PCSK9 is regulated by sterol response binding element protein-2 (SREBP-2) and has marked diurnal rhythm, parallel to cholesterol synthesis [33]. In addition, multiple genetic, hormonal and metabolic factors may influence plasma PCSK9 level [30]. Regulation of PCSK9 production is different in insulin deficiency and insulin resistance state.…”

Methotrexate Decreases the Level of PCSK9—A Novel Indicator of the Risk of Proatherogenic Lipid Profile in Psoriasis. The Preliminary Data

“…Based on the available literature's data, our study is the first one assessing serum PCSK9 concentrations in patients with psoriasis and evaluating the impact of conservative and well-established treatments. A number of studies addressed the potential role of PCSK9 in systemic metabolism, obesity, and other CMDs [24,25]. To our knowledge, there is only one paper investigating PCSK9 in psoriasis.…”

“…Recently there has been more research performed to comprehend the role of PCSK9 in other diseases besides dyslipidemia [23]. Current literature has pointed that expression and release of PCSK9 depends on other chronic conditions including chronic kidney disease, hyperinsulinemia, hypothyroidism or non-alcoholic fatty liver disease (NAFLD) and also inflammation, which is a significant factor in psoriatic pathogenesis [24,25]. As well as NAFLD which shares similar pathogenetic pathways, particularly metabolic or immunological, with psoriasis, with co-occurence in up to 50% of the patients [26,27], there is increasing interest to comprehend whether PCSK9 has a positive or negative impact on the inflammation in chronic and autoimmune diseases [28,29].…”

Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations

“…The decrease in free PCSK9 on alirocumab administration is followed by a decrease in LDL-C levels. [14][15][16] As clearance of the PCSK9:alirocumab complex is slow compared with free PCSK9, 17,18 accumulation of the complex is reflected by an increase in total PCSK9 after alirocumab administration; however, although an increase in total PCSK9 concentrations is observed, the majority of the total PCSK9 will be bound to alirocumab and, therefore, biologically inactive.…”