PCSK9 Functions in Atherosclerosis Are Not Limited to Plasmatic LDL-Cholesterol Regulation

Abstract

The relevance of PCSK9 in atherosclerosis progression is demonstrated by the benefits observed in patients that have followed PCSK9-targeted therapies. The impact of these therapies is attributed to the plasma lipid-lowering effect induced when LDLR hepatic expression levels are recovered after the suppression of soluble PCSK9. Different studies show that PCSK9 is involved in other mechanisms that take place at different stages during atherosclerosis development. Indeed, PCSK9 regulates the expression of key receptors expressed in macrophages that contribute to lipid-loading, foam cell formation and atherosclerotic plaque formation. PCSK9 is also a regulator of vascular inflammation and its expression correlates with pro-inflammatory cytokines release, inflammatory cell recruitment and plaque destabilization. Furthermore, anti-PCSK9 approaches have demonstrated that by inhibiting PCSK9 activity, the progression of atherosclerotic disease is diminished. PCSK9 also modulates thrombosis by modifying platelets steady-state, leukocyte recruitment and clot formation. In this review we evaluate recent findings on PCSK9 functions in cardiovascular diseases beyond LDL-cholesterol plasma levels regulation.

PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology

“…Several studies have demonstrated that SMCs secrete functional PCSK9 into the atheroma that exerts effects on monocytes migration in the intima. The overexpression of PCSK9 by SMCs in atherosclerotic plaques also reduces the ability of macrophages to ingest aggregated LDL (agLDL) and oxLDL molecules through scavenger receptors and LDLR related proteins [4,65]. PCSK9 secreted by SMCs not just plays a paracrine effect, PCSK9 also regulates the metabolism in SMCs.…”

“…Hepatocytes are the primary source of PCSK9 that is secreted into the circulation. However, also other cells can produce and secrete PCSK9, like cells in the intestines [3,4], pancreas [5], adipose tissue [6], kidneys [7] and brain [8]. Interestingly, the circulating levels of PCSK9 biologically increases in the late night, and decreases in the late afternoon, following a diurnal rhythm [9].…”

Role of PCSK9 in Homocysteine-Accelerated Lipid Accumulation in Macrophages and Atherosclerosis in ApoE−/− Mice

“…Many large clinical trials have revealed that PCSK9 inhibitors can decrease LDL-C level significantly and ameliorate the main adverse cardiovascular events and even reverse plaque accumulation (13,32,33). Recent studies have provided more evidence of the PCSK9 on macrophages by promoting cholesterol uptake, inhibiting cholesterol efflux, and activating inflammation or apoptosis (15,34). We have found (10) that Hcy promoted lipid accumulation mainly by regulating receptors responsible for cholesterol efflux.…”

“…In recent years, PCSK9 has attracted much attention in the field of lipid-lowering because of the powerful reduction of plasma LDL-C levels, amelioration of main adverse cardiovascular events and effect on stabilizing plaques with its inhibition (12,13). In addition to promoting the lysosomal degradation of LDL receptor LDLR on the surface of hepatocytes (14), PCSK9 can also act directly on blood vessel walls, by disrupting lipid intake and efflux of macrophages, promoting the secretion of inflammatory factors and inducing apoptosis to participate in atherosclerosis and even plaque destabilization (15,16). Ding et al (17) found that silencing PCSK9 in THP-1 macrophages could inhibit the formation of foam cells by downregulating the scavenger receptor CD36.…”

IMPACT of PCSK9 inhibition on clinical outcome in patients during the inflammatory stage of the SARS-COV-2 infection: Rationale and protocol of the IMPACT-SIRIO 5 study

“…Further data suggest that the nuclear factor kappa B (NF-κB) signaling pathway plays a key role in PCSK9-mediated vascular inflammation and thrombosis [27][28][29]. In fact, PCSK9 inhibition by using small interfering RNA (siRNA) has shown to suppress expression of LOX-1 and secretion of pro-inflammatory cytokines in macrophages by inhibiting NF-κB translocation into the nucleus [29][30][31][32][33].…”