Jonathan Pirruccello

Introduction: Cardiovascular disease is the leading cause of mortality in the United States.¹ The major risk factor for cardiovascular disease is elevated blood cholesterol, most notably low-density-lipoprotein cholesterol (LDL-C).^1,2 Statins are the current first-line therapy for hyperlipidemic patients, but carry adverse effects such as myalgia and rhabdomyolysis that tends to limit compliance to therapy.³ Recently, the FDA approved Evolocumab, a proprotein converase subtilisin/kexin type 9 (PCSK9) inhibitor. PCSK9 inhibitors bind to PCSK9 and inhibit its binding to and degradation of low-density lipoprotein receptors (LDLR) on hepatocyte surfaces leading to an increase uptake of LDL-C via LDLR and decreased blood LDL-C.⁴ Animal studies have suggested that inhibition of PCSK9 may have beneficial effects extending beyond an increase in LDLRs. PCSK9 inhibition may decrease foam cell formation and decrease vascular inflammation in response to oxidized LDL.^5,6 Methods: Mouse peritoneal macrophages, obtained from wild type and LDL-R deficient strains, were treated with LXR/RXR, hydroxycholesterol and 9-cis retinoic acid in order to induce Abca1 expression. The rate of cholesterol efflux was measured after addition of PCSK9.⁵ In a separate study, THP-1 derived macrophages were exposed to oxidized LDL and then the mRNA level of inflammatory cytokines IL-1α, IL-6, TNF-α along with the PCSK9 mRNA levels were measured. In order to determine the specific role of PCSK9 in this inflammatory response, the researchers used an siRNA to inhibit the transcribed PCSK9 mRNA in response to oxidized LDL-C.⁶ Results:The cells that were stimulated with PCSK9 demonstrated a 55% decrease in cholesterol efflux compared to those cell that were not incubated with PCSK9. When the researchers added recombinant antibody to PCSK9 to the mixture, the inhibition of cholesterol efflux was diminished.⁵ In THP-1 derived macrophages exposed to oxidized LDL, researchers found that the inflammatory cytokines IL-1α, IL-6, TNF-α and PCSK9 mRNA were all increased in a dose dependent manner in response to oxidized LDL-C.⁶ In the macrophages exposed to the siRNA, the expression and secretion of pro-inflammatory cytokines IL-1α, IL-6 and TNF-α were significantly decreased.⁶ Following exposure to oxidized LDL-C, macrophages that were not treated siRNA were found to have a higher level of the transcriptional regulator of inflammatory mediators NF-κB in the nucleus.⁶  Conclusion: These studies suggest that through its downregulation of Abca and upregulation of inflammatory cytokines, PCSK9’s contribution to atherosclerosis is multifactorial and inhibition of PCSK9 may limit the rate of foam cell formation and minimize inflammatory pathogenesis of atherosclerosis.

1. Editor T. Blood Cholesterol Treatment: The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) Guideline. BIRDEM Medical Journal. 2016;5(2):68. doi:10.3329/birdem.v5i2.28382.
2. Correction to: Heart Disease and Stroke Statistics—2017 Update: A Report From the American Heart Association. Circulation. 2017;135(10). doi:10.1161/cir.0000000000000491.
3. Psaty BM, Weiss NS. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol. Jama. 2014;311(5):461. doi:10.1001/jama.2013.284203.
4. Repatha (evolocumab) injection. Thousand Oaks, CA: Amgen Inc.; 2017 Jan
5. Adorni MP, Cipollari E, Favari E, et al. Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages. Atherosclerosis. 2017;256:1-6. doi:10.1016/j.atherosclerosis.2016.11.019.
6. Liu L. PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-κB activation in THP-1-derived macrophages. International Journal of Molecular Medicine. 2012. doi:10.3892/ijmm.2012.1072.