Effect of PCSK9 on atherosclerotic cardiovascular diseases and its mechanisms: Focus on immune regulation

Abstract

Atherosclerosis is a basic pathological characteristic of many cardiovascular diseases, and if not effectively treated, patients with such disease may progress to atherosclerotic cardiovascular diseases (ASCVDs) and even heart failure. The level of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) is significantly higher in patients with ASCVDs than in the healthy population, suggesting that it may be a promising new target for the treatment of ASCVDs. PCSK9 produced by the liver and released into circulation inhibits the clearance of plasma low-density lipoprotein-cholesterol (LDL-C), mainly by downregulating the level of LDL-C receptor (LDLR) on the surface of hepatocytes, leading to upregulated LDL-C in plasma. Numerous studies have revealed that PCSK9 may cause poor prognosis of ASCVDs by activating the inflammatory response and promoting the process of thrombosis and cell death independent of its lipid-regulatory function, yet the underlying mechanisms still need to be further clarified. In patients with ASCVDs who are intolerant to statins or whose plasma LDL-C levels fail to descend to the target value after treatment with high-dose statins, PCSK9 inhibitors often improve their clinical outcomes. Here, we summarize the biological characteristics and functional mechanisms of PCSK9, highlighting its immunoregulatory function. We also discuss the effects of PCSK9 on common ASCVDs.

Interpretable Machine Learning Leverages Proteomics to Improve Cardiovascular Disease Risk Prediction and Biomarker Identification

“…3F ) (Gudgeon, Marin-Rubio, & Trost, 2022). PCSK9 (ranked 19 in the EBM Proteomics model), which inhibits the clearance of plasma LDL by downregulating the LDL-C receptor, has been identified as a contributing factor to atherosclerosis risk when overexpressed ( Supplementary Figure 9B ) (Ma, Hou, & Liu, 2023).…”

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

“…Inflammation is recognized as a critical factor in the pathophysiology of CVD. 143 , 144 As aforementioned, Denis and the team revealed that PCSK9-deficient mice had significantly lower aortic cholesteryl esters and less severe aortic lesions than those with normal or high levels of PCSK9. However, LDLR-deficient mice demonstrated similar levels of the accumulation of plasma cholesterol and cholesteryl ester, irrespective of PCSK9 levels, indicating that PCSK9’s influence on atherosclerosis is primarily through the LDLR.…”

Interorgan communication with the liver: novel mechanisms and therapeutic targets

“…It not only triggers inflammatory responses, but also fosters thrombotic events and cellular demise. PCSK9 can trigger activation of the TLR4/MyD88/NF-κB signaling cascade, exert influence on the compositional makeup of macrophages, monocytes, and T cells, and augment the release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), thereby instigating tissue damage ( 332 ). Inhibitors of PCSK9 can regulate inflammatory cell infiltration by regulating macrophage polarization in vivo and in vitro , resulting in diminished infarct area in cases of acute myocardial infarction (AMI) and enhanced cardiac function ( 366 ).…”