Physiology and role of PCSK9 in vascular disease: Potential impact of localized PCSK9 in vascular wall

Abstract

Proprotein convertase subtilisin/kexin type‐9 (PCSK9), a member of the proprotein convertase family, is an important drug target because of its crucial role in lipid metabolism. Emerging evidence suggests a direct role of localized PCSK9 in the pathogenesis of vascular diseases. With this in our consideration, we reviewed PCSK9 physiology with respect to recent development and major studies (clinical and experimental) on PCSK9 functionality in vascular disease. PCSK9 upregulates low‐density lipoprotein (LDL)‐cholesterol levels by binding to the LDL‐receptor (LDLR) and facilitating its lysosomal degradation. PCSK9 gain‐of‐function mutations have been confirmed as a novel genetic mechanism for familial hypercholesterolemia. Elevated serum PCSK9 levels in patients with vascular diseases may contribute to coronary artery disease, atherosclerosis, cerebrovascular diseases, vasculitis, aortic diseases, and arterial aging pathogenesis. Experimental models of atherosclerosis, arterial aneurysm, and coronary or carotid artery ligation also support PCSK9 contribution to inflammatory response and disease progression, through LDLR‐dependent or ‐independent mechanisms. More recently, several clinical trials have confirmed that anti‐PCSK9 monoclonal antibodies can reduce systemic LDL levels, total nonfatal cardiovascular events, and all‐cause mortality. Interaction of PCSK9 with other receptor proteins (LDLR‐related proteins, cluster of differentiation family members, epithelial Na+ channels, and sortilin) may underlie its roles in vascular disease. Improved understanding of PCSK9 roles and molecular mechanisms in various vascular diseases will facilitate advances in lipid‐lowering therapy and disease prevention.

Increased serum PCSK9 in patients with idiopathic pulmonary arterial hypertension: insights from inflammatory cytokines

“…It is well known that PCSK9 is mainly expressed in the liver but is also highly expressed in many other tissues and cells, such as colon, kidney, endothelial cells, smooth muscle cells, and macrophages. 29 However, the main source of elevated serum PCSK9 in IPAH patients in our study was uncertain and further studies are needed to clarify this.…”

“…3 , serum PCSK9 was positively correlated with TNF-α, IL-6, and MCP-1, as well as hemodynamic and echocardiographic parameters (PASP, PADP, mPAP, PVR, and RVD), and our findings were consistent with the notion that PCSK9 also exerted various effects on the cardiovascular system via certain mechanisms independent of LDL‐C regulation. 29 …”

Variants of PCSK9 Gene Are Associated with Subclinical Atherosclerosis and Cardiometabolic Parameters in Mexicans. The GEA Project

“…A larger presence of the A allele in SA suggests that it could be a risk marker for Mexican individuals with SA. On the other hand, high serum levels of PCSK9 have been associated with different vascular diseases such as vasculitis, atherosclerosis, arterial calcification, cerebrovascular, and aortic diseases [ 26 ]. Additionally, various reports have linked PCSK9 with systemic lupus erythematosus [ 27 , 28 ], rheumatoid arthritis [ 29 , 30 ], psoriasis [ 31 , 32 ], systemic sclerosis [ 33 ], and nephrotic syndrome [ 34 ].…”

Reducing Cardiac Injury during ST-Elevation Myocardial Infarction: A Reasoned Approach to a Multitarget Therapeutic Strategy

“…PCSK9 can enhance the degradation of LDL-receptor (LDL-r) and its closest structural family members, thereby increasing vascular inflammation and affecting ECM homeostasis [203]. PCSK9 may also contribute to the degradation of other receptors, including CD36, which is a regulator of platelet aggregation [204].…”