PCSK9 Inhibition: From Current Advances to Evolving Future

Hypercholesterolemia plays a crucial role in the development of atherosclerosis, but it remains an undertreated and underdiagnosed disease. Taking into consideration the high prevalence of lipid disorders, long duration of the asymptomatic course of the disease, life-threatening complications resulting from inaccurate therapy, and stringent treatment goals concerning LDL cholesterol level in the prevention of cardiovascular events, novel lipid-lowering therapies have been introduced in the last few years. In this article, a drug belonging to the group of small interfering RNA (siRNA) called inclisiran is described. It is a novel molecule that increases the number of LDL receptors (LDLRs) on the surface of hepatic cells by preventing the formation of proprotein convertase subtilisin/kexin type 9 (PCSK9) responsible for the degradation of LDLRs. With great potential for lowering plasma LDL cholesterol level, high liver specificity, comfortable dosing regimen, and good tolerance without significant adverse effects, it could play an important part in future hypolipemic therapies.

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“…CVI-LM001: first-in-class oral small molecule PCSK9 modulator inhibiting PCSK9 transcription and degradation of LDLR mRNA [ 110 , 114 ];…”

Section: Possible Future Lipid-lowering Treatmentmentioning

confidence: 99%

“…PCSK9 vaccine (AT04A, AT06A): mimicking the domain of PCSK9 on its N-terminus in phase I study [ 111 , 112 , 113 , 114 , 115 , 116 ]…”

Section: Possible Future Lipid-lowering Treatmentmentioning

confidence: 99%

Inclisiran—A Revolutionary Addition to a Cholesterol-Lowering Therapy

Dec

Niemiec

Wojciechowska

et al. 2023

IJMS

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“…Cardiovascular disease (CVD) is one of the most important causes of human death worldwide. According to the latest data, the number of CVD deaths per year is estimated to be 18.6 million [ 1 , 2 ]. Ischemic heart disease can be classified as coronary artery disease and myocardial disease.…”

Section: Introductionmentioning

confidence: 99%

Myocardial injury: where inflammation and autophagy meet

Liu

Chen

et al. 2023

Burns &Amp; Trauma

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Autophagy is a highly conserved bulk degradation mechanism that degrades damaged organelles, aged proteins and intracellular contents to maintain the homeostasis of the intracellular microenvironment. Activation of autophagy can be observed during myocardial injury, during which inflammatory responses are strongly triggered. Autophagy can inhibit the inflammatory response and regulate the inflammatory microenvironment by removing invading pathogens and damaged mitochondria. In addition, autophagy may enhance the clearance of apoptotic and necrotic cells to promote the repair of damaged tissue. In this paper, we briefly review the role of autophagy in different cell types in the inflammatory microenvironment of myocardial injury and discuss the molecular mechanism of autophagy in regulating the inflammatory response in a series of myocardial injury conditions, including myocardial ischemia, ischemia/reperfusion injury and sepsis cardiomyopathy.

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“…Beyond its role in cholesterol homeostasis, PCSK9 mediates inflammatory responses by binding to Toll-like receptors (TLRs) and promotes platelet activation and thrombosis by binding to scavenger receptor class B (SR-B) receptors. In addition, binding to low-density lipoprotein receptor-related protein 1 (LRP1), apolipoprotein E receptor-2 (ApoER2), very-low-density lipoprotein receptor (VLDLR), and other receptors promotes vascular endothelial hyperplasia and increases lipoprotein levels [ 12 ]. PCSK9 loss-of-function variants have been associated with a reduction in circulating LDL-C levels and risk of coronary heart disease [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Interplay between microRNAs, Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), and Lipid Parameters in Patients with Very High Lipoprotein(a) Treated with PCSK9 Inhibitors

Levstek

Karun

Likozar

et al. 2023

Genes

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has an important function in the regulation of lipid metabolism. PCSK9 reduces hepatic low-density lipoprotein receptors, thereby increasing low-density lipoprotein cholesterol levels. However, its regulation remains to be elucidated, including post-transcriptional regulation by microRNAs (miRNAs). We aimed to explore the interplay between miRNAs, total serum PCSK9, and lipids during treatment with PCSK9 inhibitors. A total of 64 patients with stable coronary artery disease and very high lipoprotein(a) levels and 16 sex- and age-matched control subjects were enrolled. Patients received a PCSK9 inhibitor (evolocumab or alirocumab). Total serum PCSK9 levels were measured by immunoassay. RNA was isolated from plasma using magnetic beads, and expression of selected miRNAs was analyzed by quantitative PCR. Total serum PCSK9 levels were significantly higher in control subjects compared with patients. After 6 months of treatment with PCSK9 inhibitors, total serum PCSK9 levels increased significantly. The expression of miR-191-5p was significantly lower, and the expression of miR-224-5p and miR-483-5p was significantly higher in patients compared with control subjects. Using linear regression, the expression of miR-483-5p significantly predicted the serum PCSK9 level at baseline. After the 6-month period of therapy, the expression of miR-191-5p and miR-483-5p significantly increased. Our results support a role for miR-483-5p in regulating circulating PCSK9 in vivo. The difference in expression of miR-191-5p, miR-224-5p, and miR-337-3p between patients and control subjects suggests their possible role in the pathogenesis of coronary artery disease.

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PCSK9 Inhibition: From Current Advances to Evolving Future

Cited by 45 publications

References 113 publications

Inclisiran—A Revolutionary Addition to a Cholesterol-Lowering Therapy

Inclisiran—A Revolutionary Addition to a Cholesterol-Lowering Therapy

Myocardial injury: where inflammation and autophagy meet

Interplay between microRNAs, Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), and Lipid Parameters in Patients with Very High Lipoprotein(a) Treated with PCSK9 Inhibitors

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