Non-coding RNA-Associated Therapeutic Strategies in Atherosclerosis

Abstract

Atherosclerosis has been the main cause of disability and mortality in the world, resulting in a heavy medical burden for all countries. It is widely known to be a kind of chronic inflammatory disease in the blood walls, of which the key pathogenesis is the accumulation of immunologic cells in the lesion, foam cells formation, and eventually plaque rupture causing ischemia of various organs. Non-coding RNAs (ncRNAs) play a vital role in regulating the physiologic and pathophysiologic processes in cells. More and more studies have revealed that ncRNAs also participated in the development of atherosclerosis and regulated cellular phenotypes such as endothelial dysfunction, leukocyte recruitment, foam cells formation, and vascular smooth muscle cells phenotype-switching and apoptosis. Given the broad functions of ncRNAs in atherogenesis, they have become potential therapeutic targets. Apart from that, ncRNAs have become powerful blueprints to design new drugs. For example, RNA interference drugs were inspired by small interfering RNAs that exist in normal cellular physiologic processes and behave as negative regulators of specific proteins. For instance, inclisiran is a kind of RNAi drug targeting PCKS9 mRNA, which can lower the level of LDL-C and treat atherosclerosis. We introduce some recent research progresses on ncRNAs related to atherosclerotic pathophysiologic process and the current clinical trials of RNA drugs pointed at atherosclerosis.

Non-coding RNA and Atherosclerosis

“…Understanding the main pathological factors contributing to atherosclerosis development allows us to guess the sequence of events during the initial stages of atherosclerosis development. 119 there is disturbed blood flow even at a very early age. 120 Vascular SMCs migrate from the media into the intima, leading to the production of a negatively charged extracellular matrix that can bind to positively charged ApoB-based lipoproteins.…”

Recent Updates on Epigenetic-Based Pharmacotherapy for Atherosclerosis

“…These drugs are classified as antisense oligonucleotides (ASO), small interfering RNA (siRNA), and miRNAs. [63][64][65][66][67][68][69][70]85 ASOs target miRNAs and block their functions, such as antagomiRs, and lock nucleic acid (LNA)based anti-miRs, whereas siRNA acts as a mediator of the complementary mRNA degradation and miRNA imitates native double-stranded RNAs to invert the protective elements within cells. 85 Some examples of ASOs are MRG-110, IONIS-ANGPTL3-LRx, AKCEA-APOCIIILR, mipomersen, ISIS APO(a)-Rx, IONIS APO(a)-LRx, and volanesorsen, while the example of siRNA is inclisiran (Table 1).…”

“…85 Some examples of ASOs are MRG-110, IONIS-ANGPTL3-LRx, AKCEA-APOCIIILR, mipomersen, ISIS APO(a)-Rx, IONIS APO(a)-LRx, and volanesorsen, while the example of siRNA is inclisiran (Table 1). [63][64][65][66][67][68][69][70] MRG-110 was found to target miR-92a-3p and to bind to 3′UTR of KLF2 and KLF4 which resulted in the inhibition of endothelial inflammation stimulated by shear stress and oxLDL. 63 IONIS-ANGPTL3-LRx was reported to have the ability to lower the levels of ANGPTL3 protein, triglycerides, LDL, VLDL, apolipoprotein B, and apolipoprotein C-III in human subjects after 6 weeks of treatment.…”

“…[63][64][65][66][67][68][69][70] MRG-110 was found to target miR-92a-3p and to bind to 3′UTR of KLF2 and KLF4 which resulted in the inhibition of endothelial inflammation stimulated by shear stress and oxLDL. 63 IONIS-ANGPTL3-LRx was reported to have the ability to lower the levels of ANGPTL3 protein, triglycerides, LDL, VLDL, apolipoprotein B, and apolipoprotein C-III in human subjects after 6 weeks of treatment. 64 A phase I/IIa study investigating the efficacy and tolerability of AKCEA-APOCIIILR treatment suggested that this medication significantly reduced the level of total cholesterol, apolipoprotein B, VLDL cholesterol, and increased the level of HDL-C by targeting hepatic APOC3.…”

Antisense Oligonucleotides and Small Interfering RNA for the Treatment of Dyslipidemias

“…Inclisiran, a siRNA directed against PCSK9, is giving very promising results [97]. Preliminary data have described the advantages of using inclisiran, but longer follow-ups are necessary to assess its long-term tolerability, efficacy, and safety [98].…”