ADAR RNA editing for cardiovascular disease: Targetingto modulate lipid metabolism through reduced galactosyltransferase activity
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Cardiovascular disease remains a leading cause of mortality despite current therapies targeting low-density lipoprotein cholesterol (LDL-C). Beta-1,4-galactosyltransferase 1 (B4GALT1), a central glycosyltransferase enzyme that regulates lipoprotein metabolism and hemostasis, is a promising therapeutic target. To evaluate its therapeutic potential as a protective variant,p.Asn352Ser was introduced into the ribonucleic acid (RNA) of healthy wild-type and APOE∗3-Leiden.CETP transgenic mice, a well-established model for hyperlipidemia with a humanized lipoprotein metabolism, using editing oligonucleotides and the endogenous adenosine deaminases acting on RNA enzymes. The impact on hepatic glycosylation and systemic lipid homeostasis was investigated using multi-omics profiling. Editing ofmessenger RNA (∼9%−18%) resulted in substantial reductions in total cholesterol (−61%), apolipoprotein B (−72%), LDL-C (−30%), fibrinogen (−55%) (all 0.05), without alteringexpression. Proteomics of plasma and liver identified early suppression of lipogenesis and lipoprotein assembly, followed by sustained suppression of cholesterol biosynthesis and coagulation pathways. Glycomic analysis revealed remodeling of circulating glycoprotein architecture, consistent with altered B4GALT1 activity. Transcript-protein concordance was strongest in lipid pathways, while glycosylation and coagulation showed domain-specific regulatory patterns. These findings support targetingusing RNA editing to reduce cardi
Abstract
Cardiovascular disease remains a leading cause of mortality despite current therapies targeting low-density lipoprotein cholesterol (LDL-C). Beta-1,4-galactosyltransferase 1 (B4GALT1), a central glycosyltransferase enzyme that regulates lipoprotein metabolism and hemostasis, is a promising therapeutic target. To evaluate its therapeutic potential as a protective variant,p.Asn352Ser was introduced into the ribonucleic acid (RNA) of healthy wild-type and APOE∗3-Leiden.CETP transgenic mice, a well-established model for hyperlipidemia with a humanized lipoprotein metabolism, using editing oligonucleotides and the endogenous adenosine deaminases acting on RNA enzymes. The impact on hepatic glycosylation and systemic lipid homeostasis was investigated using multi-omics profiling. Editing ofmessenger RNA (∼9%−18%) resulted in substantial reductions in total cholesterol (−61%), apolipoprotein B (−72%), LDL-C (−30%), fibrinogen (−55%) (all 0.05), without alteringexpression. Proteomics of plasma and liver identified early suppression of lipogenesis and lipoprotein assembly, followed by sustained suppression of cholesterol biosynthesis and coagulation pathways. Glycomic analysis revealed remodeling of circulating glycoprotein architecture, consistent with altered B4GALT1 activity. Transcript-protein concordance was strongest in lipid pathways, while glycosylation and coagulation showed domain-specific regulatory patterns. These findings support targetingusing RNA editing to reduce cardiometabolic risk. abs0010 Graphical abstract http://www.w3.org/1999/xlink float portrait ga1.webp undfig1 anchor portrait graphical abs0015 In this study, Platenburg and colleagues demonstrate that targeted RNA editing can introduce a cardioprotectivevariant, reducing lipid and coagulation markers without altering DNA. This work highlights a reversible, programmable therapeutic strategy for modulating cardiovascular disease risk. teaser abs0020