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Activation of Imprinted Gene PW1 Promotes Cardiac Fibrosis After Ischemic Injury

Circulation

Circulation, Ahead of Print. BACKGROUND:Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition in the myocardium, is an important target for heart disease treatments.Pw1(paternally expressed gene 3) is an imprinted gene expressed from the paternal allele, and de novo purine biosynthesis (DNPB) is a crucial pathway for nucleotide synthesis. However, the roles of PW1 and DNPB in ECM production by cardiac fibroblasts during myocardial ischemia are not yet understood.METHODS:To induce myocardial damage, we performed left anterior descending coronary artery ligation. We generatedPw1CreER-2A-eGFPandPw12A-CreERknock-in mouse lines to evaluate the expression of the 2Pw1alleles in normal and injured hearts. Bisulfite sequencing was used to analyze the DNA methylation of thePw1imprinting control region. We identified the phosphoribosylformylglycinamidine synthase (Pfas) gene, encoding the DNPB enzyme PFAS, as a direct target of PW1 using chromatin immunoprecipitation sequencing and real-time quantitative polymerase chain reaction. The role of DNPB in ECM production and cardiac fibrosis after injury was examined in vitro using cultured cardiac fibroblasts and in vivo withPfas-deficient mice.RESULTS:Our study demonstrates that myocardial infarction reduces DNA methylation at the imprinting control region of the maternally imprinted genePw1, triggering a switch from monoallelic imprinting to biallelic expression ofPw1in cardiac fibroblasts. In activated cardiac fibroblasts, increasedPw1expression promotes purine biosynthesis and induces ECM production by transcriptionally activating the DNPB factorPfas. We identified that DNPB is essential for ECM production in activated fibroblasts and that loss ofPfasin fibroblasts limits cardiac fibrosis and improves heart function after injury.CONCLUSIONS:This study demonstrates thatPw1imprinting is disrupted after injury and reveals a novel role for the downstream target PFAS in ECM production and cardiac fibrogenesis. Targeting the PW1/PFAS signaling pathway presents a promising therapeutic strategy for improving cardiac repair after injury.

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Dicembre 2024
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