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Oxidized LDL-dependent pathway as new pathogenic trigger in arrhythmogenic cardiomyopathy

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Item Type:Article
Title:Oxidized LDL-dependent pathway as new pathogenic trigger in arrhythmogenic cardiomyopathy
Creators Name:Sommariva, E. and Stadiotti, I. and Casella, M. and Catto, V. and Dello Russo, A. and Carbucicchio, C. and Arnaboldi, L. and De Metrio, S. and Milano, G. and Scopece, A. and Casaburo, M. and Andreini, D. and Mushtaq, S. and Conte, E. and Chiesa, M. and Birchmeier, W. and Cogliati, E. and Paolin, A. and König, E. and Meraviglia, V. and De Musso, M. and Volani, C. and Cattelan, G. and Rauhe, W. and Turnu, L. and Porro, B. and Pedrazzini, M. and Camera, M. and Corsini, A. and Tondo, C. and Rossini, A. and Pompilio, G.
Abstract:Arrhythmogenic cardiomyopathy (ACM) is hallmarked by ventricular fibro-adipogenic alterations, contributing to cardiac dysfunctions and arrhythmias. Although genetically determined (e.g., PKP2 mutations), ACM phenotypes are highly variable. More data on phenotype modulators, clinical prognosticators, and etiological therapies are awaited. We hypothesized that oxidized low-density lipoprotein (oxLDL)-dependent activation of PPARγ, a recognized effector of ACM adipogenesis, contributes to disease pathogenesis. ACM patients showing high plasma concentration of oxLDL display severe clinical phenotypes in terms of fat infiltration, ventricular dysfunction, and major arrhythmic event risk. In ACM patient-derived cardiac cells, we demonstrated that oxLDLs are major cofactors of adipogenesis. Mechanistically, the increased lipid accumulation is mediated by oxLDL cell internalization through CD36, ultimately resulting in PPARγ upregulation. By boosting oxLDL in a Pkp2 heterozygous knock-out mice through high-fat diet feeding, we confirmed in vivo the oxidized lipid dependency of cardiac adipogenesis and right ventricle systolic impairment, which are counteracted by atorvastatin treatment. The modulatory role of oxidized lipids on ACM adipogenesis, demonstrated at cellular, mouse, and patient levels, represents a novel risk stratification tool and a target for ACM pharmacological strategies.
Keywords:ARVC, Arrhythmogenic Cardiomyopathy, Adipogenesis, Lipoproteins, Oxidative Stress, Animals, Mice
Source:EMBO Molecular Medicine
ISSN:1757-4676
Publisher:Wiley
Volume:13
Number:9
Page Range:e14365
Date:7 September 2021
Official Publication:https://doi.org/10.15252/emmm.202114365
PubMed:View item in PubMed

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