EMBO Molecular Medicine (Sep 2021)
Oxidized LDL‐dependent pathway as new pathogenic trigger in arrhythmogenic cardiomyopathy
- Elena Sommariva,
- Ilaria Stadiotti,
- Michela Casella,
- Valentina Catto,
- Antonio Dello Russo,
- Corrado Carbucicchio,
- Lorenzo Arnaboldi,
- Simona De Metrio,
- Giuseppina Milano,
- Alessandro Scopece,
- Manuel Casaburo,
- Daniele Andreini,
- Saima Mushtaq,
- Edoardo Conte,
- Mattia Chiesa,
- Walter Birchmeier,
- Elisa Cogliati,
- Adolfo Paolin,
- Eva König,
- Viviana Meraviglia,
- Monica De Musso,
- Chiara Volani,
- Giada Cattelan,
- Werner Rauhe,
- Linda Turnu,
- Benedetta Porro,
- Matteo Pedrazzini,
- Marina Camera,
- Alberto Corsini,
- Claudio Tondo,
- Alessandra Rossini,
- Giulio Pompilio
Affiliations
- Elena Sommariva
- Unit of Vascular Biology and Regenerative Medicine Centro Cardiologico Monzino IRCCS Milan Italy
- Ilaria Stadiotti
- Unit of Vascular Biology and Regenerative Medicine Centro Cardiologico Monzino IRCCS Milan Italy
- Michela Casella
- Heart Rhythm Center Centro Cardiologico Monzino IRCCS Milan Italy
- Valentina Catto
- Heart Rhythm Center Centro Cardiologico Monzino IRCCS Milan Italy
- Antonio Dello Russo
- Heart Rhythm Center Centro Cardiologico Monzino IRCCS Milan Italy
- Corrado Carbucicchio
- Heart Rhythm Center Centro Cardiologico Monzino IRCCS Milan Italy
- Lorenzo Arnaboldi
- Department of Pharmacological and Biomolecular Sciences Università degli Studi di Milano Milan Italy
- Simona De Metrio
- Department of Pharmacological and Biomolecular Sciences Università degli Studi di Milano Milan Italy
- Giuseppina Milano
- Unit of Vascular Biology and Regenerative Medicine Centro Cardiologico Monzino IRCCS Milan Italy
- Alessandro Scopece
- Unit of Vascular Biology and Regenerative Medicine Centro Cardiologico Monzino IRCCS Milan Italy
- Manuel Casaburo
- Unit of Vascular Biology and Regenerative Medicine Centro Cardiologico Monzino IRCCS Milan Italy
- Daniele Andreini
- Unit of Cardiovascular Imaging Centro Cardiologico Monzino IRCCS Milan Italy
- Saima Mushtaq
- Unit of Cardiovascular Imaging Centro Cardiologico Monzino IRCCS Milan Italy
- Edoardo Conte
- Unit of Cardiovascular Imaging Centro Cardiologico Monzino IRCCS Milan Italy
- Mattia Chiesa
- Bioinformatics and Artificial Intelligence facility Centro Cardiologico Monzino IRCCS Milan Italy
- Walter Birchmeier
- Max Delbrück Center for Molecular Medicine Berlin‐Buch Germany
- Elisa Cogliati
- Treviso Tissue Bank Foundation Treviso Italy
- Adolfo Paolin
- Treviso Tissue Bank Foundation Treviso Italy
- Eva König
- Institute for Biomedicine Eurac Research Affiliated Institute of the University of Lübeck Bozen Italy
- Viviana Meraviglia
- Institute for Biomedicine Eurac Research Affiliated Institute of the University of Lübeck Bozen Italy
- Monica De Musso
- Institute for Biomedicine Eurac Research Affiliated Institute of the University of Lübeck Bozen Italy
- Chiara Volani
- Institute for Biomedicine Eurac Research Affiliated Institute of the University of Lübeck Bozen Italy
- Giada Cattelan
- Institute for Biomedicine Eurac Research Affiliated Institute of the University of Lübeck Bozen Italy
- Werner Rauhe
- General Hospital Bolzano/Bozen Bolzano Italy
- Linda Turnu
- Unit of Metabolomics and Cellular Biochemistry of Atherothrombosis Centro Cardiologico Monzino IRCCS Milan Italy
- Benedetta Porro
- Unit of Metabolomics and Cellular Biochemistry of Atherothrombosis Centro Cardiologico Monzino IRCCS Milan Italy
- Matteo Pedrazzini
- Laboratory of Cardiovascular Genetics Istituto Auxologico Italiano IRCCS Milan Italy
- Marina Camera
- Department of Pharmacological and Biomolecular Sciences Università degli Studi di Milano Milan Italy
- Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences Università degli Studi di Milano Milan Italy
- Claudio Tondo
- Heart Rhythm Center Centro Cardiologico Monzino IRCCS Milan Italy
- Alessandra Rossini
- Institute for Biomedicine Eurac Research Affiliated Institute of the University of Lübeck Bozen Italy
- Giulio Pompilio
- Unit of Vascular Biology and Regenerative Medicine Centro Cardiologico Monzino IRCCS Milan Italy
- DOI
- https://doi.org/10.15252/emmm.202114365
- Journal volume & issue
-
Vol. 13,
no. 9
pp. n/a – n/a
Abstract
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