Oxidized LDL-dependent pathway as new pathogenic trigger in arrhythmogenic cardiomyopathy
| Autor: | Alberto Corsini, Lorenzo Arnaboldi, Ilaria Stadiotti, Giuseppina Milano, Edoardo Conte, Claudio Tondo, Saima Mushtaq, Giada Cattelan, Eva König, Daniele Andreini, Elena Sommariva, Giulio Pompilio, Elisa Cogliati, Monica De Musso, Adolfo Paolin, Walter Birchmeier, Alessandro Scopece, Viviana Meraviglia, Valentina Catto, Corrado Carbucicchio, Chiara Volani, Linda Turnu, Mattia Chiesa, Antonio Russo, Werner Rauhe, Manuel Casaburo, Simona De Metrio, Alessandra Rossini, Michela Casella, Matteo Pedrazzini, Benedetta Porro, Marina Camera |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Medicine (General)
Cancer Research media_common.quotation_subject CD36 Cell Cardiomyopathy QH426-470 medicine.disease_cause Cardiovascular System Article adipogenesis Mice R5-920 Downregulation and upregulation Risk Factors Genetics medicine ARVC oxidative stress Animals Humans News & Views Internalization Arrhythmogenic Cardiomyopathy Arrhythmogenic Right Ventricular Dysplasia media_common biology business.industry Arrhythmias Cardiac Articles medicine.disease lipoproteins Lipoproteins LDL medicine.anatomical_structure Phenotype Adipogenesis Cancer research biology.protein Molecular Medicine lipids (amino acids peptides and proteins) business Oxidative stress Lipoprotein |
| Zdroj: | EMBO Molecular Medicine EMBO Molecular Medicine, Vol 13, Iss 9, Pp n/a-n/a (2021) |
| Popis: | 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. ACM mutations are necessary but not sufficient for disease penetrance. The contribution of oxidised lipids as novel pharmacologically targetable cofactors was demonstrated by a multi‐layer approach (patients – in vitro – in vivo), leading to an advancement in the knowledge of ACM pathogenesis. |
| Databáze: | OpenAIRE |
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