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

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...

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Vydané v:	EMBO molecular medicine Ročník 13; číslo 9; s. e14365 - n/a
Hlavní autori:	Sommariva, Elena, Stadiotti, Ilaria, Casella, Michela, Catto, Valentina, Dello Russo, Antonio, Carbucicchio, Corrado, Arnaboldi, Lorenzo, De Metrio, Simona, Milano, Giuseppina, Scopece, Alessandro, Casaburo, Manuel, Andreini, Daniele, Mushtaq, Saima, Conte, Edoardo, Chiesa, Mattia, Birchmeier, Walter, Cogliati, Elisa, Paolin, Adolfo, König, Eva, Meraviglia, Viviana, De Musso, Monica, Volani, Chiara, Cattelan, Giada, Rauhe, Werner, Turnu, Linda, Porro, Benedetta, Pedrazzini, Matteo, Camera, Marina, Corsini, Alberto, Tondo, Claudio, Rossini, Alessandra, Pompilio, Giulio
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 07.09.2021 EMBO Press John Wiley and Sons Inc Springer Nature
Predmet:	Adipogenesis Arrhythmogenic Cardiomyopathy ARVC Atorvastatin Cardiac arrhythmia Cardiomyocytes Cardiomyopathy CD36 antigen Cofactors EMBO04 Genes Genotype & phenotype Heart failure High fat diet Internalization Lipid peroxidation Lipids lipoproteins Low density lipoprotein Mutation Oxidative stress Patients Peroxisome proliferator-activated receptors Phenotypes Plasma Ventricle ARVC Arrhythmogenic Cardiomyopathy adipogenesis oxidative stress lipoproteins
ISSN:	1757-4676, 1757-4684, 1757-4684
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Shrnutí:	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. Synopsis 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. ACM patients show high oxLDL plasma levels, which stratify ACM phenotype severity. oxLDL worsen adipogenic differentiation of ACM cells by altering the CD36/13HODE/PPARγ axis. By increasing oxLDL in an ACM mouse model with low penetrance, ACM‐specific tissue remodelling, functional and electrical impairments are unveiled. NAC and Atorvastatin can prevent ACM phenotypes in vitro / in vivo . Graphical Abstract 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.
Bibliografia:	These authors contributed equally to this work ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1757-4676 1757-4684 1757-4684
DOI:	10.15252/emmm.202114365