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.

Oxidized LDL-dependent pathway as new pathogenic trigger in arrhythmogenic cardiomyopathy / E. Sommariva, I. Stadiotti, M. Casella, V. Catto, A. Dello Russo, C. Carbucicchio, L. Arnaboldi, S. De Metrio, G. Milano, A. Scopece, M. Casaburo, D. Andreini, S. Mushtaq, E. Conte, M. Chiesa, W. Birchmeier, E. Cogliati, A. Paolin, E. Konig, V. Meraviglia, M. De Musso, C. Volani, G. Cattelan, W. Rauhe, L. Turnu, B. Porro, M. Pedrazzini, M. Camera, A. Corsini, C. Tondo, A. Rossini, G. Pompilio. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4676. - 13:9(2021 Sep 07), pp. e14365.1-e14365.23. [10.15252/emmm.202114365]

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

Stadiotti I.;Casella M.;Arnaboldi L.;Andreini D.;Conte E.;Volani C.;Turnu L.;Pedrazzini M.;Camera M.;Tondo C.;Pompilio G.
2021-09-07

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.
adipogenesis; Arrhythmogenic Cardiomyopathy; ARVC; lipoproteins; oxidative stress
Settore MED/11 - Malattie dell'Apparato Cardiovascolare
ago-2021
EMBO MOLECULAR MEDICINE
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/866886
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