Oxidized LDL-dependent pathway as new pathogenic trigger in Arrhythmogenic cardiomyopathy – Mardi 10 octobre 11h
Arrhythmogenic cardiomyopathy (ACM) is hallmarked by fibro-adipogenic alterations of the ventricles, contributing to cardiac dysfunctions and arrhythmias. Although genetically determined (e.g., PKP2mutations), ACM phenotypes are highly variable. More data on phenotype modulators are awaited. We hypothesized that modulation PPARγ, a recognized effector of ACM adipogenesis, may influence the severity of the disease, and in particular, that oxidized low-density lipoprotein (oxLDL) activation of PPARγmay contribute 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 oxLDL are key cofactors of adipogenesis. Mechanistically, the increased lipid accumulation is mediated by oxLDL cell internalization through CD36, ultimately resulting in PPARγupregulation. By boosting oxLDL in a Pkp2 heterozygous knock-out mice through high-fat diet feeding, we enhanced cardiac adipogenesis and right ventricle systolic impairment, which can be 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.
Sommariva E, Stadiotti I, Casella M, Catto V, Dello Russo A, Carbucicchio C, Arnaboldi L, De Metrio S, Milano G, Scopece A, Casaburo M, Andreini D, Mushtaq S, Conte E, Chiesa M, Birchmeier W, Cogliati E, Paolin A, König E, Meraviglia V, De Musso M, Volani C, Cattelan G, Rauhe W, Turnu L, Porro B, Pedrazzini M, Camera M, Corsini A, Tondo C, Rossini A, Pompilio G.
EMBO Mol Med. 2021 Sep 7;13(9):e14365. doi: 10.15252/emmm.202114365.
Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy.
Sommariva E, Brambilla S, Carbucicchio C, Gambini E, Meraviglia V, Dello Russo A, Farina FM, Casella M, Catto V, Pontone G, Chiesa M, Stadiotti I, Cogliati E, Paolin A, Ouali Alami N, Preziuso C, d’Amati G, Colombo GI, Rossini A, Capogrossi MC, Tondo C, Pompilio G.
Eur Heart J. 2016 Jun 14;37(23):1835-46. doi: 10.1093/eurheartj/ehv579.