Abstract 13150: Role of Cardiac Stromal Cells in the pathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy
Background: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a genetic disorder due to mutations in desmosomal genes, characterized by progressive adipose and fibrous replacement of the myocardium, arrhythmias and sudden death. At present it is still unclear which cell type is responsible for the fibro-fatty replacement and which molecular mechanisms lead to these structural changes. Cardiac Stromal Cells (CStC) are the most abundant cell population in the heart. We were among the first to characterize their propensity to differentiate into several cell types, including adipocytes.
Aim: Aim of the study was to investigate whether CStC present functional alteration associated to ARVC phenotype
Results: CStC can be obtained from right ventricle endomyocardial biopsies of ARVC and NON-ARVC patients, are easily expanded, and show a panel of surface antigens typical of mesenchymal cells. We found that CStC express desmosomal genes, mutated in ARVC patients. CStC from ARVC patients show lower expression of Plakophilin (PKP2) and Plakoglobin (PG) desmosomal proteins. PKP2-mutated CStC derived from ARVC patients, cultured in adipogenic medium, accumulate more fat droplets than those from non-ARVC controls (at 72 h 55.6%± 14.5 of ARVC CStC are positive to Oil Red O staining, vs 1.4%±1.7 of non-ARVC CStC, p P<0.001). PG, the desmosomal protein with high homology to βcatenin shows a preferential nuclear localization in ARVC CStC, not observed in CStC from non-ARVC controls. Since it was proposed that nuclear PG competes with βcatenin, inhibiting the canonical WNT pathway activation, we tested the expression of WNT target genes: indeed the expression of adipogenic genes such as PPARγ, ADIPOQ, FABP4 is upregulated in ARVC vs non-ARVC CStC in adipogenic medium, while cell cycle genes and WNT-specific genes are down regulated.
Conclusion: CStC derived from ARVC patients recapitulate the features of ARVC structural changes, representing a novel, scalable, patient-specific in-vitro tool for mechanistic studies. Moreover, our findings support the hypothesis that CStC contribute to the adipogenic substitution observed in patient’s hearts.
Author Disclosures: E. Sommariva: None. S. Brambilla: None. C. Carbucicchio: None. A. Dello Russo: None. M. Casella: None. G. Pontone: None. V. Meraviglia: None. A. Rossini: None. M.C. Capogrossi: None. G. Pompilio: None. C. Tondo: None.
- © 2014 by American Heart Association, Inc.