TY - JOUR 
A1 - García Quintáns, Nieves
AU - Sacristán, Silvia
AU - Márquez López, Cristina
AU - Sánchez Ramos, Cristina
AU - Martínez de Benito, Fernando
AU - Siniscalco, David
AU - González Guerra, Andrés
AU - Camafeita, Emilio
AU - Sanz Rosa, David
AU - Bernal, Juan Antonio
AU - Et al.
T1 - MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM)
Y1 - 2023
SN - 2041-1723
UR - http://hdl.handle.net/11268/12330
AB - The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic deletion mutations in the desmosomal protein PKP2, here we identify a general mechanism by which PKP2 delocalization restricts actomyosin network organization and cardiac sarcomeric contraction in this untreatable disease. Computational modeling of PKP2 variants reveals that the carboxy-terminal (CT) domain is required for N-terminal domain stabilization, which determines PKP2 cortical localization and function. In mutant PKP2 cells the expression of the interacting protein MYH10 rescues actomyosin disorganization. Conversely, dominant-negative MYH10 mutant expression mimics the pathogenic CT–deletion PKP2 mutant causing actin network abnormalities and right ventricle systolic dysfunction. A chemical activator of non-muscle myosins, 4-hydroxyacetophenone (4-HAP), also restores normal contractility. Our findings demonstrate that activation of MYH10 corrects the deleterious effect of PKP2 mutant over systolic cardiac contraction, with potential implications for ACM therapy.
KW - Cardiomiopatías
KW - Enfermedad cardiovascular
KW - Medicina preventiva
KW - Genética humana
LA - eng
ER -