Cristina Márquez-López

Spanish National Centre for Cardiovascular Research

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Juan A. Bernal

Spanish National Centre for Cardiovascular Research

David Sanz‐Rosa

Spanish National Centre for Cardiovascular Research

Silvia Sacristán

Instituto Ramón y Cajal de Investigación Sanitaria

Nieves García-Quintáns

Spanish National Centre for Cardiovascular Research

Mariya Lytvyn

Spanish National Centre for Cardiovascular Research

Andrés González-Guerra

Spanish National Centre for Cardiovascular Research

Daniel Martín-Pérez

Spanish National Centre for Cardiovascular Research

Cristina Sánchez‐Ramos

Instituto de Investigaciones Biomédicas Sols-Morreale

David Siniscalco

Le Mans Université

Ricardo Garcı́a

University of Puerto Rico System

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Spanish National Centre for Cardiovascular Research

Hospital Universitario Fundación Jiménez Díaz

Centro de Investigación en Red en Enfermedades Cardiovasculares

Centro de Investigación Biomédica en Red

Instituto de Salud Carlos III

Universidad Autónoma de Madrid

Universitat de València

Consejo Superior de Investigaciones Científicas

Instituto de Investigaciones Biomédicas Sols-Morreale

Centro de Estudios Andaluces

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SARS-CoV-2 protein Nsp1 alters actomyosin cytoskeleton and phenocopies arrhythmogenic cardiomyopathy-related PKP2 mutant

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Cristina Márquez-López Marta Roche-Molina Nieves García-Quintáns Silvia Sacristán David Siniscalco

Abstract Mutations in desmosomal Plakophilin-2 (PKP2) are the most prevalent drivers of arrhythmogenic cardiomyopathy (ACM) and a common cause of sudden cardiac death in young athletes. However, partner proteins that elucidate PKP2 cellular mechanism to understand cardiac dysfunction in ACM are mostly unknown. Here we identify the actin-based motor proteins Myh9 and Myh10 as key PKP2 interactors, and demonstrate that the expression of the ACM-related PKP2 mutant R735X alters actin fiber organization and cell mechanical stiffness. We also show that SARS-CoV-2 Nsp1 protein acts similarly to this known pathogenic R735X mutant, altering the actomyosin component distribution on cardiac cells. Our data reveal that the viral Nsp1 hijacks PKP2 into the cytoplasm and mimics the effect of delocalized R735X mutant. These results demonstrate that cytoplasmic PKP2, wildtype or mutant, induces the collapse of the actomyosin network, since shRNA- PKP2 knockdown maintains the cell structure, validating a critical role of PKP2 localization in the regulation of actomyosin architecture. The fact that Nsp1 and PKP2 mutant R735X share similar phenotypes also suggests that direct SARS-CoV-2 heart infection could induce a transient ACM-like disease in COVID-19 patients, which may contribute to right ventricle dysfunction, observed in patients with poor survival prognosis. Highlights The specific cardiac isoform Plakophilin-2a (PKP2) interacts with Myh9 and Myh10. PKP2 delocalization alters actomyosin cytoskeleton component organization. SARS-CoV-2 Nsp1 protein hijacks PKP2 from the desmosome into the soluble fraction where it is downregulated. Viral Nsp1 collapses the actomyosin cytoskeleton and phenocopies the arrhythmogenic cardiomyopathy-related mutant R735X.

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Plakoglobin

10.1101/2020.09.14.296178

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MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM)

Nature Communications (2023)

Nieves García-Quintáns Silvia Sacristán Cristina Márquez-López Cristina Sánchez‐Ramos Fernando Martínez

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.

Contractility

10.1038/s41467-023-41981-5

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Beta-3 adrenergic receptor overexpression reverses aortic stenosis–induced heart failure and restores balanced mitochondrial dynamics

Basic Research in Cardiology (2022)

Andrés Pun-García Agustín Clemente‐Moragón Rocío Villena-Gutiérrez Mónica Gómez David Sanz‐Rosa

Abstract Aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and heart failure (HF). There is a lack of therapies able to prevent/revert AS-induced HF. Beta3 adrenergic receptor (β3AR) signaling is beneficial in several forms of HF. Here, we studied the potential beneficial effect of β3AR overexpression on AS-induced HF. Selective β3AR stimulation had a positive inotropic effect. Transgenic mice constitutively overexpressing human β3AR in the heart (c-hβ3tg) were protected from the development of HF in response to induced AS, and against cardiomyocyte mitochondrial dysfunction (fragmented mitochondria with remodeled cristae and metabolic reprogramming featuring altered substrate use). Similar beneficial effects were observed in wild-type mice inoculated with adeno-associated virus (AAV9) inducing cardiac-specific overexpression of human β3AR before AS induction. Moreover, AAV9-hβ3AR injection into wild-type mice at late disease stages, when cardiac hypertrophy and metabolic reprogramming are already advanced, reversed the HF phenotype and restored balanced mitochondrial dynamics, demonstrating the potential of gene-therapy-mediated β3AR overexpression in AS. Mice with cardiac specific ablation of Yme1l (cYKO), characterized by fragmented mitochondria, showed an increased mortality upon AS challenge. AAV9-hβ3AR injection in these mice before AS induction reverted the fragmented mitochondria phenotype and rescued them from death. In conclusion, our results step out that β3AR overexpression might have translational potential as a therapeutic strategy in AS–induced HF.

Pressure overload

10.1007/s00395-022-00966-z

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Citations (10)