Characterization of novel mechanisms involved in the development of hypertensive cardiac damage: role of mitochondrial dysfunction

Anno
2020
Proponente Speranza Donatella Rubattu - Professore Ordinario
Sottosettore ERC del proponente del progetto
LS4_7
Componenti gruppo di ricerca
Componente Categoria
Allegra Battistoni Componenti strutturati del gruppo di ricerca / Structured participants in the research project
Damiano Magri' Componenti strutturati del gruppo di ricerca / Structured participants in the research project
Giovanna Gallo Dottorando/Assegnista/Specializzando componente non strutturato del gruppo di ricerca / PhD/Assegnista/Specializzando member non structured of the research group
Giuliano Tocci Componenti strutturati del gruppo di ricerca / Structured participants in the research project
Andrea Berni Componenti strutturati del gruppo di ricerca / Structured participants in the research project
Componente Qualifica Struttura Categoria
Rosita Stanzione PhD IRCCS Neuromed, Pozzilli (Isernia) Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca / Other aggregate personnel Sapienza or other institution, holders of research scholarships
Maria Cotugno Laboratory technician IRCCS Neuromed, Pozzilli (Isernia) Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca / Other aggregate personnel Sapienza or other institution, holders of research scholarships
Abstract

Mitochondrial dysfunction is involved in the pathogenesis of several cardiovascular diseases in both animal models and in humans. The mechanisms underlying the relationship between mitochondrial dysfunction and cardiovascular diseases have not yet been fully elucidated. In the present research project we propose to investigate the impact of mitochondrial Complex I (C-I) deficiency on the development of hypertensive cardiac disease, and the underlying molecular mechanisms, in an animal model of spontaneous hypertension. For this purpose, we will use the animal model of the spontaneously hypertensive rat (SHR)-Ndufc2/KO, carrying a heterozygous deletion of the Ndufc2 gene (encoding a subunit of C-I), and its strain of origin (SHR). In vitro, we will evaluate the role of C-I deficiency in a commercially available cell line (H9c2) and in primary cardiomyocytes from neonatal rats. In this context, the knockdown of Ndufc2 gene will be performed to evaluate the impact on cell hypertrophy development and the underlying signaling pathway. Moreover, we will test, both in vivo and in vitro, the impact of nicotinamide administration, able to restore C-I function, on the development of cardiac abnormalities. Finally, we will perform a translation of the experimental data to the human disease. In fact, we will evaluate the role of a common variant of the human gene (rs23117379/NDUFC2), showing 30-40% frequency in the general population and associated with a significant reduction of gene expression, consequent C-I deficiency and mitochondrial dysfunction, on the development of cardiac hypertrophy in hypertensive patients.
The results of our study may provide important new information on the role of mitochondrial C-I deficiency in the development of cardiac hypertrophy and remodeling in hypertension. These novel insights may open the way toward novel therapeutic approaches able to counteract the hypertensive cardiac damage and the subsequent development of heart failure.

ERC
LS4_1, LS1_10
Keywords:
CARDIOLOGIA, MEDICINA MOLECOLARE, BIOLOGIA CELLULARE

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