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.