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.
Cardiovascular diseases represent a common health problem worldwide with a significant impact on morbidity and mortality. Hypertension and its related consequences, including cardiac damage leading to heart failure, rank among the first.
Strategies aimed at reducing the impact of these pathologies are urgently needed. A deeper understanding of the molecular mechanisms underlying the cardiac consequences of hypertension is a key step in order to improve preventive, diagnostic and therapeutic approaches to reduce the burden of heart failure.
The contributory role of mitochondrial dysfunction has been underscored in several diseases, including cardiovascular diseases. Additional studies are needed to explain in deeper details the mechanisms underlying the link between mitochondrial dysfunction and cardiovascular diseases. In fact, there is a growing interest to develop novel therapeutic approaches able to preserve and to improve mitochondrial function and to treat all major cardiovascular diseases. In this regard, it is important to note that the recent administration of Elamipretide, a molecule able to restore mitochondrial C-I activity, has significantly improved cardiac function in heart failure patients (1).
Our previous studies in the SHRSP and in the novel animal model of the SHR/Ndufc2-KO demonstrated that both rat strains represent suitable experimental tools for studies of the human disease. In particular, following our discovery of Ndufc2 as a stroke gene in the SHRSP, that was confirmed in the KO rat model (2), we showed that the C-I deficit, dependent from the reduced expression of the Ndufc2 subunit, is significantly involved into the higher susceptibility to vascular damage also in humans (3), and it is significantly associated to increased risk of juvenile ischemic stroke and of myocardial infarction in human patients (2, 4).
Therefore, as a result of our project, we expect to find that the mitochondrial dysfunction dependent from the C-I deficit (caused by the reduced expression of Ndufc2 subunit) promotes cardiac hypertrophy through an involvement of the sirtuins pathway, and of the processes regulating mitochondrial dynamics and mitophagy. We expect to observe that the restoration of C-I function may counteract the phenomena of increased cellular mortality in vitro and of cardiac remodeling in vivo. Moreover, we may expect to find that hypertensive subjects carrying the allelic variant at rs11237379/NDUFC2 (responsible of C-1 deficit and of consequent mitochondrial dysfunction) may develop a higher degree of cardiac hypertrophy as compared to non carrier patients.
Based on the above mentioned experience with the two animal models, we expect that the results of our project will allow to gain novel insights on mitochondrial dysfunction as a contributory mechanism to the hypertensive cardiac damage, and that they will provide information on potentially molecular targets for novel preventive and therapeutic strategies toward the human disease, particularly heart failure.
References
1. Chatfield KC. et al. J Am Coll Cardiol Basic Trans Science 2019; 4:147-57.
2. Rubattu S. et al. J. Am. Heart Assoc. 2016; 5. pii: e002701.
3. Raffa S. et al. Human Molec. Genet, 2017; 26:4541-55.
4. Raffa S. et al. Int J Cardiol. 2019;286:127-33.