ANP is a cardiac hormone secreted by atria, which elicits diuretic and vasorelaxant effects. ANP also plays important pleiotropic functions in the heart through paracrine mechanisms. It limits cardiac hypertrophy and dysfunction in response to stress independently of blood pressure. However, the molecular mechanisms underlying the beneficial effects of ANP in the cardiovascular system still need to be elucidated. We will evaluate for the first time and through different experimental approaches whether ANP protects cardiovascular structure and function against metabolic abnormalities and mechanical stress through the activation of autophagy, a protective intracellular degradation process of damaged proteins and organelles. We will also test whether ANP promotes survival and regenerative capacities of resident/transplanted cardiac progenitor cells (CPCs), thereby favoring myocardial regeneration after injury.
EXPECTED OUTCOMES
Aim 1
ANP gene deletion, particularly if homozygous, will lead to severe cardiovascular damage after HFD. Conversely, augmentation of circulating ANP levels will limit HFD-induced cardiac derangements. ANP KO mice will show impaired autophagy as a consequence of TFEB inhibition [10]. Autophagy will mediate the beneficial effects of ANP during stress in vivo.
Aim 2
Survival and function of CPCs will be reduced in ANP KO mice, particularly after HFD. ANP will promote survival and regenerative capacities of transplanted CPCs, and reduce ischemic remodeling.
RISK ANALYSIS, POSSIBLE PROBLEMS AND SOLUTIONS
ANP -/- mice show higher levels of BP [12]. However, we will also characterize the phenotype of ANP +/- mice, which show normal baseline BP levels [12]. In case it will be impossible to isolate CPCs from ANP KO mice, we will transduce WT CPCs with lentiviruses targeting NPR-A. Similarly, if the experiments with lentiviruses overexpressing ANP in CPCs fail, we will try to overexpress NPR-A in these cells.
SIGNIFICANCE AND INNOVATION
The present project will rely on the complementary skills and expertise of the project leader with that of the participants, all involved in cardiac biomedical research at both translational and clinical levels.
In Aim 1 we will clarify the potential beneficial role of ANP in the cardiovascular protection in response to metabolic derangements. We will study for the first time the phenotype of mice with ANP gene deletion in response to HFD. In addition, we will dissect for the first time the role of ANP in the regulation of autophagy and the importance of this process in the cellular effects elicited by ANP in the cardiovascular system.
In Aim 2, we will study for the first time the potential beneficial role of ANP to empower survival, proliferation and regenerative capacities of resident/transplanted CPCs.
Our integrated approach, in which biotechnological and medical competences will be synergistically integrated, will promote research excellence in order to provide results and knowledge that could be translated into effective, scalable and innovative strategies in the near future.
TRANSLATIONAL RELEVANCE AND IMPACT FOR THE NATIONAL HEALTH SYSTEM
Despite great improvements in therapeutic interventions to prevent the occurrence of CVDs, heart failure (HF) and myocardial infarction are still among the leading causes of mortality in the Western world. In the European Union, cardiovascular pathologies are responsible to more than 2 million deaths every year, costing more than 192 billion of euros, and representing a critical health issue with considerable social and economic costs. More than 30% of all HF patients die within two years since diagnosis. Current treatments for HF can increase life quality and expectancy, but cannot cure the disease. Moreover, patients with HF experience many episodes of hospitalization before death, evidencing the significant socio-economic impact of this highly morbid disease. Our research project may constitute an original, cutting-edge proposal to counteract CVD progression and promote cardiac regeneration, and responds to Horizon 2020 priorities for the development of personalized treatments for chronic medical conditions in the aging population.
In fact, our study may provide a solid basis for the development of novel efficient pharmacological strategies for the treatment of CVDs, acting on basic cellular mechanisms of cardioprotection. These therapies could reduce the high social and medical costs for the clinical management of these diseases with a considerable positive impact on the National Health Service.