Aging is a process of accumulation of damage to molecules, cells and tissues over a lifetime, that often leads to frailty and malfunction. Cardiac aging is associated with left ventricular hypertrophy and fibrosis leading to diastolic dysfunction and heart failure. Age-related diastolic dysfunction has a significant impact on the elderly health, in fact the left ventricular filling is impaired, limiting intense exercise tolerance and reducing the quality of life. Moderate and regular training prevents and improves heart function and attenuates the problems correlated to increased blood flow demand. Regular and moderate physical activity improves cardiac performance in elderly people. Exercise provides protection against age-induced remodelling of the left ventricle by inhibiting the increase of connective tissue and myocyte hypertrophy consequent to myocytes loss. There are evidences that distinct signalling pathways and genes mediate pathological and physiological cardiac hypertrophy and fibrosis. Very few informations are available about the putative role of phoshodiesterase (PDEs) in ageing hearts. To address this issue we propose to investigate i) an animal model of trained mice to verify the effects of physical exercise on cardiac hypertrophy, fibrosis and PDEs expression; ii) verify the potential role of PDEs (in particular 4 and 5) in the secretion of extracellular protein matrix in a model of isolated cardiomyocytes stimulated in presence of specific PDEs inhibitors. The obtained results will have a relevant impact in the field because they will give an important piece of information regarding the potential use of the pharmacological inhibitors of PDE4 and PDE5.
The innovative points of the project are the translational implications of biological mechanisms which induce fibrosis in ageing hearts leading to cardiac failure and the identification of molecular targets activated by the beneficial effects of exercise. In the heart, fibrotic accumulation causes several cardiac dysfunctions either by reducing the ejection fraction due to a stiffened myocardial matrix, or by impairing electric conductance that ultimately might lead to death. Since it is well known the positive effect of exercise on ageing hearts it is very important to understand the potential protective mechanisms which are activated by physical activity and, in particular, the possible involvement of phosphodiesterase 4 and 5 in the synthesis of collagen by cardiac fibroblasts isolated by the heart of sedentary and trained young and old animals. If our hypothesis will be confirmed it will be an important step ahead in order to clarify the biological mechanism of the positive effect of exercise in preventing cardiac fibrosis.