Rol of growth factor signaling in age-related cardiovascular impairment.

A vast increase in elderly people represents an expanding socio-economic burden and leads to new medical challenges. In the cardiovascular system, aging causes stiffening of the heart and vasculature, providing a background for diseases. The aging process is incompletely understood and new insights are needed to improve preventive and therapeutic strategies.This project unravels the role of two growth factor signaling pathways, insulin-like growth factor (IGF) and neuregulin-1 (NRG1)/ErbB, in age-related cardiovascular impairment. The cardioprotective nature of these pathways has been described in several conditions. Surprisingly, a decrease in IGF has been associated with longevity. To unravel this paradox, we examine the behavior and function of IGF and NRG1/ErbB signaling in an aging mouse model that displays early onset of age-related cardiovascular impairment. First, senescence-prone mice will be subjected to life-style risk factors that aggravate the course of their cardiovascular dysfunction. Changes in IGF and NRG1/ErbB signaling will be characterized. Next, we will activate and inhibit these pathways in vivo using recombinant proteins and specific receptor inhibitors respectively to examine whether the aging phenotype is accentuated or soothed. In the last part of this study, the question is addressed whether exercise training has beneficial effects via alterations in growth factor signaling. Mice will be subjected to treadmill running and randomized to receive growth factors or tyrosine kinase inhibitors. Additionally, a link between growth factor signaling and changes in miR expression (non-coding small RNAs that function as modulators of physiological processes) will be investigated. Specific miRs have been linked to aging and, interestingly, some of these appear to influence growth factor signaling. These miRs therefore bare diagnostic and therapeutic potential. In all parts of our study, changes in miR expression will be linked to growth factor signaling. A functional link can be made in a second stage using miR inhibitors or mimics. In summary, this project is the first to study the role of IGF and NRG1/ErbB pathways in age-related cardiovascular impairment. Over the past decade IGF and NRG1 came forward as powerful cardioprotective agents in conditions of heart failure and phase II clinical trials have been initiated. Uncovering the effects of IGF1 and NRG1 in the aging cardiovascular system is clinically very important.

Keywords:MOUSE MODELS, CARDIOVASCULAR DISORDERS, GROWTH FACTORS, AGEING

Disciplines:Cardiac and vascular medicine, Physiology