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Title: Gene and cell therapy strategies for the treatment of cardiac hypertrophy : understanding the role of insulin-like growth factor-1
Author: Poggioli, Tommaso
ISNI:       0000 0004 5348 5195
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Cardiac hypertrophy is a growth response elicited in the heart by intrinsic and extrinsic stimuli in pathological as well as physiological conditions. The insulin-like growth factor-1 (IGF-1) propeptides regulate cardiac hypertrophy during normal development, although their role during pathological hypertrophy has yet to be explored. Previous data from our laboratory has shown that the locally acting propeptide IGF-1Ea inhibited angiotensin-induced pathological hypertrophy in vitro and more importantly regulated cardiac physiological growth in vivo. To investigate the specific role of IGF-1Ea in cardiac pathological growth response, I mimicked a clinical-like scenario in an animal model by inducing cardiac workload with the beta-adrenergic agonist isoproterenol and by cell-mediated delivery of IGF-1Ea and IGF-1 mature protein into the myocardial wall of immunodepleted mice. I observed that IGF-1Ea inhibited isoproterenol-induced increase of heart weight-to-body weight (HW/BW) ratio compared to IGF-1 treated mice. In parallel, isoproterenol-mediated increase of cardiomyocytes cross-sectional area was inhibited by IGF-1Ea, but not by IGF-1 mature protein. Importantly, in vivo magnetic resonance imaging (MRI) showed that only IGF-1Ea maintained end-diastolic volume, stroke volume, left ventricle mass and left ventricle weight-to-body weight ratio similar to control levels. In conclusion, these in vivo data indicate that IGF-1Ea controls workload-induced maladaptive cardiac growth compared to IGF-1 mature protein and suggest further investigations into the role of IGF-1 propeptides in modulating the balance between physiological versus pathological growth response. The outcome will be relevant for future clinical interventions to prevent degenerating growth responses in patients with cardiovascular disease.
Supervisor: Rosenthal, Nadia; Santini, Maria Paola; Want, Elizabeth Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available