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Modulation of regulatory genes of fatty acid oxidation in the myocardium: Role in the progression from compensated remodeling to heart failure

English title Modulation of regulatory genes of fatty acid oxidation in the myocardium: Role in the progression from compensated remodeling to heart failure
Applicant Lerch René
Number 109212
Funding scheme Project funding
Research institution Service de Cardiologie Département de Médecine Interne Hôpitaux Universitaires de Genève
Institution of higher education University of Geneva - GE
Main discipline Cardiovascular Research
Start/End 01.10.2005 - 30.09.2009
Approved amount 336'627.00
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Keywords (7)

heart failure; remodeling; myocytes; transgenic mice; gene expression; metabolism; angiotensin II

Lay Summary (English)

Lead
Lay summary
Heart failure is the endstage condition of a number of cardio-vascular disorders. Prolonged stress related to hypertension or ischemia initiate progressive changes in the ventricular myocardium at the molecular, cellular and whole-tissue level. Modification of the morphologic phenotype of cardiac muscle cells during myocardial hypertrophy and progression to heart failure is associated with metabolic changes characterized by downregulation of the fatty acid oxidation pathway. Altered metabolic regulation may contribute to myocardial injury by energy starvation and intracellular accumulation of fatty acids ("lipotoxicity"). Elucidation of the cellular and molecular mechanisms underlying altered fatty acid metabolism may be relevant for the development of new therapeutic strategies for the prevention of heart failure in cardio-vascular disease. The present project is designed to elucidate causes and consequences of altered fatty acid metabolism with particular emphasis on the role of angiotensin II. During the first two years of the grant interval we have investigated the effect of prolonged exposure of cardiac myocytes to angiotensin II on myocardial fatty acid metabolism. Transgenic mice which overexpress angiotensin II in the heart muscle develop progressive left ventricular hypertrophy. After one year heart failure ensues. We observed that angiotensin II-induced cardiac hypertrophy is associated with progressive reduction mRNA expression of enzymes of fatty acid metabolism. However, despite reduced transcription, both protein expression of fatty acid oxidation enzymes and the rate of fatty acid oxidation remained unchanged unless heart failure occurred. This suggests the involvement of posttranscriptional mechanisms in the metabolic changes associated with heart failure. The signaling pathways mediating downregulation of the fatty acid oxidation pathway in response to angiotensin II are investigated in adult rat cardiomyocytes in long-term culture. We have observed that prolonged exposure of cardiac myocytes to angiotensin II elicits first downregulation of transcription of fatty acid oxidation enzymes followed at a later stage by a drop of proteins of enzymes and of fatty acid oxidation. The drop of protein expression of enzymes and of metabolic rate coincides with enhanced expression of the cytokine tumor necrosis factor-alpha (TNF-alpha) in the myocardium. Taken together the results obtained so far are compatible with the interpretation that downregulation of the fatty acid oxidation pathway at the protein level may be mediated by angiotensin II-induced upregulation of TNF-alpha in the myocardium. The project is presently ongoing.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
67873 Plasticity of expression pattern of key regulatory proteins of glucose and fatty acid metabolism during myocyte remodeling. 01.10.2002 Project funding

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