Résumé
The spontaneously hypertensive rat (SHR) is a model of hypertension with a Cd36 gene defect, which develops left ventricular hypertrophy (LVH) between 9 and 12 weeks. At 15 weeks, perfused SHR hearts display a reduced capacity to use long chain fatty acids (LCFAs) but not carbohydrates (CHOs) for energy production. In this study, we have further examined LCFA metabolism and its potential (dys) regulation in SHR hearts prior to LVH.
SHR and control Wistar rat hearts (7 weeks) have been used for: i) functional and metabolic phenotyping using
ex vivo perfusion with
13C-labeled substrates, ii) metabolic gene expression profiling using qPCR, iii) studies of mechanisms regulating-oxydation (malonyl-CoA, AMPK) and of the functional impact of the gene mutation in the LCFA transporter Cd36 (western blot, confocal microscopy, qPCR, gene analysis).
Compared to controls, 7-week-old SHR hearts display a lower contribution of LCFA (i.e. oleate) to oxidation (40%) and triglyceride (2.8-fold) formation, which is associated with a compensatory increase in CHO oxidation. These alterations cannot be explained by changes in metabolic gene expression or common mechanisms regulating-oxidation. Western analyses demonstrate that compared to controls, cardiac CD36 protein level is lower in the SHR, while data from confocal microscopy indicate a similar intracellular localization. Sequence alignment of Cd36 cDNA indicates non-synonymous mutations in the SHR that do not impact on the molecular weight of the native protein, but may affect its post-translational modification (PTM). This notion is supported by additional data, which suggest an alteration in
O-linked-N-acetylglucosamination.
Our results emphasize the role of the SHR Cd36 gene defect as the factor underlying its cardiac restricted LCFA utilization. The functional impact of this gene defect includes alterations in CD36 protein level and susceptibility to PTM.