|Des Rosiers, Christophe|
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 4/18/2007
Publication Date: 6/18/2007
Citation: Khairallah, R., Young, M.E., Allen, B.G., Lopaschuk, G., Deschepper, C., Des Rosiers, C. 2007. Cardioprotective cGMP favors exogenous fatty acid incorporation into tyiglycerides over direct beta-oxidation [abstract]. 5th Annual Conference of the Society for Heart and Vascular Metabolism. p. 28. Interpretive Summary:
Technical Abstract: While cardiac hypertrophy has been associated with a shift in substrate selection for energy production from fatty acids (FA) to carbohydrates (CHO), it remains controversial whether this shift is adaptive or maladaptive. Since enhanced cGMP signalling can prevent hypertrophy, we hypothesized that this cardioprotection may involve changes in substrate selection. The present study documents the metabolic and functional profiles of hearts from mice overexpressing a constitutively active soluble guanylate cyclase in a cardiomyocyte-specific manner (Tg) using ex vivo perfusion at physiological workload with 13c-labeled substrates. Compared to non-Tg littermates, hearts from Tg mice displayed improved membrane integrity (38 +/- 14% lower lactate dehydrogenase release), while sustaining normal cardiac work. These hearts also showed a 38 +/- 9% lower contribution of exogenous FA to acetyl-CoA formation, while CHO (both endogenous and exogenous) contribution was similar despite a two-fold increase in glycolytic flux. Since calculated ciiric acid cycle flux, tissue malonyl-CoA (a P-oxidation inhibitor), acetyl-CoA and free CoA levels were similar in both groups, these observations suggested an increased contribution from an endogenous FA source, namely triglycerides, in Tg mice hearts. Additionally, we observed a two-fold increase in exogenous oleate incorporation into triglycerides and a decreased (37 +/- 13%) phosphorylated AMPK (which inhibits triglyceride hydrolysis) in Tg hearts. Altogether, it appears that cardioprotective cGMP simultaneously may promote both triglyceride hydrolysis and synthesis in cardiomyocytes. Since we detected no differences in the expression of key metabolic genes, the documented changes in substrate selection with chronic activation of cGMP signalling are likely to result from post-transcriptional modifications.