Increasing ketone body metabolism reduces cardiac dysfunction in a murine model of pressure-overload-induced heart failure
Contributor: Chris Sobowale
In a mouse model of pressure overload-induced heart failure, D-beta-hydroxybutyrate dehydrogenase I (Bdh1), an enzyme that catalyzes the interconversion of two major ketone bodies produced during fatty acid catabolism (acetoacetate and beta-hydroxybutyrate) is upregulated and increases ketone-body oxidation rate, i.e ketone body metabolism (KBM). Uchihashi et al generated cardiac-specific Bdh1-overexpressing mice to determine the role of ketone-body metabolism in the myocardium. They demonstrate that overexpression of Bdh1 resulted in increased ketone body utilization, resistance to pathologic cardiac remodeling, and a reduction in reactive oxygen species generation.
Ketone bodies are generated from Acetyl-CoA stemming from fatty acid metabolism in the liver. Ketones are then oxidized back to Acetyl-CoA in various tissues to provide energy. Interestingly, Beta-hydroxybutyrate (a component of ketone bodies) decreases ischemic reperfusion injury in rat hearts and decreases oxidative stress by inhibiting histone deacetylases (HDACs) and upregulating antioxidant genes. The less HDACs, the more histone acetylation, and the less oxidative stress.
Bhd1-overexpressing transgenic (Bdh1 Tg) mice were made by injecting Bdh1 cDNA into mouse embryos. All Bdh1 Tg and wild type (WT) mice then underwent a left thoracotomy. Half of the mice had traverse aortic constriction (TAC) by ligation of the transverse thoracic aorta to cause pressure overload-induced heart failure. The other half (sham group) had no ligation. Bdh1 levels were measured using proteomics and DNA microarray, and were further confirmed by PCR and Western Blot. The ketone body oxidation rate (KBM) was evaluated by measuring 14CO2 isotope levels 8 weeks after TAC.
At baseline, Bdh1 Tg mice had a significant increase in Bhd1 protein levels (2.5 fold) and KBM (1.7 fold) when compared to WT mice (p<0.05). TAC caused a significant increase in Bhd1 expression (2.8 fold higher in Bdh1 Tg mice) (p<0.05). Overall, the TAC Bdh1 Tg mice had a significant increase in KBM compared to TAC WT mice (p<0.05) (Figure 2A).
TAC caused enlargement of the LVEDd and reduction in EF. TAC operated Bdh1 Tg mice had less LV dilation and significantly less cardiac dysfunction compared to WT mice (p<0.05). The area of fibrosis after TAC was significantly decreased in Bdh1 Tg mice. Immunostaining revealed that reactive oxygen species (ROS) were induced by TAC but significantly reduced in TAC Bhd1 Tg mice compared to TAC WT mice (p<0.05). Also, gene expression of superoxide dismutase, an antioxidant was upregulated in TAC Bdh1 Tg mice.
No study is perfect. There were no hemodynamic data provided and it is unclear how working heart models will correlate with the Langendorff heart model used in this study.