Background: Heart failure is associated with a metabolic switch to glucose oxidation while usage of long chain fatty acids (LCA) is decreased. Using transcriptional profiling in combination with untargeted metabolic profiling in mice subjected to transverse aortic constriction (TAC), we found a downregulation of L2-hydroxyglutarate dehydrogenase (L2HGDH) which is associated with accumulation of its substrate L-2-hydroxyglutarate (L2-HG). L2HGDH is involved in the energy generation process by catalyzing L-2-hydroxyglutarat (L2-HG) to a-ketoglutarate (a-KG), and therefore plays an important role in the tricarboxylic acid (TCA) cycle. However, the potential connection between L2-HG accumulation, L2HGDH down-regulation and heart failure is unclear.
Aim of our study was to investigate whether adeno-associated virus (AAV) 9-mediated cardiac expression of L2HGDH is able to ameliorate the development of heart failure in a mouse model of heart failure due to TAC.
Methods: C57BL/6N mice were randomly assigned to treatment with AAV9-L2HGDH and vector control (AAV9-luciferase) through tail vein injection. Two weeks later, mice were subjected to TAC surgery. Successful TAC was confirmed by echocardiography 2 days after TAC.
Results: 6 weeks after TAC, AAV9-luciferase control-treated mice showed progressive deterioration of contractile function and left ventricular remodeling. In contrast, over-expression of L2HGDH protein (30%) in AAV9-L2HGDH treated animals was associated with a significantly improved ejection fraction (EF) and fractional shortening (FS) at the end of the study. While AAV9-L2HGDH treated animals revealed an EF of 36.18 ± 6.63 % (n=12, mean± SD) and a FS of 16.72 ± 4.01 % (n=12, mean± SD), AAV9-luciferase treated mice showed a lower EF (20.14 ± 8.24%, n=15, p<0.001) and a reduced FS (12.66 ± 6.66 %, n=15, p<0.05). Furthermore, AAV9-L2HGDH-treated TAC mice revealed significantly reduced heart weight to tibia length ratios (HW/TL) as indicator of ameliorated cardiac hypertrophy and decreased lung weight to tibia length ratios (LW/TL) as indicator of decreased heart failure when compared to the vector control group (each p<0.01). Quantification of myocyte cross section area confirmed reduced hypertrophy in the AAV9-L2HGDH group (p<0.001). ANP, BNP, RCAN1.1, and RCAN1.4 as molecular markers of heart failure were also considerably decreased in AAV9-L2HGDH-treated mice (p<0.05). In addition, quantification of Masson's trichrom stainings revealed a significant reduction of fibrous tissue in the L2HGDH over-expression group (perivascular fibrosis, p<0.01 and interstitial fibrosis, p<0.001).
Conclusion: Cardiac over-expression of L2HGDH is able to ameliorate the development of cardiac hypertrophy and fibrosis as well as heart failure in a pressure-overload model. Therefore, upregulation of L2HGDH represents a promising approach for future therapy of heart failure.