Overexpression of VEGF-B alters cardiac lipid metabolism and predisposes to heart failure

Abstract

Abstract Background The compensatory phase of left ventricular hypertrophy (LVH) is characterised by sufficient mitochondrial density and energy production, but prolonged stress leads to cardiac decompensation and decreased mitochondrial biogenesis. This results in energy deficiency and compromised contractile ability, eventually leading to heart failure (HF). Vascular endothelial growth factor B (VEGF-B) is a potent inducer of cardiac angiogenesis and LVH, and more recently it has been associated with lipid metabolism and cardiac function. However, its exact role in these processes has remained unresolved. Purpose We wanted to elucidate the effects of VEGF-B overexpression on cardiac metabolism and the development of LVH and HF. Methods We used mice expressing VEGF-B transgene under cardiac-specific MHCα promoter and induced pressure overload with angiotensin II infusion. We monitored the cardiac function with high-resolution transthoracic echocardiography and performed immunohistochemical analyses to assess the level of cardiac fibrosis. Furthermore, we analyzed cardiac lipid metabolism with non-targeted LC-MS metabolite profiling and performed functional 3H -labelled triolein uptake studies combined with quantitative RT-PCR. Results In this study, we show that the cardiac-specific overexpression of VEGF-B leads to increased plasma triglyceride and free fatty acid levels but reduced cardiac lipid accumulation. Non-targeted LC-MS profiling analysis revealed that the level of cardiac glycerolipids and glycerophospholipids were significantly downregulated although changes in cardiac lipid uptake on functional or gene expression level were not detected. To assess how these metabolic changes affect the development of LVH and HF, we subjected MHCα-VEGF-B mice to angiotensin II infusion. Surprisingly, the survival of MHCα-VEGF-B mice dramatically started to decline after four days of angiotensin II infusion and was only 30% at the 14-day time point. Echocardiographic measurements revealed that the MHCα-VEGF-B mice developed severe HF seen as reduced ejection fraction when compared to control mice (32.2% vs. 64.2% respectively), significantly increased LV end-diastolic diameter and LV volume when compared to the controls. VEGF-B overexpression during pressure overload resulted in severe cardiac fibrosis and downregulation of genes responsible for lipid and glucose uptake, metabolic regulation and mitochondrial function indicating severe cardiac energy deficit. Interestingly, a high fat diet feeding prevented the development of HFrEF by 100% and the suppression of all metabolic pathways. Conclusion VEGF-B regulates cardiac energy production and the overexpression of VEGF-B results in cardiac energy deficit that during pressure overload leads to HFrEF and severe mortality. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ERC and H2020