Key result
VEGF-B overexpression accelerates systolic heart failure progression in hypertensive rats via severe ATP depletion.
Why the study?
Cardiac energy metabolism is central to HF progression and VEGF-B modulates metabolism to induce physiological hypertrophy, but its proteomic and metabolic adaptation during hypertensive challenges remained unclear.
Does VEGF-B overexpression alter cardiac metabolic adaptation and heart failure progression in rats subjected to hypertensive challenges?
Does VEGF-B overexpression alter cardiac metabolic adaptation and heart failure progression in rats subjected to hypertensive challenges?
VEGF-B overexpression accelerates metabolic maladaptation and progression to systolic heart failure in a rat model of hypertension.
May caution against VEGF-B targeting in hypertensive HF; hypothesis-generating and leaves human translation open.
Aims Cardiac energy metabolism is centrally involved in heart failure (HF), although the direction of the metabolic alterations is complex and likely dependent on the particular stage of HF progression. Vascular endothelial growth factor B (VEGF-B) has been shown to modulate metabolic processes and to induce physiological cardiac hypertrophy; thus, it could be cardioprotective in the failing myocardium. This study investigates the role of VEGF-B in cardiac proteomic and metabolic adaptation in HF during aldosterone and high-salt hypertensive challenges. Methods and results Male rats overexpressing the cardiac-specific VEGF-B transgene (VEGF-B TG) were treated for 3 or 6 weeks with deoxycorticosterone-acetate combined with a high-salt (HS) diet (DOCA + HS) to induce hypertension and cardiac damage. Extensive longitudinal echocardiographic studies of HF progression were conducted, starting at baseline. Sham-treated rats served as controls. To evaluate the metabolic alterations associated with HF, cardiac proteomics by mass spectrometry was performed. Hypertrophic non-treated VEGF-B TG hearts demonstrated high oxygen and adenosine triphosphate (ATP) demand with early onset of diastolic dysfunction. Administration of DOCA + HS to VEGF-B TG rats for 6 weeks amplified the progression from cardiac hypertrophy to HF, with a drastic drop in heart ATP concentration. Dobutamine stress echocardiographic analyses uncovered a significantly impaired systolic reserve. Mechanistically, the hallmark of the failing TG heart was an abnormal energy metabolism with decreased mitochondrial ATP, preceding the attenuated cardiac performance and leading to systolic HF. Conclusions This study shows that the VEGF-B TG accelerates metabolic maladaptation which precedes structural cardiomyopathy in experimental hypertension and ultimately leads to systolic HF.
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Samuelsson et al. (2023) studied this question. VEGF-B transgene overexpression accelerates metabolic maladaptation, leading to a drastic drop in ATP and progression to systolic heart failure in hypertensive rats.
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