Abstract
Vagus nerve stimulation (VNS) restores autonomic balance, suppresses inflammation action and minimizes cardiomyocyte injury. However, little knowledge is known about the VNS’ role in cardiomyocyte phenotype, sarcomere organization, and energy metabolism of infarcted hearts. VNS in vivo and acetylcholine (ACh) in vitro optimized the levels of α/β-MHC and α-Actinin positive sarcomere organization in cardiomyocytes while reducing F-actin assembly of cardiomyocytes. Consistently, ACh improved glucose uptake while decreasing lipid deposition in myocytes, correlating both with the increase of Glut4 and CPT1α and the decrease of PDK4 in infarcted hearts in vivo and myocytes in vitro, attributing to improvement in both glycolysis by VEGF-A and lipid uptake by VEGF-B in response to Ach. This led to increased ATP levels accompanied by the repaired mitochondrial function and the decreased oxygen consumption. Functionally, VNS improved the left ventricular performance. In contrast, ACh-m/nAChR inhibitor or knockdown of VEGF-A/B by shRNA powerfully abrogated these effects mediated by VNS. On mechanism, ACh decreased the levels of nuclear translocation of FoxO3A in myocytes due to phosphorylation of FoxO3A by activating AKT. FoxO3A overexpression or knockdown could reverse the specific effects of ACh on the expression of VEGF-A/B, α/β-MHC, Glut4, and CPT1α, sarcomere organization, glucose uptake and ATP production. Taken together, VNS optimized cardiomyocytes sarcomere organization and energy metabolism to improve heart function of the infarcted heart during the process of delaying and/or blocking the switch from compensated hypertrophy to decompensated heart failure, which were associated with activation of both P13K/AKT-FoxO3A-VEGF-A/B signaling cascade.
Highlights
The chronic autonomic sympathetic/parasympathetic imbalance is a characteristic of cardiac disease, and Official journal of the Cell Death Differentiation AssociationLuo et al Cell Death and Disease (2020)11:971 cardiomyocytes phenotype and energy metabolism during the heart repair remains to be determined.Cardiomyocyte phenotype changes and energy metabolism occur in a series of transitions from a healthy heart to compensated hypertrophy or even decompensated HF5
Vagus nerve stimulation (VNS) improved cardiac sarcomere structure and heart function in infracted heart To efficiently prepare the therapeutic model of VNS in infarcted hearts, firstly, the left ventricle vagal innervation were confirmed by immunostaining of vesicular ACh transporter (VACHT), the vagal nerves were disorganized decreased in the infracted hearts (Supplementary Fig. S1A and B)
Because previous studies showed that VEGF-A and VEGF-B involved in myocardium energy metabolism[19,20,21,22], we explored the involvement of ACh-induced VEGF in cardiomyocytes and its energy metabolism
Summary
The chronic autonomic sympathetic/parasympathetic imbalance is a characteristic of cardiac disease, and Official journal of the Cell Death Differentiation AssociationLuo et al Cell Death and Disease (2020)11:971 cardiomyocytes phenotype and energy metabolism during the heart repair remains to be determined.Cardiomyocyte phenotype changes and energy metabolism occur in a series of transitions from a healthy heart to compensated hypertrophy or even decompensated HF5. The unique effects of p53 are mainly evident in the HF model induced by adriamycin treatment[10], mutations in the cardiac α-actin gene (Actc1)[11], and pressure overload[9], rather than in the myocardial infarction (MI) model by coronary artery ligation[12].
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