Vascular Endothelial Growth Factor-B Induces a Distinct Electrophysiological Phenotype in Mouse Heart

Abstract

Vascular endothelial growth factor B (VEGF-B) is a potent mediator of vascular, metabolic, growth, and stress responses in the heart, but the effects on cardiac muscle and cardiomyocyte function are not known. The purpose of this study was to assess the effects of VEGF-B on the energy metabolism, contractile, and electrophysiological properties of mouse cardiac muscle and cardiac muscle cells. In vivo and ex vivo analysis of cardiac-specific VEGF-B TG mice indicated that the contractile function of the TG hearts was normal. Neither the oxidative metabolism of isolated TG cardiomyocytes nor their energy substrate preference showed any difference to WT cardiomyocytes. Similarly, myocyte Ca2+ signaling showed only minor changes compared to WT myocytes. However, VEGF-B overexpression induced a distinct electrophysiological phenotype characterized by ECG changes such as an increase in QRSp time and decreases in S and R amplitudes. At the level of isolated TG cardiomyocytes, these changes were accompanied with decreased action potential upstroke velocity and increased duration (APD60–70). These changes were partly caused by downregulation of sodium current (INa) due to reduced expression of Nav1.5. Furthermore, TG myocytes had alterations in voltage-gated K+ currents, namely decreased density of transient outward current (Ito) and total K+ current (Ipeak). At the level of transcription, these were accompanied by downregulation of Kv channel-interacting protein 2 (Kcnip2), a known modulatory subunit for Kv4.2/3 channel. Cardiac VEGF-B overexpression induces a distinct electrophysiological phenotype including remodeling of cardiomyocyte ion currents, which in turn induce changes in action potential waveform and ECG.

PGC-1α4 Interacts with REST to Upregulate Neuronal Genes and Augment Energy Consumption in Developing Cardiomyocytes

“…We decided to investigate the phenotype of neonatal α4 + mice where pathological transcriptional remodelling has not yet manifested. During the neonatal phase (postnatal day 1-2), the observed genotype ratio did not differ from the Mendelian ratio, whereas at the time of genotyping (postnatal day [16][17][18][19][20][21][22][23][24] the ratio was significantly altered, with the α4 + genotype underrepresented (Figure 4c). This suggests that PGC-1α4 overexpression becomes detrimental within two weeks of birth.…”

“…An Axopatch 200B patch-clamp amplifier in combination with a Digidata 1440A and Clampex 10 software (Molecular Devices Inc., Sunnyvale, CA, USA) were used for the whole cell currents and action potential (AP) recordings as previously [6]. See detailed methods as well as protocols for action potential [21], sodium current [22], L-type calcium [23] current and sodium/potassium pump current [24] recordings in Supplementary Materials online.…”

PGC-1α deficiency reveals sex-specific links between cardiac energy metabolism and EC-coupling during development of heart failure in mice

“…For echocardiography, a high-resolution Vevo2100 Ultrasound imaging system (Visual Sonics Inc., Toronto, Canada) was used as described previously. 28 Animals at the ages of 10, 12, and 16 weeks were imaged under inhalation anaesthesia [induction with 3.5–4% isoflurane (Baxter International Inc., Deerfield, IL, USA) and 350–400 mL/min air, maintenance with 2–2.5% isoflurane and 200–250 mL/min air] and kept on a heated platform during and shortly after the imaging.…”

Therapeutic Potential of VEGF-B in Coronary Heart Disease and Heart Failure: Dream or Vision?

“…VEGF-B167 induces α-MHC , SERCA2a , RYR , ANF , BNP , and PGC1α genes and represses the expression of β-MHC and α-actin 1 genes, which attenuate the loss of myocardial mass and maintain cardiac contractility [ 50 ]. Additionally, VEGF-B overexpression was found to have effects on cardiac electrophysiology (e.g., downregulation of sodium current (I Na ), transient outward current (I to ), and total K + current (I peak )) as well as hinder Ca 2+ signaling in the mouse heart [ 77 ]. VEGF-B186 transgene delivery has been shown to improve cardiac ejection fraction following myocardial infarction [ 52 ].…”