Objectives Left ventricular (LV) assist device (LVAD) support reduces pathological loading. However, load-induced adaptive responses may be suppressed. Pathological loading dysregulates cardiac G protein-coupled receptor (GPCR) signaling. Signaling through G proteins is deleterious, whereas beta (β)-arrestin-mediated signaling is cardioprotective. We examined the effects of pathological LV loading/LV dysfunction and treatment via LVAD, on β-arrestin-mediated signaling, and genetic networks downstream of load. Methods An ovine myocardial infarction (MI) model was used. Sheep underwent sham thoracotomy (n = 3), mid-left anterior descending coronary artery ligation to produce MI (n = 3), or MI with placement of a small-platform catheter-based LVAD (n = 3). LVAD support was continued for 2 weeks. Animals were maintained for a total of 12 weeks. Myocardial specimens were harvested and analyzed. Results MI induced β-arrestin activation. Increased interactions between epidermal growth factor receptor and β-arrestins were observed. LVAD support inhibited these responses to MI (P <.05). LVAD support inhibited the activation of cardioprotective signaling effectors Akt (P <.05), and, to a lesser extent, extracellular regulated kinase 1/2 (P not significant); however, MI resulted in regional activation of load-induced GPCR signaling via G proteins, as assessed by the induction of atrial natriuretic peptide mRNA expression in the MI-adjacent zone relative to the MI-remote zone (P <.05). MI-adjacent zone atrial natriuretic peptide expression was renormalized with LVAD support. Conclusions LVAD support inhibited cardioprotective β-arrestin-mediated signaling. However, net benefits of normalization of load-induced GPCR signaling were observed in the MI-adjacent zone. These findings may have implications for the optimal extent and duration of unloading, and for the development of adjunctive medical therapies.
- intracellular signaling
- left ventricular dysfunction
- mechanical circulatory support
- myocardial infarction
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Cardiology and Cardiovascular Medicine