Effects of apoptosis signal- regulating kinase 1 (ASK1) inhibition in experimental pressure overload-induced right ventricular dysfunction

Abstract

Introduction: Apoptosis signal-regulating kinase 1 (ASK1) is a redox-sensitive kinase that acts through activation of p38 and c-Jun N-terminal kinase (JNK) pathways. However, the role of ASK1 in the pathogenesis of right ventricular (RV) remodeling and dysfunction is unknown. We sought to investigate the effects of the selective ASK1 inhibitor GS-444217 on pressure overload-induced RV remodeling. Methods: The effects of GS-444217 were evaluated in mice subjected to pulmonary artery banding (PAB) or sham operation. Seven days after surgery, PAB-challenged mice were randomized and treated either with placebo or GS-444217 for 14 days. RV function and remodeling were determined using echocardiography along with invasive hemodynamic measurements. Total RV collagen content was assessed by Picro-sirius red staining. Results: After 21 days, PAB resulted in right heart hypertrophy, reduced cardiac output and RV fibrosis. Animals treated with GS-444217 had increased cardiac output (14.98±1.21 ml/min vs. 10.81±0.72 ml/min, p Conclusions: ASK1 inhibition significantly attenuates RV dysfunction and fibrosis induced by PAB in mice. These results suggest that ASK1 plays a pathological role in RV remodeling and failure following chronic pressure overload.