Abstract 3277: Role of p38-MAPK and Small Heat Shock Protein 27 (HSP27) Phosphorylation in Regulation of Myocardial Function Following Cardioplegic Arrest‘
Introduction: We previously demonstrated that myocardial p38-MAPK and HSP27 are phosphorylated following cardioplegic arrest in patients undergoing cardiac surgery and correlate with reduced cardiac function. The following studies were performed to determine if inhibition of p38-MAPK and/or overexpression of non-phosphorylatable HSP27 improves cardiac function following cardioplegic arrest.
Methods: Langendorff-perfused isolated rat hearts were subjected to 2 hrs intermittent cold cardioplegia followed by 30 min reperfusion. Hearts were treated with (CP+SB) or without (CP) the p38-MAPK inhibitor, SB-203580 (5uM) supplied in the cardioplegia. Sham treated hearts served as controls. In separate experiments, isolated rat ventricular myocytes were subjected to 3 hrs cold hypoxic cardioplegia and simulated reperfusion (CP) followed by videomicroscopy and length change measurements. Myocytes were infected with adenovirus encoding either control GFP or a non-phosphorylatable HSP27 mutant (3A-HSP27).
Results: Baseline parameters of cardiac function were similar between groups (mean values: LVDP: 119±4.9, ±dP/dt: 3231±172, 2339±85). CP resulted in reduced cardiac function (LVDP:44±6.2%,±dP/dt: 37±4.9%, −45±8.5% decrease compared to baseline). Treatment with SB203580 significantly improved CP-induced cardiac function (LVDP: 22±0., ±dP/dt: 12±3.0%, 16±4% decrease, (p=.03, .01, and .04 CP+SB vs CP)). Inhibition of p38-MAPK significantly reduced ser82-HSP27 phosphorylation (CP:11.8±1.4 vs CP+SB:4.7±2.4 fold increase over control (p=.04)). In vitro CP with isolated myocytes decreased myocyte length changes from 9.2±1.2% (GFP) to 3.9±0.8% (GFP+CP) (p<.05). Infection with 3A-HSP27 completely rescued CP-induced decreased myocyte contraction (3A-HSP27+CP, 8.9±1.0%, p<.05 vs GFP+CP). In vitro CP also associated with significantly increased HSP27 phosphorylation (p<.05 GFP+CP vs. GFP).
Conclusions: Inhibition of p38-MAPK and subsequent HSP-27 phosphorylation and/or overexpression of non-phosphorylatable HSP27 significantly improve cardiac performance following cardioplegic arrest, Modulation of HSP27 phosphorylation may improve myocardial recovery following cardiac surgery.
This research has received full or partial funding support from the American Heart Association, National Center.