Abstract 560: Blockade of Diabetes (DM)-mediated p90RSK Activation Reduces Small Ubiquitin-related Modification of ERK5 Kinase (ERK5-SUMOylation) and DM-induced Exacerbation of Left Ventricular (LV) Remodeling After Myocardial Infarction (MI)
Post-MI left ventricular function is significantly worse in diabetic compared with non-diabetic patients, but the exact mechanism remains unclear. ERK5, an atypical mitogen activated protein kinase with transcriptional (trans) activity, inhibits apoptosis, and ERK5 trans activity itself is subjected to down regulation by high glucose and reactive oxygen species-dependent SUMOylation. p90RSK activity was increased in DM, and MI-mediated cardiac dysfunction and apoptosis was decreased in non-DM cardiac-specific overexpression of dominant negative-p90RSK mice (DN-p90RSK-Tg). In the current study, we investigated the role of p90RSK activation on DM-mediated ERK5-SUMOylation and subsequent LV dysfunction after MI. First, we found that H2O2 significantly inhibited ERK5 trans activity, which was reversed by DN-p90RSK, and co-transfection of p90RSK wild type significantly inhibited ERK5 trans activity, suggesting that the inhibition of ERK5 trans activity by H2O2 is, at least partially, p90RSK-dependent. Since transfection of p90RSK wild type also significantly increased ERK5-SUMOylation (co-immunoprecipitation of ERK5 with SUMO), we determined the involvement of ERK5-SUMOylation on the inhibition of p90RSK-mediated ERK5 trans activity. Both ERK5 K6R/K22R double mutant of SUMOylation sites and PIAS1 (E3 ligase) siRNA prevented p90RSK-mediated inhibition of ERK5 trans activity, supporting the idea that the inhibition of ERK5 trans activity by p90RSK was dependent on ERK5-SUMOylation. Finally, we investigated the role of p90RSK activation in DM-mediated exacerbation of LV remodeling and ERK5-SUMOylation. MI was induced in streptozotocin (STZ)-injected (DM + MI group) or vehicle-injected mice (MI group) by ligating the left coronary artery. Although LV remodeling was significantly exacerbated in DM + MI group, diabetic DN-p90RSK-Tg mice showed improved LV function one week after MI compared with diabetic non-transgenic littermate control mice (FS%: 23.2 ± 2.5 vs. 15.8 ± 1.2 p<0.05), and the induction of ERK5-SUMOylation in DM + MI group was significantly decreased in DN-p90RSK-Tg mice. These data suggest that the activation of p90RSK is critical for DM + MI-mediated ERK5-SUMOylation and subsequent exacerbation of LV remodeling.