Abstract 1056: Association of ERK5 with MEK5 (upstream kinase of ERK5), but not ERK5 Kinase Activation, Inhibits Small Ubiquitin-related Modification of ERK5 Kinase (ERK5-SUMOylation), and Prevents Diabetes (DM)-mediated Exacerbation of Left Ventricular (LV) Remodeling After Myocardial Infarction (MI)
DM contributes to the exacerbation of LV dysfunction after MI. Activation of ERK5, an atypical mitogen activated protein kinase with transcriptional (trans) activity, inhibits doxorubicin-induced apoptosis and LV dysfunction. SUMOylation has been proposed as a negative regulator of various transcription factors. In the current study, we investigated the role of ERK5-SUMOylation in ERK5 trans activity as well as DM-mediated exacerbation of LV remodeling and apoptosis after MI. ERK5 was modified by SUMO1/3 at two conserved sites, Lys 6 and Lys 22. ERK5 wild type trans activity was inhibited by Ubc9 (SUMO E2 conjugase) or PIAS1 (E3 ligase), but not in the ERK5-SUMOylation defective mutant (K6R/K22R). H2O2 and high glucose, two well-known mediators of DM, induced ERK5-SUMOylation, and the K6R/K22R mutant, dominant negative form of Ubc9, and siRNA PIAS1 reversed H2O2-mediated reduction of ERK5 trans activity in cardiomyocytes. These data defined SUMOylation-dependent ERK5 transcriptional repression. Constitutively active form of MEK5α (CA-MEK5α) inhibited ERK5-SUMOylation independent of kinase activity, but dependent on MEK5-ERK5 association at amino acids 71–90 region of ERK5. To investigate the role of ERK-SUMOylation in DM + MI mice, we utilized cardiac specific CA-MEK5α transgenic mice (CA-MEK5α-Tg). MI was induced in streptozotocin (STZ)-injected (DM + MI group) or vehicle-injected mice (MI group) by ligating the left coronary artery. Echocardiography one week after MI showed LV dilatation and dysfunction in the MI group, but with both measures exaggerated in the DM + MI group. The ERK5-SUMOylation was increased in DM + MI, but not in MI group. ERK5-SUMOylation, the exacerbation of LV remodeling, and the numbers of TUNEL positive cells in DM + MI were significantly inhibited, and survival rate was improved in CA-MEK5α-Tg mice compared with non-transgenic littermate control (NLC) mice (FS%: 25.8 ± 4.2 vs.14.1 ± 1.5, p<0.01). Of note, we could not detect any difference of cardiac dysfunction after MI in non-diabetic CA-MEK5α-Tg and NLC mice. These results demonstrated that ERK5 transcriptional activity is subject to down regulation by DM-dependent SUMOylation, which results in a pro-apoptotic condition to contribute to poor post-MI LV function.