Published online before print May 8, 2008, doi: 10.1161/CIRCRESAHA.107.168138
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 18, 2007
Revised on April 27, 2008
Accepted on April 30, 2008
Association of MEK5 With ERK5, but not ERK5 Kinase Activation, Inhibits Small Ubiquitin-Related Modification of ERK5 Kinase (ERK5-SUMOylation), and Prevents Diabetes-Mediated Exacerbation of Left Ventricular Dysfunction After Myocardial Infarction
Tetsuro Shishido ;
From the Aab Cardiovascular Research Institute (T.S., C.-H.W., B.D., C.M., C.Y., J.A.), University of Rochester School of Medicine and Dentistry, Rochester, NY; the Department of Anesthesiology (J.Y.), Columbia University P & S, New York; and the Department of Biology and Molecular Biology (C.A.M.), Montclair State University, Montclair, NJ.
* To whom correspondence should be addressed. E-mail: Jun-ichi_Abe{at}urmc.rochester.edu.
Diabetes mellitus (DM) contributes to the exacerbation of left ventricle (LV) dysfunction after myocardial infarction (MI). Activation of ERK5, an atypical mitogen activated protein kinase with transcriptional activity, inhibits apoptosis and LV dysfunction after doxorubicin treatment. 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 transcriptional activity as well as on DM-mediated exacerbation of LV dysfunction and apoptosis after MI. ERK5 wild-type transcriptional activity was inhibited by Ubc9 (SUMO E2 conjugase) or PIAS1 (E3 ligase), but not in the ERK5-SUMOylation-site defective mutant (K6R/K22R). H2O2 and high glucose, 2 well-known mediators of diabetes, induced ERK5-SUMOylation, and the K6R/K22R mutant, dominant negative form of Ubc9, and siRNA-PIAS1 reversed H2O2-mediated reduction of ERK5 transcriptional activity in cardiomyocytes, indicating the presence of SUMOylation-dependent ERK5 transcriptional repression. Constitutively active form of MEK5
(CA-MEK5) inhibited ERK5-SUMOylation independent of kinase activity, but dependent on MEK5-ERK5 association. To investigate the pathological role of ERK5-SUMOylation in DM mice after MI, we used cardiac specific CA-MEK5 transgenic mice (CA-MEK5-Tg). MI was induced in streptozotocin (STZ)-injected (DM+MI group) or vehicle-injected mice (MI group) by ligating the left coronary artery. The ERK5-SUMOylation was increased in the DM+MI, but not in the MI group. ERK5-SUMOylation, the exacerbation of LV dysfunction, and the number of TUNEL-positive cells in DM+MI was significantly inhibited in CA-MEK5-Tg mice. Of note, we could not detect any difference of cardiac function after MI in non-diabetic CA-MEK5-Tg and non-transgenic littermate control mice. These results demonstrated that ERK5 transcriptional activity is subject to downregulation by diabetes-dependent SUMOylation, which resulted in a proapoptotic condition contributing to poor post-MI LV function.
Key words: ERK5 • SUMOylation • diabetes • myocardial infarction • apoptosis