Effects of MEK5/ERK5 association on small ubiquitin-related modification of ERK5: implications for diabetic ventricular dysfunction after myocardial infarction.
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 MEK5alpha (CA-MEK5alpha) 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-MEK5alpha transgenic mice (CA-MEK5alpha-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-MEK5alpha-Tg mice. Of note, we could not detect any difference of cardiac function after MI in non-diabetic CA-MEK5alpha-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.
Shishido
Tetsuro
T
Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, West Henrietta, NY 14586, USA.
Woo
Chang-Hoon
CH
Ding
Bo
B
McClain
Carolyn
C
Molina
Carlos A
CA
Yan
Chen
C
Yang
Jay
J
Abe
Jun-Ichi
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism; D048671:MAP Kinase Kinase 5 / Q000378:metabolism*; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D013311:Streptozocin; D014158:Transcription, Genetic / Q000187:drug effects; D044763:Ubiquitin-Conjugating Enzymes / Q000494:pharmacology; D018754:Ventricular Dysfunction / Q000209:etiology / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D016877:Oxidants; D025841:Small Ubiquitin-Related Modifier Proteins; D013311:Streptozocin; D006861:Hydrogen Peroxide; D044763:Ubiquitin-Conjugating Enzymes; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; D000098843:Ubiquitin-Conjugating Enzyme UBC9