Effects of MEK5/ERK5 association on small ubiquitin-related modification of ERK5: Implications for diabetic ventricular dysfunction after myocardial infarction

Tetsuro Shishido, Chang Hoon Woo, Bo Ding, Carolyn McClain, Carlos A. Molina, Chen Yan, Jay Yang, Jun Ichi Abe

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Abstract

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 MEK5α (CA-MEK5α) 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-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. 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-MEK5α-Tg mice. Of note, we could not detect any difference of cardiac function after MI in non-diabetic CA-MEK5α-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.

Original languageEnglish
Pages (from-to)1416-1425
Number of pages10
JournalCirculation Research
Volume102
Issue number11
DOIs
StatePublished - 6 Jun 2008

Fingerprint

Ventricular Dysfunction
Sumoylation
Ubiquitin
Myocardial Infarction
Diabetes Mellitus
Heart Ventricles
gamma-Glutamyl Hydrolase
Apoptosis
Ubiquitin-Protein Ligases
Experimental Diabetes Mellitus
In Situ Nick-End Labeling
Mitogen-Activated Protein Kinases
Cardiac Myocytes
Doxorubicin
Small Interfering RNA
Transgenic Mice
Coronary Vessels
Transcription Factors
Phosphotransferases
Down-Regulation

Keywords

  • Apoptosis
  • Diabetes
  • ERK5
  • Myocardial infarction
  • SUMOylation

Cite this

Shishido, Tetsuro ; Woo, Chang Hoon ; Ding, Bo ; McClain, Carolyn ; Molina, Carlos A. ; Yan, Chen ; Yang, Jay ; Abe, Jun Ichi. / Effects of MEK5/ERK5 association on small ubiquitin-related modification of ERK5 : Implications for diabetic ventricular dysfunction after myocardial infarction. In: Circulation Research. 2008 ; Vol. 102, No. 11. pp. 1416-1425.
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Effects of MEK5/ERK5 association on small ubiquitin-related modification of ERK5 : Implications for diabetic ventricular dysfunction after myocardial infarction. / Shishido, Tetsuro; Woo, Chang Hoon; Ding, Bo; McClain, Carolyn; Molina, Carlos A.; Yan, Chen; Yang, Jay; Abe, Jun Ichi.

In: Circulation Research, Vol. 102, No. 11, 06.06.2008, p. 1416-1425.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effects of MEK5/ERK5 association on small ubiquitin-related modification of ERK5

T2 - Implications for diabetic ventricular dysfunction after myocardial infarction

AU - Shishido, Tetsuro

AU - Woo, Chang Hoon

AU - Ding, Bo

AU - McClain, Carolyn

AU - Molina, Carlos A.

AU - Yan, Chen

AU - Yang, Jay

AU - Abe, Jun Ichi

PY - 2008/6/6

Y1 - 2008/6/6

N2 - 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 MEK5α (CA-MEK5α) 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-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. 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-MEK5α-Tg mice. Of note, we could not detect any difference of cardiac function after MI in non-diabetic CA-MEK5α-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.

AB - 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 MEK5α (CA-MEK5α) 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-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. 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-MEK5α-Tg mice. Of note, we could not detect any difference of cardiac function after MI in non-diabetic CA-MEK5α-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.

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