Epidemiological studies strongly indicate that diabetes mellitus (DM) is an independent risk factor for both mortality and morbidity following myocardial infarction (MI), especially since post-MI left ventricular function is significantly worse in DM patients. However, what is lacking is a plausible relationship between diabetes and any of the known regulators of cardiomyocyte apoptosis known to play a significant role in the post-MI cardiac dysfunction. Our group has demonstrated that down-regulation of phosphodiesterase 3A (PDE3A) is associated with apoptosis and induction of inducible cAMP early repressor (ICER), a proapoptotic transcriptional repressor, providing a mechanistic framework for how angiotensin II (Ang II) regulates myocyte apoptosis. We also showed that ERK5 activation induced by cardiac specific overexpression of CA- MEK51 (constitutively active form of MEK51) in transgenic mice (Tg) inhibited ICER induction and myocyte apoptosis in DM mice after myocardial infarction (DM + MI), but the mechanism between ERK5 and ICER reduction remains unknown. Our preliminary data show that extracellular signal regulated protein kinase 5 (ERK5) and the chaperone-dependent E3 ubiquitin ligase CHIP (carboxyl terminus of Hsp70-interacting protein) are important in regulating heart damage after myocardial infarction in diabetes. ERK5 activation has a strong cardio-protective effect via inhibition of cardiomyocyte apoptosis. Moreover, ICER is ubiquitinated and degraded by CHIP and ERK5 activation enhances CHIP ubiquitin ligase activity, subsequent ICER and FoxO1 degradation, and inhibits both cardiomyocyte apoptosis and autophagy. Since CHIP knockout mice (KO) showed increased myocyte apoptosis and autophagy after pressure overlaod, our working hypothesis is that ERK5-mediated Ub ligase CHIP activation is a key modulator of ICER and FoxO1 protein degradation and protects cardiomyocytes from both apoptosis and autophagy after MI in DM. Activation of CHIP-mediated ubiquitination is not the "only" downstream target of ERK5 activation, and there are several downstream molecules affected by ERK5 likely to impact MI injury. In this resubmission, we added a study on peroxisome proliferator-activated receptor (PPAR) 4 since ERK5 regulates PPAR4 transactivation in a CHIP-independent manner providing us with a platform to study CHIP-dependent vs. independent signaling in ERK5-mediated cardio-protection. Understanding the role and molecular mechanisms of ERK5-CHIP-mediated ICER and FoxO1 degradation and subsequent cardio-protection should provide insight into the reasons for poor cardiac recovery after MI in DM and possibly reveal a novel therapeutic target. The significance lies in the novel hypothesis on the role of the Ub-ligase CHIP in regulating both apoptosis and autophagy, and the proposed mechanistic study of a highly clinically relevant problem.

Public Health Relevance

The key role of cell death in cardiovascular disease and diabetes has become increasingly evident. At the basic science level understanding the specific signaling events involved in these mechanisms is a key issue that will be addressed here by biochemistry, cell biology, and in vivo transgenic mice. These studies should provide insight into mechanisms by which hyperglycemia promotes myocyte death and potentially facilitate development of new therapeutic approaches to limit cardiac dysfunction after myocardial infarction in patients with DM.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108551-03
Application #
8477267
Study Section
Special Emphasis Panel (ZRG1-CVRS-B (02))
Program Officer
Wong, Renee P
Project Start
2011-08-15
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$366,758
Indirect Cost
$116,739
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Le, Nhat-Tu; Takei, Yuichiro; Izawa-Ishizawa, Yuki et al. (2014) Identification of activators of ERK5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents. J Immunol 193:3803-15
Abe, Jun-ichi; Berk, Bradford C (2014) Novel mechanisms of endothelial mechanotransduction. Arterioscler Thromb Vasc Biol 34:2378-86
Heo, Kyung-Sun; Cushman, Hannah J; Akaike, Masashi et al. (2014) ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis. Circulation 130:180-91
Duellman, Tyler; Warren, Christopher; Yang, Jay (2014) Single nucleotide polymorphism-specific regulation of matrix metalloproteinase-9 by multiple miRNAs targeting the coding exon. Nucleic Acids Res 42:5518-31
Abe, Jun-ichi; Berk, Bradford C (2013) Cezanne paints inflammation by regulating ubiquitination. Circ Res 112:1526-8
Le, Nhat-Tu; Heo, Kyung-Sun; Takei, Yuichiro et al. (2013) A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis. Circulation 127:486-99
Heo, Kyung-Sun; Chang, Eugene; Takei, Yuichiro et al. (2013) Phosphorylation of protein inhibitor of activated STAT1 (PIAS1) by MAPK-activated protein kinase-2 inhibits endothelial inflammation via increasing both PIAS1 transrepression and SUMO E3 ligase activity. Arterioscler Thromb Vasc Biol 33:321-9
Heo, Kyung-Sun; Chang, Eugene; Le, Nhat-Tu et al. (2013) De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis. Circ Res 112:911-23
Abe, Jun-ichi; Berk, Bradford C (2013) Atheroprone flow activation of the sterol regulatory element binding protein 2 and nod-like receptor protein 3 inflammasome mediates focal atherosclerosis. Circulation 128:579-82
Oikawa, Masayoshi; Wu, Meiping; Lim, Soyeon et al. (2013) Cyclic nucleotide phosphodiesterase 3A1 protects the heart against ischemia-reperfusion injury. J Mol Cell Cardiol 64:11-9

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