Activation of Extracellular Signal-Regulated Kinase 5 Reduces Cardiac Apoptosis and Dysfunction via Inhibition of a Phosphodiesterase 3A/Inducible cAMP Early Repressor Feedback Loop

Abstract

Substantial evidence suggests that the progressive loss of cardiomyocytes caused by apoptosis significantly contributes to the development of heart failure. beta-Adrenergic receptor activation and subsequent persistent phosphodiesterase 3A (PDE3A) downregulation and concomitant inducible cAMP early repressor (ICER) upregulation (PDE3A/ICER feedback loop) has been proposed to play a key role in the pathogenesis of cardiomyocyte apoptosis. In contrast, insulin-like growth factor-1 can activate cell survival pathways, providing protection against cell death and restoring muscle function. In this study, we found that insulin-like growth factor-1 activates extracellular signal-regulated kinase 5 (ERK5) and inhibits PDE3A/ICER feedback loop. Insulin-like growth factor-1 normalized isoproterenol-mediated PDE3A downregulation and ICER upregulation via ERK5/MEF2 activation, and also inhibited isoproterenol-induced myocyte apoptosis. To determine the physiological relevance of ERK5 activation in regulating PDE3A/ICER feedback loop, we investigated the PDE3A/ICER expression and cardiomyocyte apoptosis in transgenic mice with cardiac specific expression of a constitutively active form of mitogen-activated protein (MAP)/extracellular signal-regulated protein kinase (ERK) kinase 5alpha (MEK5alpha) (CA-MEK5alpha-Tg). In wild-type mice, pressure overload- or doxorubicin-induced significant reduction of PDE3A expression and subsequent ICER induction. Cardiac specific expression of CA-MEK5alpha rescued pressure overload- or doxorubicin-mediated PDE3A downregulation and ICER upregulation and inhibited myocyte apoptosis as well as subsequent cardiac dysfunction in vivo. These data suggest that preventing the feedback loop of PDE3A/ICER by ERK5 activation could inhibit progression of myocyte apoptosis as well as cardiac dysfunction. These data suggest a new therapeutic paradigm for end stage of heart failure by inhibiting the PDE3A/ICER feedback loop via activating ERK5.

Mitogen-Activated Protein Kinases in Heart Development and Diseases

“…141 In addition, the same group demonstrated a link between ERK5 activity induced by insulin-like growth factor-1 and phosphodiesterase 3A/inducible cAMP early repressor loop to regulate myocyte apoptosis and contractile function. 142 The reason for such discrepancies is not clear, although different MEK5 isoforms used in these studies may be one of the causes. Potentially, intracellular targeting of ERK5 activity to different compartments may dictate specific functional outcome.…”

“…Ras-Raf-MEK-ERK Nanoon and Nanoon-like syndromes [27][28][29][30][31][32][33][34][35][36][37][38] Concentric hypertrophy1 54,55 ( [134][135][136] Eccentric hypertrophy12 [137][138][139]141 Cardiac protection1 142 Contractile dysfunction2 142 …”

Effects of MEK5/ERK5 Association on Small Ubiquitin-Related Modification of ERK5: Implications for Diabetic Ventricular Dysfunction After Myocardial Infarction

“…8 H 2 O 2 and advanced glycation end products (AGE), 2 well-known mediators of diabetes, negatively regulated ERK5 transcriptional activity via ERK5-SUMOylation in endothelial cells. Because ERK5 demonstrates a cardio-protective effect, 7 we investigated the effect of STZ-mediated hyperglycemia and MI on the ERK5-SUMOylation. As shown in Figure 2, we found a slight increase of ERK5-SUMOylation in both the DM (with sham operation) and MI (without STZ treatment) groups.…”

“…ERK5, an atypical mitogen activated protein kinase with transcriptional activity, negatively regulates the executor PDE3A-ICER feedback loop and subsequent apoptosis. 7 Our recent data indicated that ERK5 transcriptional activity itself is subjected to downregulation by reactive oxygen species (ROS) and advanced glycogen endproducts (AGE)-dependent small ubiquitin-related modification (SUMO), and inhibits KLF2 and eNOS expression in endothelial cells. 8 ERK5-SUMOylation at the NH 2 -terminal region (K6 and K22) significantly inhibits COOH-terminal ERK5 transcriptional activity.…”

ICER expression inhibits leukemia phenotype and controls tumor progression

“…6 The inducible cyclic AMP (cAMP) early repressor has been demonstrated to influence cell growth in neuroendocrine tissue, cardiac myocytes and the liver. [7][8][9] Recently, it has been proposed as a tumor suppressor gene in prostate and pituitary cancers. 10,11 We previously documented that ICER was downregulated at diagnosis of acute leukemia in a cohort of pediatric patients, whereas CREB protein was found to be overexpressed.…”