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Pro-survival function of MEF2 in cardiomyocytes is enhanced by β -blockers

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ABSTRACT

β1-Adrenergic receptor (β1-AR) stimulation increases apoptosis in cardiomyocytes through activation of cAMP/protein kinase A (PKA) signaling. The myocyte enhancer factor 2 (MEF2) proteins function as important regulators of myocardial gene expression. Previously, we reported that PKA signaling directly represses MEF2 activity. We determined whether (a) MEF2 has a pro-survival function in cardiomyocytes, and (b) whether β-adrenergic/PKA signaling modulates MEF2 function in cardiomyocytes. Initially, we observed that siRNA-mediated gene silencing of MEF2 induces cardiomyocyte apoptosis as indicated by flow cytometry. β1-AR activation by isoproterenol represses MEF2 activity and promotes apoptosis in cultured neonatal cardiomyocytes. Importantly, β1-AR mediated apoptosis was abrogated in cardiomyocytes expressing a PKA-resistant form of MEF2D (S121/190A). We also observed that a β1-blocker, Atenolol, antagonizes isoproterenol-induced apoptosis while concomitantly enhancing MEF2 transcriptional activity. β-AR stimulation modulated MEF2 cellular localization in cardiomyocytes and this effect was reversed by β-blocker treatment. Furthermore, Kruppel-like factor 6, a MEF2 target gene in the heart, functions as a downstream pro-survival factor in cardiomyocytes. Collectively, these data indicate that (a) MEF2 has an important pro-survival role in cardiomyocytes, and (b) β-adrenergic signaling antagonizes the pro-survival function of MEF2 in cardiomyocytes and β-blockers promote it. These observations have important clinical implications that may contribute to novel strategies for preventing cardiomyocyte apoptosis associated with heart pathology.

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Summary of MEF2 regulation by β-adrenergic signaling in cardiomyocyte survival. On the left side, acute activation of β-adrenergic receptors invokes cAMP-mediated PKA activation in cardiomyocytes, resulting in suppression of MEF2 transcriptional activity by direct phosphorylation. Expression of pro-survival genes such as KLF6 is prevented resulting in enhanced cardiomyocyte death. On the right side, β-blockers, such as Atenolol, competitively inhibit the activation of the β-adrenergic receptors by agonists resulting in enhanced MEF2 activity, thereby promoting cardiomyocyte survival.
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fig7: Summary of MEF2 regulation by β-adrenergic signaling in cardiomyocyte survival. On the left side, acute activation of β-adrenergic receptors invokes cAMP-mediated PKA activation in cardiomyocytes, resulting in suppression of MEF2 transcriptional activity by direct phosphorylation. Expression of pro-survival genes such as KLF6 is prevented resulting in enhanced cardiomyocyte death. On the right side, β-blockers, such as Atenolol, competitively inhibit the activation of the β-adrenergic receptors by agonists resulting in enhanced MEF2 activity, thereby promoting cardiomyocyte survival.

Mentions: Interestingly, we also observed that exogenous overexpression of KLF6 can reduce the amount of cell death provoked by Iso treatment (Figure 6c). To examine whether the expression of KLF6 is targeted when MEF2 activity is repressed by β1-AR–PKA signaling, cardiomyocytes were treated with Iso (10 μM) followed by western blot analysis of KLF6. As shown in Figure 6d, KLF6 protein expression level was suppressed by activation of β1-AR–PKA signaling. These data indicate that reduction in KLF6 expression by β1-AR activation occurs through MEF2 inhibition. Collectively, these data summarized in Figure 7, suggest that KLF6 functions downstream of MEF2 in a cardiomyocyte survival pathway.


Pro-survival function of MEF2 in cardiomyocytes is enhanced by β -blockers
Summary of MEF2 regulation by β-adrenergic signaling in cardiomyocyte survival. On the left side, acute activation of β-adrenergic receptors invokes cAMP-mediated PKA activation in cardiomyocytes, resulting in suppression of MEF2 transcriptional activity by direct phosphorylation. Expression of pro-survival genes such as KLF6 is prevented resulting in enhanced cardiomyocyte death. On the right side, β-blockers, such as Atenolol, competitively inhibit the activation of the β-adrenergic receptors by agonists resulting in enhanced MEF2 activity, thereby promoting cardiomyocyte survival.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979494&req=5

fig7: Summary of MEF2 regulation by β-adrenergic signaling in cardiomyocyte survival. On the left side, acute activation of β-adrenergic receptors invokes cAMP-mediated PKA activation in cardiomyocytes, resulting in suppression of MEF2 transcriptional activity by direct phosphorylation. Expression of pro-survival genes such as KLF6 is prevented resulting in enhanced cardiomyocyte death. On the right side, β-blockers, such as Atenolol, competitively inhibit the activation of the β-adrenergic receptors by agonists resulting in enhanced MEF2 activity, thereby promoting cardiomyocyte survival.
Mentions: Interestingly, we also observed that exogenous overexpression of KLF6 can reduce the amount of cell death provoked by Iso treatment (Figure 6c). To examine whether the expression of KLF6 is targeted when MEF2 activity is repressed by β1-AR–PKA signaling, cardiomyocytes were treated with Iso (10 μM) followed by western blot analysis of KLF6. As shown in Figure 6d, KLF6 protein expression level was suppressed by activation of β1-AR–PKA signaling. These data indicate that reduction in KLF6 expression by β1-AR activation occurs through MEF2 inhibition. Collectively, these data summarized in Figure 7, suggest that KLF6 functions downstream of MEF2 in a cardiomyocyte survival pathway.

View Article: PubMed Central - PubMed

ABSTRACT

β1-Adrenergic receptor (β1-AR) stimulation increases apoptosis in cardiomyocytes through activation of cAMP/protein kinase A (PKA) signaling. The myocyte enhancer factor 2 (MEF2) proteins function as important regulators of myocardial gene expression. Previously, we reported that PKA signaling directly represses MEF2 activity. We determined whether (a) MEF2 has a pro-survival function in cardiomyocytes, and (b) whether β-adrenergic/PKA signaling modulates MEF2 function in cardiomyocytes. Initially, we observed that siRNA-mediated gene silencing of MEF2 induces cardiomyocyte apoptosis as indicated by flow cytometry. β1-AR activation by isoproterenol represses MEF2 activity and promotes apoptosis in cultured neonatal cardiomyocytes. Importantly, β1-AR mediated apoptosis was abrogated in cardiomyocytes expressing a PKA-resistant form of MEF2D (S121/190A). We also observed that a β1-blocker, Atenolol, antagonizes isoproterenol-induced apoptosis while concomitantly enhancing MEF2 transcriptional activity. β-AR stimulation modulated MEF2 cellular localization in cardiomyocytes and this effect was reversed by β-blocker treatment. Furthermore, Kruppel-like factor 6, a MEF2 target gene in the heart, functions as a downstream pro-survival factor in cardiomyocytes. Collectively, these data indicate that (a) MEF2 has an important pro-survival role in cardiomyocytes, and (b) β-adrenergic signaling antagonizes the pro-survival function of MEF2 in cardiomyocytes and β-blockers promote it. These observations have important clinical implications that may contribute to novel strategies for preventing cardiomyocyte apoptosis associated with heart pathology.

No MeSH data available.


Related in: MedlinePlus