Beta-Blockers Enhance the Pro-Survival Function of Mef2 in Post-Heart Attack Cardiomyocytes

Investigators at York University (Toronto, Canada) had shown previously that MEF2 gene activity was suppressed by beta1-adrenergic receptor (beta1-AR) stimulation, which after heart attack, increased apoptosis in cardiomyocytes through activation of cAMP/protein kinase A (PKA) signaling.

The adrenergic receptors (subtypes alpha 1, alpha 2, beta 1, and beta 2) are a prototypic family of guanine nucleotide binding regulatory protein-coupled receptors that mediate the physiological effects of the hormone epinephrine and the neurotransmitter norepinephrine. Specific polymorphisms in this gene have been shown to affect the resting heart rate and can be involved in heart failure. In addition, flow cytometry identified siRNA-mediated gene silencing of MEF2 as inducing cardiomyocyte apoptosis.

In a follow-up study published in the September 14, 2015, online edition of the journal Cell Death Discovery, the investigators reported that beta1-AR-mediated apoptosis was abrogated in cardiomyocytes expressing a PKA-resistant form of MEF2. They also showed that a beta1-blocker, Atenolol, antagonized the apoptosis pathway while concomitantly enhancing MEF2 transcriptional activity. Beta-AR stimulation modulated MEF2 cellular localization in cardiomyocytes, and this effect was reversed by beta-blocker treatment. Furthermore, Kruppel-like factor 6 (KFL6), a MEF2 target gene in the heart, functioned as a downstream pro-survival factor in cardiomyocytes.

Collectively, these data indicated that (a) MEF2 had an important pro-survival role in cardiomyocytes, and (b) beta-adrenergic signaling antagonized the pro-survival function of MEF2 in cardiomyocytes and beta-blockers promoted it.

Senior author Dr. John McDermott, professor of biology at York University, said, "An initial clue was the accumulating evidence that the primary function of the MEF2 protein complex in neurons is to protect them from dying off. We suspected that these proteins might play a similar role in the heart."

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