Title

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of beta-adrenergic receptor signaling

UMMS Affiliation

Department of Cell and Developmental Biology; Stephen Jones Lab

Publication Date

9-7-2017

Document Type

Article

Disciplines

Cardiology | Cell Biology | Developmental Biology | Oncology

Abstract

The oncoprotein Mdm2 is a RING domain-containing E3 ubiquitin ligase that ubiquitinates G protein-coupled receptor kinase 2 (GRK2) and beta-arrestin2, thereby regulating beta-adrenergic receptor (betaAR) signaling and endocytosis. Previous studies showed that cardiac Mdm2 expression is critical for controlling p53-dependent apoptosis during early embryonic development, but the role of Mdm2 in the developed adult heart is unknown. We aimed to identify if Mdm2 affects betaAR signaling and cardiac function in adult mice. Using Mdm2/p53-KO mice, which survive for 9-12 months, we identified a critical and potentially novel role for Mdm2 in the adult mouse heart through its regulation of cardiac beta1AR signaling. While baseline cardiac function was mostly similar in both Mdm2/p53-KO and wild-type (WT) mice, isoproterenol-induced cardiac contractility in Mdm2/p53-KO was significantly blunted compared with WT mice. Isoproterenol increased cAMP in left ventricles of WT but not of Mdm2/p53-KO mice. Additionally, while basal and forskolin-induced calcium handling in isolated Mdm2/p53-KO and WT cardiomyocytes were equivalent, isoproterenol-induced calcium handling in Mdm2/p53-KO was impaired. Mdm2/p53-KO hearts expressed 2-fold more GRK2 than WT. GRK2 polyubiquitination via lysine-48 linkages was significantly reduced in Mdm2/p53-KO hearts. Tamoxifen-inducible cardiomyocyte-specific deletion of Mdm2 in adult mice also led to a significant increase in GRK2, and resulted in severely impaired cardiac function, high mortality, and no detectable betaAR responsiveness. Gene delivery of either Mdm2 or GRK2-CT in vivo using adeno-associated virus 9 (AAV9) effectively rescued beta1AR-induced cardiac contractility in Mdm2/p53-KO. These findings reveal a critical p53-independent physiological role of Mdm2 in adult hearts, namely, regulation of GRK2-mediated desensitization of betaAR signaling.

Keywords

Cardiology, Oncology, Heart failure, Ubiquitin-proteosome system

DOI of Published Version

10.1172/jci.insight.95998

Source

JCI Insight. 2017 Sep 7;2(17). pii: 95998. doi: 10.1172/jci.insight.95998. Link to article on publisher's site

Journal/Book/Conference Title

JCI insight

Related Resources

Link to Article in PubMed

PubMed ID

28878120

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