GRK5-Mediated Exacerbation of Pathological Cardiac Hypertrophy Involves Facilitation of Nuclear NFAT Activity
Rationale: G protein-coupled receptor (GPCR) kinases (GRKs) acting in the cardiomyocyte regulate important signaling events that control cardiac function. Both GRK2 and GRK5, the predominant GRKs expressed in the heart, have been shown to be up-regulated in failing human myocardium. While the canonical role of GRKs is to desensitize GPCRs via phosphorylation, it has been demonstrated that GRK5, unlike GRK2, can reside in the nucleus of myocytes and exert GPCR-independent effects that promote maladaptive cardiac hypertrophy and heart failure (HF).
Objective: To explore novel mechanisms by which GRK5 acting in the nucleus of cardiomyocytes participates in pathological cardiac hypertrophy.
Methods and Results: In this study, we have found that GRK5-mediated pathological cardiac hypertrophy involves the activation of nuclear factor of activated T-cells (NFAT) as GRK5 causes enhancement of NFAT-mediated hypertrophic gene transcription. Transgenic mice with cardiomyocyte-specific GRK5 overexpression activate an NFAT-reporter in mice basally and after hypertrophic stimuli including transverse aortic constriction (TAC) and phenylephrine treatment. Complimentary to this, GRK5 null mice exhibit less NFAT transcriptional activity after TAC. Further, loss of NFATc3 expression in the heart protected GRK5 overexpressing transgenic mice from the exaggerated hypertrophy and early progression to HF seen after TAC. Molecular studies suggest that GRK5 acts in concert with NFAT to increase hypertrophic gene transcription in the nucleus via GRK5's ability to bind DNA directly without a phosphorylation event.
Conclusions: GRK5, acting in a kinase-independent manner, is a facilitator of NFAT activity and part of a DNA binding complex responsible for pathological hypertrophic gene transcription.
- Received May 27, 2014.
- Revision received October 15, 2014.
- Accepted October 20, 2014.