Long-Term Biased β-Arrestin Signaling Improves Cardiac Structure and Function in Dilated Cardiomyopathy
Background—Biased agonism of the angiotensin receptor (AT1R) is known to promote cardiac contractility. Our laboratory indicated that these effects may be due to changes at the level of the myofilaments. However, these signaling mechanisms remain unknown. As a common finding in dilated cardiomyopathy (DCM) is a reduction in the myofilament-Ca2+-response, we hypothesized that β-arrestin signaling would increase myofilament-Ca2+-responsiveness in a model of familial DCM and improve cardiac function and morphology.
Methods—We treated a DCM-linked mouse model expressing a mutant tropomyosin (Tm-E54K), for three months with either TRV120067, a β-arrestin 2 biased ligand of the AT1R, or losartan, an AT1R blocker. At the end of the treatment protocol, we assessed cardiac function using echocardiography, the myofilament-Ca2+-response of detergent-extracted fiber bundles, and used proteomic approaches to understand changes in post-translational modifications of proteins that may explain functional changes. We also assessed signaling pathways altered in vivo and using isolated myocytes.
Results—TRV120067- treated Tm-E54K mice showed improved cardiac structure and function, whereas losartan-treated mice had no improvement. Myofilaments of TRV120067-treated Tm-E54K mice had significantly improved myofilament-Ca2+-responsiveness, which was depressed in untreated Tm-E54K mice. We attributed these changes to increased MLC2v and MYPT1/2 phosphorylation seen only in TRV120067-treated mice. We found that the functional changes were due to an activation of ERK1/2-RSK3 signaling, mediated through β-arrestin, which may have a novel role in increasing MLC2v phosphorylation through a previously unrecognized interaction of β-arrestin localized to the sarcomere.
Conclusions—Long-term β-arrestin 2 biased agonism of the AT1R may be a viable approach to the treatment of DCM by not only preventing maladaptive signaling, but also improving cardiac function by altering the myofilament-Ca2+-response via β-arrestin signaling pathways.
- Biased ligand
- Calcium sensitivity
- angiotensin receptor
- angiotension II receptor blocker
- dilated cardiomyopathy
- sarcomere physiology
- Received July 13, 2016.
- Revision received December 8, 2016.
- Accepted January 12, 2017.