pepducin-mediated cardioprotection via beta-arrestin-biased beta2-adrenergic receptor-specific signaling.pdf (2.3 MB)

pepducin-mediated cardioprotection via beta-arrestin-biased beta2-adrenergic receptor-specific signaling.pdf

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journal contribution
posted on 08.03.2019 by Laurel A. Grisanti, Toby P. Thomas, Rhonda L. Carter, Claudio de Lucia, Erhe Gao, Walter J. Koch, Jeffrey L. Benovic, Douglas G. Tilley
Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces
further cardiomyocyte death. β-arrestin (βarr)-biased β-adrenergic receptor (βAR) activation promotes
survival signaling responses in vitro; thus, we hypothesize that this pathway can mitigate cardiomyocyte death
at the time of reperfusion to better preserve function. However, a lack of efficacious βarr-biased orthosteric
small molecules has prevented investigation into whether this pathway relays protection against ischemic injury
in vivo. We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from
the first intracellular loop of β2AR, allosterically engaged pro-survival signaling cascades in a βarr-dependent
manner in vitro. Thus, in this study we tested whether ICL1-9 relays cardioprotection against
ischemia/reperfusion (I/R)-induced injury in vivo.
Methods: Wild-type (WT) C57BL/6, β2AR knockout (KO), βarr1KO and βarr2KO mice received
intracardiac injections of either ICL1-9 or a scrambled control pepducin (Scr) at the time of ischemia (30 min)
followed by reperfusion for either 24 h, to assess infarct size and cardiomyocyte death, or 4 weeks, to monitor
the impact of ICL1-9 on long-term cardiac structure and function. Neonatal rat ventricular myocytes (NRVM)
were used to assess the impact of ICL1-9 versus Scr pepducin on cardiomyocyte survival and mitochondrial
superoxide formation in response to either serum deprivation or hypoxia/reoxygenation (H/R) in vitro and to
investigate the associated mechanism(s).
Results: Intramyocardial injection of ICL1-9 at the time of I/R reduced infarct size, cardiomyocyte death and
improved cardiac function in a β2AR- and βarr-dependent manner, which led to improved contractile function
early and less fibrotic remodeling over time. Mechanistically, ICL1-9 attenuated mitochondrial superoxide
production and promoted cardiomyocyte survival in a RhoA/ROCK-dependent manner. RhoA activation could
be detected in cardiomyocytes and whole heart up to 24 h post-treatment, demonstrating the stability of
ICL1-9 effects on βarr-dependent β2AR signaling.
Conclusion: Pepducin-based allosteric modulation of βarr-dependent β2AR signaling represents a novel
therapeutic approach to reduce reperfusion-induced cardiac injury and relay long-term cardiac remodeling
benefits.

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