Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 297

2.3.3 Cardiac arrs as signal transducers

In contrast to their action on cardiac b ARs as desensitizers, b arr actions on
cardiac b ARs as signal transducers have been studied directly and at an
accelerating pace, and these studies have yielded several interesting, if not
eye-opening, findings. A consensus for cardiac b 1 AR signaling is beginning
to unfold, according to which cardiac b 1 AR signaling is beneficial for the
heart when it is mediated by b arrs, but cardiotoxic when it is G-protein-
dependent. In HF, chronic catecholaminergic stimulation of the b 1 AR
promotes cardiac hypertrophy, decreases contractility, and increases myocyte
apoptosis. 61 As a result, administration of b -blockers is currently part of stan-
dard care in the clinical management of congestive HF. 62,63

ARs and

b b

b arrs have been
shown in vitro to mediate the mitogenic signaling of EGF (epidermal growth
factor) receptor (EGFR) transactivation by the b 1 AR. As inhibition of EGFR
contributes to dilated cardiomyopathy, b 1 AR signaling via b arr2 appears to
have protective rather than deleterious effects on the heart 25 and b arr2-
dependent EGFR transactivation might exert a cardioprotective effect 26,27
( Table 12.1 ). The physiologic relevance of EGFR transactivation by
b 1 AR-bound b arr2 has been demonstrated in transgenic mice overexpressing
wild-type b 1 ARs or mutant b 1 ARs lacking GRK phosphorylation sites that
are unable to undergo GRK-mediated phosphorylation and bind b arrs.
Under conditions of chronic catecholamine stress, transgenic mice over-
expressing the mutant b 1 AR are incapable of transactivating cardiac EGFRs
and show marked myocyte apoptosis and left ventricular dilatation compared
tomice expressingwild-type b 1 ARs. 25 Further substantiating a role for EGFR
transactivation in the mechanism underlying these findings, pretreatment of
mice overexpressing the wild-type b 1 AR in their hearts with the selective
EGFR inhibitor, erlotinib, prevents any improvement in cardiac function
upon chronic stimulation with catecholamines. 25 Finally, data from our lab
in post-MI b arr1KO mice confirm that b arr2 (and not b arr1) is the b arr iso-
form that mediates EGFR transactivation by the cardiac b 1 AR in vivo ,andthat
cardiac b arr1 might physiologically antagonize this effect of b arr2. We found
that compared to wild-type control mouse hearts, post-MI b arr1KO mouse
hearts display significantly elevated EGFR activity levels in vivo in response to
treatment with isoproterenol in the presence of the b 2 AR-selective antagonist
ICI 118,551, that is, a treatment that activates only cardiac b 1 ARs.
With regard to physiologic relevance of b 2 AR-elicited b arr signaling in
the heart, very little (if anything) is known. It appears that b arr binding to
this receptor subtype in the heart is predominantly deleterious, since, by
means of classical desensitization,

it blocks the G s protein-mediated