Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 301

effects of b arr2onAT 1 R-elicitedcontractility and relaxation, that is, b arr1pro-
motes negative inotropy and lusitropy upon AT 1 R activation in cardiac
myocytes. 33 These findings are consistent with the specialized roles of the var-
ious GRK isoforms described in transfected systems, 48 and also with the con-
cept of GRK-induced receptor “barcoding,” that is, the hypothesis that
different GRK isoforms acting on the same GPCR induce recruitment of
different b arr isoforms, resulting in different downstream signaling events and
cellular responses, by phosphorylating the receptor at different sites/residues. 79
In contrast to isolated murine cardiac myocytes, SII-activated AT 1 Rs (i.e.,
AT 1 R-bound b arrs) do not seem to produce inotropic or chronotropic effects
in isolated Langendorff-perfused cardiac preparations, despite the fact that
ERK1/2, which presumably mediates the positive inotropic effects of b arr2
in isolated cardiac myocytes, 33 is also activated by AT 1 R-bound b arrs in Lan-
gendorff preparations. 32 Thus, it seems that the positive inotropic effects of car-
diac b arr2 are strongly cell type- and experimental condition-dependent.
Nevertheless, a consensus has emerged, according to which cardiomyocyte
AT 1 Rs promotehypertrophy and cardiomyocyte proliferationvia b arrs, as well
as contractility via (at least) b arr2, whereas cardiac fibroblast AT 1 Rs promote
fibrosis and cardiac adverse remodeling via the classical G q/11
protein-PKC-Ca 2 þ signaling pathway. Since b arr2 also terminates the
G-protein-mediated signaling of the AT 1 R, stimulation of cardiac b arr2 activ-
ity and/or blockade of cardiac b arr1 activity at theAT 1 Rs of the heart might be
beneficial for the treatment of post-MI HF and the cardiac hypertrophy and
adverse remodeling that accompany this devastating disease ( Table 12.1 ).
Indeed, TRV120027, a compound analogous to SII, that is, a b arr-biased
AT 1 R agonist that selectively activates b arrs while blocking G protein signal-
ing, has shown promising results in animal models, blocking the undesirable
G-protein-mediated AT 1 R-induced vasoconstriction, thereby preserving
renal function while, at the same time, enhancing the desirable (in acute
HF) b arr-dependent contractility of cardiac myocytes. TRV120027 is cur-
rently under development for the clinical treatment of HF. 80
Another interesting example of cardiac AT 1 R b arr-mediated signaling is
mechanical stretch-activation of the AT 1 R. 34 Rakesh et al. showed that sim-
ple mechanical stretch (in the absence of any ligand) can activate the AT 1A R,
leading to selective b arr recruitment and signaling without concomitant
G protein activation. 34 What is more, the authors showed in an ex vivo
murine heart model that this stretch-activated AT 1A R-elicited b arr signaling
resulted in enhanced ERK1/2 and Akt (protein kinase B; PKB) activation,
as well as EGFR transactivation, effects believed to mediate enhanced