Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 317

b AR (and AT 1 R) procontractile signaling, promotes AngII-dependent
aldosterone production/secretion by the adrenal gland, and mediates
niacin-induced “flushing” via the GPR109A receptor. Furthermore, since
it theoretically competes with b arr2 for GPCR binding, inhibition of b arr1
would indirectly enhance b arr2 activity and its purportedly beneficial effects
in the heart. What has become crystal clear from the studies on cardiovas-
cular b arrs to date is that the two b arr isoforms are by no means redundant
with regard to their cardiovascular actions; in fact, more often than not, their
signaling paths end at diametrically opposite cellular responses. Conse-
quently, targeting of b arrs for cardiovascular disease treatment might lead
to unexpected, and adverse, outcomes.
It appears likely that cardiovascular tissue- and/or individual b arr
isoform-specific targeting will ultimately prove to be the only realistic
approach to exploiting b arr-dependent signaling in the cardiovascular sys-
tem for therapeutic purposes. Thus, agents acting specifically in the cardiac
muscle and selectively inhibiting b arr1 or selectively stimulating b arr2
therein might be useful for HF therapy, as might adrenal b arr1-specific
inhibitors, whereas vascular-selective drugs with the reverse properties, that
is, b arr2 inhibitors or b arr1 stimulators, might be useful in the treatment of
atherosclerosis and vessel (re)stenosis. Future studies will hopefully clarify
the roles of individual b arr isoforms in vivo in each part of the cardiovascular
system. For the time being, synthesis and development of new cardiovascu-
lar GPCR “biased” ligands, which selectively activate one signaling pathway
over others or stimulate one signaling pathway, for example, b arr, while
blocking another, for example, G protein, seems the most reasonable and
pragmatic way to move forward. In any case, the field of physiology of car-
diovascular b arrs, regardless of whether they are viewed in their traditional
role of GPCR desensitizers or in their newly emerged role of receptor signal
transducers, appears to be a treasure-trove of possibilities for novel cardio-
vascular therapies. Thus, it is bound to flourish with tremendous amounts of
new information in the foreseeable future.
8. CONCLUSIONS
Given the tremendously important roles of several GPCRs in regulation
of cardiovascular physiology and function, it comes as no surprise that cardio-
vascular b arrs, which act upon these receptors either to desensitize/internalize
them or to mediate their signal transduction to various cellular effectors, are
extremely important regulators of cardiovascular biology. As more and more