Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 299

of hypertensive subjects 66 and studies directly testing the effects of VSM
b arrs on b AR-mediated vasodilation are lacking and likely to be inconclu-
sive, given the large number of vasoconstrictive and vasodilatory GPCRs
present in VSM that are regulated by b arrs.
Finally, b ARs (of both the b 1 and b 2 subtypes) are also expressed in the
adrenal medulla of mice and rats, where, contrary to their a 2 AR counter-
parts, they enhance catecholamine release, acting as presynaptic facilitatory
autoreceptors in an autocrine positive feedback manner. 18,68,69 Therefore,
adrenal b arrs would be expected to limit adrenal catecholamine release by
desensitizing these b ARs. However, adrenal a 2 ARs appear to play the dom-
inant role in regulation of catecholamine secretion, given that they are the
only GPCRs known to date that suppress catecholamine release from this
organ. Thus, adrenal b arr actions on a 2 ARs (rather than on b ARs) are
the determining factor in the regulation of catecholamine secretion from
the adrenal medulla.
3. CARDIOVASCULAR ANGIOTENSIN II RECEPTORS
AND b ARRS
3.1. Angiotensin II type 1 receptors
3.1.1 Cardiac AT 1 Rs and b arrs as desensitizers
The AT 1 R is a very important 7TMR in cardiovascular physiology and
pathology. In the heart, it is mainly expressed in cardiac fibroblasts, where
it stimulates cellular proliferation, thus promoting fibrosis, and in cardiac
myocytes, where it stimulates growth, thus promoting cardiac hypertro-
phy. 70 Whether it can also promote cardiomycyte contractility is still a mat-
ter of debate. 70 Combined with other cellular actions that promote
inflammation and oxidative stress, cardiac AT 1 R effects are clearly maladap-
tive and damaging for both the structure and function of the cardiac muscle,
and AT 1 Rs play a pivotal role in the so-called adverse remodeling of the
post-MI heart progressing to HF. 70 Therefore, targeting cardiac AT 1 Rs,
either directly with angiotensin receptor/AT 1 R-specific blockers (ARBs)
or indirectly with angiotensin-converting enzyme inhibitors, is a major
therapeutic strategy for cardiac disease treatment.
The AT 1 R is a classic G q/11 -coupled receptor that can also couple to G i/o
proteins. With regard to their classical role as G-protein-dependent signaling
terminators (desensitizers), very little is known about b arrs and AT 1 Rs, and
even less about cardiac b arrs and AT 1 Rs. The AT 1 R is a known GRK sub-
strate; thus, cardiac b arrs are bound to promote its desensitization in the