Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 304

Importantly, adrenal b arr1 appears to be a critical regulator of circulating
aldosterone levels in vivo . Under normal conditions, its adrenal-specific
upregulation causes hyperaldosteronism. 38 In experimental animals pro-
gressing to HF after experimental MI, adrenal overexpression of b arr1 ele-
vates blood aldosterone levels, whereas its adrenal-specific blockade,
achieved via gene therapy with a b arr1 carboxyl terminal-derived protein
fragment that abolishes the trafficking and signaling activities of b arr1, mark-
edly reduces circulating aldosterone levels toward normal values. 39 This tre-
mendous sensitivity of circulating aldosterone levels to adrenal b arr1
signaling in vivo has dramatic consequences for cardiac function and struc-
tural remodeling post-MI. Adrenal b arr1-promoted hyperaldosteronism
results in accelerated adverse cardiac remodeling and deterioration of left
ventricular function, whereas normalization of aldosterone levels by adrenal
b arr1-targeted gene therapy stops or even reverses the negative structural
and functional effects of aldosterone on post-MI HF progression. 39
Thus, it appears that in the adrenal gland, b arr1 is a major driving force
behind the elevation of cardiotoxic aldosterone levels that accompanies and
aggravates HF, and its inhibition might be of therapeutic value in combating
the significant cardiovascular toxicity of this hormone, for instance, in post-
MI HF, hypertension, and other cardiovascular diseases ( Table 12.1 ). Taking
into account the fact that adrenal b arr1 also causes elevation of catechol-
amine secretion from the adrenal medulla by mediating adrenal a 2 AR
desensitization and downregulation, adrenal b arr1 emerges as a pivotal
regulator of the neurohormonal, that is, catecholaminergic and
mineralocorticoid-derived, burden on the failing heart. Blockade of adrenal
b arr1 signaling, via gene therapy or pharmacologically, might achieve a
pharmacological “killing two birds with one stone” in the treatment of
HF, that is, suppression of both catecholamine and aldosterone levels, 88
which would relieve the failing heart of a great deal of toxic hormonal stress
( Table 12.1 ).
3.2. Angiotensin II type 2 receptors
In contrast to their AT 1 R counterparts, AT 2 Rs do not appear to interact
with b arrs or even to internalize in response to AngII activation. 89 However,
few studies have examined the actions of b arrs (if any) on AT 2 Rs, and in vivo
in particular, none. Consequently, whether the striking difference in the
affinity of the two major types of AngII receptors for b arrs has any role
in the differences in the effects they elicit in cells 81 is completely unknown