Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 303

to be the “damaging” b arr isoform and b arr1 the “beneficial” one, whereas
in cardiac myocytes, it is the other way around, that is, b arr2 seems beneficial
by promoting AT 1 R-dependent contractility and b arr1 harmful by oppos-
ing it. In conclusion, b arr2 inhibition and/or b arr1 stimulation might be
desirable for the treatment of VSM hyperplasia and atherosclerotic/arterio-
sclerotic disease, contrary to HF, for which b arr2 stimulation appears to be a
valid therapeutic strategy ( Table 12.1 ).
3.1.4 Adrenal AT 1 Rs and b arrs
Aldosterone is one of a number of hormones whose levels are elevated in
HF. It produces a multitude of negative effects on the failing heart, including
promotion of salt retention, adverse post-MI cardiac remodeling, and HF
progression. 83-85 Its importance in cardiovascular pathophysiology is
highlighted by the huge success of mineralocorticoid (aldosterone) receptor
blockers, such as spironolactone and eplerenone, in the treatment of HF and
other heart diseases. 86 Aldosterone is produced and secreted by the adreno-
cortical zona glomerulosa cells in response to AT 1 R activation by AngII. 87
Until recently, the general consensus as regards AT 1 R signaling to aldoste-
rone production in the adrenal cortex was that it also proceeded through the
classical G q/11 protein-phosphoinositide-intracellular Ca 2 þ pathway. 81
However, a crucial role for adrenal b arr1-dependent signaling in AT 1 R-
induced aldosterone synthesis and secretion has now been demonstrated. 38
In adrenocortical zona glomerulosa cells in vitro , b arr1 was found to stimulate
sustained ERK1/2 activation and subsequent upregulation of the steroido-
genic acute regulatory (StAR) protein, a steroid transport protein that cat-
alyzes the rate-limiting step in adrenal steroid biosynthesis, that is,
mitochondrial cholesterol uptake. 38 These effects could be produced by
AT 1 R activation by SII, indicating that they were G-protein-independent,
and led to a marked increase in aldosterone synthesis and secretion from
these cells. 38 Of note, since StAR is the rate-limiting enzyme in the synthesis
of all adrenal steroids, adrenocortical b arr1-dependent signaling might also
affect the biosynthesis of other adrenal steroids (e.g., glucocorticoids). 38
With regard to adrenal b arr2, this b arr isoform appears to be expressed at
very low levels in the adrenal cortex and is barely detectable in human adre-
nocortical zona glomerulosa cells. 38 Whether b arr2-dependent signaling
from the adrenal AT 1 R also affects aldosterone production/secretion and
whether it affects it in a similar manner as b arr1 or opposes this effect of b arr1
remain open questions.