Biology Reference
In-Depth Information
but potentially worth exploring. In any case, the majority of AT
2
R effects
are diametrically opposite of those of the AT
1
R. For example, the AT
2
Ris
generally proapoptotic and anti-inflammatory, and specifically in VSM, it
reduces hyperplasia and cell proliferation, beneficial effects in atherosclerosis
and vascular stenosis.
81
Thus,
b
arrs, by selectively interacting with and des-
ensitizing/internalizing AT
1
Rs, may indirectly promote the effects of its
“opponent” receptor, the AT
2
R, which normally counterbalances AT
1
R
effects in cardiovascular cells and tissues. Such effects should always be con-
sidered when studying the effects of
b
arrs on cardiovascular AT
1
Rs. For
instance, part of the beneficial antiatherosclerotic actions of
b
arr1 in VSM
cells might simply be due to a “reflex” elevation of the beneficial,
proapoptotic activity of the AT
2
R, triggered by the
b
arr1-exerted suppres-
sion of AT
1
R signaling in these cells. Therefore, whenever the therapeutic
potential of stimulating the activity of a given
b
arr isoform at the AT
1
Ris
considered, especially in the cardiovascular system, the indirect impact such
a strategy might have on the function of the AT
1
R's “natural ballast,” the
AT
2
R, must always be considered.
4. OTHER CARDIOVASCULAR GPCRS AND
b
ARRS
4.1. Endothelin receptors
Like AngII, ETs are potent regulators of vascular tone and are also known to
induce VSM hyperplasia and hypertrophy, leading to hypertension and vas-
cular remodeling and occlusion (stenosis), which can severely complicate
atherosclerosis.
90
Like AngII acting through the AT
1
R, ET-1 acting
through its type A (ET
A
) receptor exerts all these effects (vasoconstriction
and VSM hyperplasia) through the classic G
q/11
protein-phospholipase
C-inositol 1,4,5-trisphosphate-diacylglycerol pathway leading to elevated
intracellular Ca
2
þ
concentration and activation of PKC. In mesenteric arte-
rial smooth muscle cells,
b
arrs have been found to antagonize this
prohypertrophic and procontractile G-protein-dependent signaling of the
ET
A
receptor, through their classical function as desensitizers of GRK2-
phosphorylated receptors.
40
Very recently, however, a novel role of
b
arrs as mediators of ET
A
recep-
tor signaling in rat aortic smooth muscle cells was uncovered. Similar to the
VSM cell AT
1
R,
b
arr2 was found to mediate not only the G protein
uncoupling of the ET
A
receptor, but also its signaling to sustained ERK
and p38 MAPK activation.
41
Notably,
b
arr1 does not seem to affect these
properties of the ET
A
receptor.
41
However, both
b
arr isoforms appear to
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