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cardiomyocyte survival and protection.
34
In mouse hearts lacking
b
arrs or
AT
1A
Rs, mechanical stretch failed to produce these responses and led,
instead, to enhanced myocyte apoptosis.
34
Thus, it appears that the heart
is capable of responding to acute increases in mechanical stress by activating
cardiac
b
arr-mediated cell survival signals, which again argues in favor of a
beneficial and therapeutically desirable physiological role for cardiac AT
1
R
b
arr-dependent signaling (at least for the cardiac
b
arr2 isoform;
Table 12.1
).
3.1.3 Vascular AT
1
Rs and
b
arrs
In VSM cells, the AT
1
R is known to promote vasoconstriction and raise
blood pressure via the classic G
q/11
protein-diacylglycerol-phosphoinositide
signaling that increases intracellular Ca
2
รพ
.
81
In addition, AngII acting through
the AT
1
R is one of the most powerful growth signals for VSM cells, stimu-
lating cell proliferation that leads to VSM hyperplasia, a major contributing
factor in vascular restenosis as occurs, for instance, after percutaneous coronary
intervention followed by placement of an intravascular stent. This hyperplasia,
combined with vascular inflammation that is also promoted by AT
1
Rs resid-
ing in VSM cells, also contributes to the development of atherosclerosis.
82
b
Arr-dependent AT
1
R signaling in VSM cells has recently been docu-
mented as contributing to the proatherosclerotic effects of AngII.
35
Neointimal hyperplasia after carotid endothelial injury is enhanced in
b
arr1KO mice but, notably, diminished in
b
arr2KO mice.
35
Loss of
b
arr2
appears to decrease GPCR-stimulated VSM cell proliferation and ERK1/2-
dependent activation/migration, consistent with a role for
b
arr2 signaling in
the injury response.
35
When the low-density lipoprotein receptor KO
mouse, a genetic model of accelerated atherogenesis, is crossed onto a
b
arr2KO background, atheroma formation is significantly reduced.
35
In vitro
, both G-protein- and
b
arr-dependent pathways elicited by the
AT
1A
R converge on EGFR transactivation to stimulate proliferation of pri-
mary VSM cells.
36
Specifically,
b
arr2 seems to enhance EGFR trans-
activation by the AT
1A
R by engaging the nonreceptor tyrosine kinase,
c-Src.
36
In addition,
b
arr2-dependent ERK1/2 activation downregulates
the proapoptotic phospho-Bcl-2-associated death promoter protein, thus
inducing cytoprotective antiapoptotic effects in rat VSM cells.
37
Thus, it appears that
b
arr2 can promote AT
1A
R-dependent VSM pro-
liferation and hypertrophy, thus contributing to the development and pro-
gression of atheromas and vascular restenosis, whereas
b
arr1, as in
cardiomyocyte AT
1
R signaling, opposes the actions of
b
arr2 in VSM cells
(
Table 12.1
). The only difference appears to be that in VSM,
b
arr2 appears
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