Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 296

signaling in the failing heart might differ substantially from the beneficial sig-
naling pattern in the normal heart; in HF, it seems to be more “diffuse,” that
is, less “compartmentalized,” and resembles more the proapoptotic cAMP
signaling pattern of its b 1 AR counterpart. 58 Therefore, the aforementioned
stoichiometric shift in favor of the “good” b 2 AR in HF appears unable to
help the heart to adapt its structure and function.
2.3.2 Cardiac b ARs and b arrs as desensitizers
b arrs are abundantly expressed in cardiac muscle. 59 As cofactors of GRKs in
cardiomyocyte b AR desensitization and/or downregulation, they contribute
to the diminished inotropic and adrenergic reserve of the failing heart and
their inhibition should theoretically be beneficial in acute HF, as it would
enhance the G a s -AC-PKA-mediated pro-contractile signaling of cardiac
b ARs, which increases cardiac contractility. 21-24 Indeed, indirect blockade
of b arr desensitizing action on cardiac b ARs, that is, by genetic blockade
of GRK2 and GRK5, the main cardiac GRKs stimulating b arr-dependent
cardiac b AR desensitization, results in several desirable therapeutic effects
in HF, such as dramatic improvement in positive inotropy and cardiac
b -adrenergic reserve, amelioration of adverse remodeling, and increased sur-
vival (reviewed in Ref. 21-24 ; Table 12.1 ). Studies in global b arr1KO mice
have confirmed that cardiac b arr1 diminishes inotropic and adrenergic
reserves by means of desensitizing cardiomyocyte b 1 -and b 2 ARs
( Table 12.1 ). The contractile response of b arr1KO mice to isoproterenol, a
b AR agonist cardio-stimulant (positive inotrope), is significantly augmented
compared to that of wild-type mice, while basal contractility is unaffected. 60
Of note, cardiac b arr2 does not appear to undergo compensatory upregulation
in b arr1KOmice or to compensate for the loss of b arr1 in the myocardium, 60
indicating that the two b arr isoforms are rarely (if at all) physiologically
interchangeable. Data from our lab in the same mice under conditions of
myocardial infarction (MI)-induced HF have confirmed this predominant
b AR desensitizing/downregulating, and hence contractility-limiting, role
of cardiac b arr1 ( Table 12.1 ). However, the majority of studies on cardiac
b AR desensitization and its inhibition for therapeutic purposes in HF have
focused on blockade of GRK action and not directly on b arr action on cardiac
b ARs per se . Therefore, any conclusions on the potential therapeutic benefits
of cardiac b arr blockade for reversing b AR desensitization and increasing car-
diac function must be drawn with caution, especially since cardiac b arr inter-
action with b ARs can have additional effects, that is, signal transduction,
beyond merely conferring b AR desensitization/downregulation.