Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 289

extremely significant and versatile. Amore complete appreciation of the car-
diovascular roles of b arrs has recently become possible due to a combination
of techniques and tools, such as utilization of the (global) b arr1 and b arr2
knockout (KO) mice, usage of isoform-specific siRNA knockdown in
in vitro systems, employment of in vitro and in vivo systems of artificially con-
structed 7TMR mutants incapable of signaling through G proteins, and,
finally, synthesis and development of signaling pathway-selective (biased)
7TMR ligands that preferentially elicit b arr signaling over G protein signaling
(and vice versa) from a given GPCR. This chapter gives a comprehensive
account of the current knowledge in the field of the roles and functions of
arrestins in the cardiovascular system, addressing each individual cardiovascu-
lar receptor type and cardiovascular organ/tissue type the b arrs act upon, and,
whenever possible, discussing whether their effects are due to their ability to
act as receptor desensitizers/internalizers or signal transducers.

2. CARDIOVASCULAR ADRENERGIC RECEPTORS AND
b ARRS
2.1. 1 -Adrenergic receptors

Cardiovascular a 1 -adrenergic receptors ( a 1 ARs), consisting of three phar-
macological subtypes ( a 1A , a 1B , a 1D ), function as stimulatory receptors
and are the classical adrenoceptors mediating vascular smooth muscle
(VSM) contraction, elevating systemic blood pressure via coupling to the
G q/11 protein-phospholipase C-Ca 2 þ mobilization pathway. 1 A fall in
blood pressure due to causes such as hemorrhage will activate the barorecep-
tor reflex, increasing sympathetic outflow to cause vasoconstriction, via
a 1 ARs, of less vital vascular beds, especially splanchnic and skin, an effect
that plays an important part in the “fight or flight” response produced by
the sympathetic nervous system to situations of acute stress. 2

a

a 1 AR antag-
onists lower blood pressure in hypertension and a 1 AR agonist-mediated
vasoconstriction can be used to treat hypotension. This vasoconstrictive
property is also taken advantage of in alleviation of nasal congestion, a con-
dition for which several preparations containing a 1 AR agonists are used.
On the other hand, a 1 ARs present in coronary artery smooth muscle can
cause vasoconstriction and precipitate angina pectoris. 2
In addition to smooth muscle cells of various vascular beds, a 1 ARs are
also expressed in cardiac myocytes, albeit to a considerably lower extent than
their b AR counterparts. Their cardiac effects are potentially harmful, since
cardiac a 1 ARs mediate pathological cardiac hypertrophy leading to heart