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Urocortin (Ucn) is a 40 amino acid peptide which is part of the hypothalamic corticotrophin releasing factor (CRF) family, which also encompasses urotensin and sauvagine. Urocortin was initially identified in rat and later in man. It is the second found mammalian member of the CRF family and exhibits 45 % amino acid sequence homology to CRF(1). Ucn is more conserved than CRF across species.
The CRF and urocortin predecessor genes consist of two exons
with the complete precursor protein encoded within the second exon. CRF
polypeptides play biologically distinct roles in the stress responses.
They act on central neurons expressing CRF receptors (1, 2). CRF
receptor agonists acting on peripheral CRF receptors contribute to the
control of cardiovascular and inflammatory responses (3). Abnormal CRF
receptor-mediated cellular signaling could be closely connected with
the pathophysiology of stress-related centrally controlled syndrome
such as anxiety, depression and impaired cardiovascular function.
Cardiovascular function is highly associated with chondrocyte actions.
Chondrocytes are the singular cell type found in cartilage. They create
and maintain the cartilaginous matrix. From least to terminally
differentiated, the chondrocytic lineage is:
1. Colony-forming unit-fibroblast (CFU-F)
2. Mesenchymal stem cell / marrow stromal cell (MSC)
3. Chondrocyte
4. Hypertrophic chondrocyte (4)
A recent study on the human heart acquired at autopsy detailed that
urocortin immunoreactivity was identified in all four chambers, with
the highest level in the left ventricle(2). Immunoreactivity of
urocortin detected in endothelial cells of rat arteries suggests that
urocortin may be locally synthesized in blood vessels (1). In contrast,
CRF immunoreactivity or CRF mRNA is essentially undetectable in the
human heart. This suggests that urocortin can be endogenously
synthesized in the human heart and may apply its cardiac action in an
autocrine and/or paracrine manner, even though the cellular position of
urocortin is not known (3).
Ucn has emerged as an important hormone in the regulation of cardiac
function, and urocortin acts directly on cardiomyocytes, binding to
CRF2 receptors and ensuing activation of multiple intracellular signal
transduction pathways that result in the positive inotropic and
cardioprotective actions (2). The physiological actions of CRF
polypeptides are arbitrated through the receptors CRF1 and CRF2,
derived from two distinct genes. Urocortin binds to CRF2 receptors with
over 100-fold greater affinity than CRF. CRF2 receptor mRNA is
extensively expressed in peripheral tissues including cardiac
myocytes(5). CRF2 (α) receptor mRNA is detected in the human heart and
CRF2 (β) receptor mRNA is chiefly expressed in the left atrium
Urocortin exerts both positive chronotropic (heart rate) and inotropic
(force of cardiac contraction) actions in the heart and increases
coronary blood flow (5, 6). These effects are linked with elevated
formation of cyclic AMP in the cardiac tissue. Urocortin accelerates
the formation of cyclic AMP. Urocortin exerts its iontropic or
chronotropic effects via a protein kinase A (PKA)-dependent vascular
K+channel (7).
Cardiac protection
Mounting evidence suggest that urocortin plays a major role in the
control of cardiovascular function (7) and may be one of the main
factors involved in the cardiovascular response to stressful
stimulation (5).
Ucn, when administered intravenously to rats, produces a slow
developing decrease in mean arterial blood pressure, which corresponds
to a rise in heart rate and cardiac output (6). A larger increase in
cardiac contractility is seen with intravenous administration of
urocortin to sheep, reflected by greater elevation in aortic blood
flow. Urocortin is more powerful than CRF in enhancing the cardiac
performance (4).
The disparity in cardiac action between CRF and urocortin may reflect
the difference in the binding affinity of the two peptides for CRF
receptors(3). Systemic administration of urocortin doesn’t enhance
cardiac performance or reduce blood pressure in CRF2 receptor-knockout
mice (1). This suggests a fundamental role of CRF2 receptors in
mediating urocortin induced peripheral haemodynamic effects. Urocortin
mRNA is detected in both cultured neonatal cardiac myocytes and the
adult heart of rats and urocortin protects the intact rat heart against
the damaging effects of ischemia and reperfusion injury (9).
Urocortin and hypoxia
Molecular and pharmacological evidence indicates that urocortin could
act as a endogenous cardioprotective factor in response to cardiac
injury (8), and may possess potential therapeutic activity in the
therapy for myocardial infarction and heart failure (10).
Urocortin exerts a protective effect in primary cardiac myocyte culture
exposed to lethal simulated hypoxia or ischemia. This effect is prompt,
occurring 30 min after urocortin administration. Urocortin is also
cardioprotective when added at the time of reoxygenation (4).
Expression of urocortin mRNA in a rat cardiac cell line or in primary
cultures of cardiomyocytes is increased in 12-18.hours after thermal
injury, it is suggested that urocortin is an endogenous cardiomyocyte
peptide which modulates the cellular response to stress (9).
Hypoxia/ischemia is the main physiological stress to the heart and
increased expression of heat shock proteins is linked to the cardiac
protection against hypoxic stress (11, 12). Heat shock protein
expression, triggered by thermal or ischemic preconditioning, results
in reduction in infarction size (12). Studies show a direct positive
correlation between amount of heat shock protein and degree of
myocardial protection, indicating several signaling pathways mediating
the cardioprotective effect of urocortin (13).
Urocortin produces a potent and enduring hypotensive action in
conscious rats which is probably due to reduced peripheral vascular
resistance (3). Its vasodilator effect was also reported in human
perfused placenta and saphenous veins. Intravenous injection of
urocortin produces vasodilatation, an effect more potent than that of
CRF (10).
Urocortin as a therapeutic agent
Coronary vasodilatation concurrent with the potential benefits in the
cardiac system highlights the potential of developing urocortin and
CRF-related peptides into therapeutic agents against the destructive
effect of ischemia and reperfusion injury to the heart. In addition to
the positive inotropism, the hypertrophic effect of urocortin may
signify a compensatory mechanism by which cardiac function could be
enhanced in response to the failing heart (9). This adaptive mechanism
may in the long run impair ventricular functioning when sustained with
increasing oxygen demand (1, 5). The hypertrophic response could reduce
the potential worth of urocortin in the treatment of ischemic heart
disease.
Many of Ucn’s actions, including vasorelaxation (both cardiac and
peripheral), positive inotropism, cytokine inhibition, and
cardio-protection, are expected to be favorable in the treatment of
disorders associated with cardiac dysfunction and overload i.e.
congestive heart failure (12). Short-term systemic administration of
Ucn in experimental ovine heart failure has been shown to produce
noticeable and dose-dependent increases in cardiac output and
reductions in peripheral resistance, arterial pressure and ventricular
filling pressure (5, 9). Whilst the mechanisms underlying these changes
(hormonal and renal) are unknown, this grouping of responses to single
peptide reductions in cardiac preload and afterload, enhanced cardiac
output, inhibition of a range of vasoconstrictor/volume-retaining
factors and improved renal function covers many of the therapeutic
objectives of heart failure management. Further studies are required to
determine Ucn's true potential in this setting (13). Ucn’s range of
cardioprotective actions (improved cell survival and bioenergetics,
increased coronary blood flow and secretion of atrial and brain
natriuretic peptide) which have demonstrated reduced damaging effects
of ischemia/reperfusion injury make it a likely direction in the
treatment of these events (8, 11). It is plausible that Ucn
administration may be a beneficial adjunctive therapy for myocardial
infarction and coronary angioplasty (9).
Conclusions and future directions
Escalating evidence indicates a role for Ucn in cardiac and pressure regulation, and in the pathophysiology of cardiovascular disease,
where it may have protecting compensatory actions (5). Recently, two
further associates of the CRF peptide family were identified, Ucn II
and Ucn III due to their homology with Ucn. In distinction to Ucn which
exhibits a comparable affinity for both CRF receptor subtypes, Ucn II
and III are highly selective for CRF-R2 exhibiting minor affinity for
CRF-R1 (11, 12). The cardiovascular effects of Ucn appear to be
principally attributed to activation of CRF-R2, very recent studies
have found Ucn II and Ucn III exhibited more potent cardioprotective
effects (both anti-necrotic and anti-apoptotic) than Ucn in
cardiomyocytes exposed to hypoxic/reperfusion injury (6), although, the
vasodilator properties of the two new Ucn peptides are less
potent than Ucn in rat thoracic aorta (4). Further investigation of the
Ucn family of peptides is necessary to establish their true
physiological and pathophysiological importance, especially study into
secretion regulation (in tissues and circulation), relationships with
hemodynamic/cardiac function, mechanisms of action interactions with
other vasoactive factors, and effects of administration both
chronically and in humans (1). This information will help verify their
potential as a therapeutic option in cardiovascular disease. If
this aptitude is attained, a challenge for the future is the
development of an orally active agent which binds to the CRF-R2
receptor (9).
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