Cardiovascular role of urotensin II: effect of chronic infusion in the rat

doi:10.1016/j.peptides.2004.03.029

Peptides

Volume 25, Issue 10, October 2004, Pages 1783-1788

https://doi.org/10.1016/j.peptides.2004.03.029 Get rights and content

Abstract

Urotensin II (UII) is a potent vaso-active peptide thought to have multiple roles in the regulation of cardiovascular physiology and pathophysiology. The actions of UII are complex and difficult to interpret given its systemic hemodynamic effects and variable action on different vascular beds and isolated vessels. Direct effects of UII on the myocardium, include myocyte hypertrophy, extracellular matrix deposition and contractility. These observations, together with elevated plasma levels found in disease, are common traits reported in other pathophysiologically implicated neurohormonal systems. In this review, we include original data obtained from chronic infusion of UII in rats. We report a reduction in first derivative of left ventricular pressure (+dP/dt), as well as an increase in the ratio of left ventricular collagen I:III, that may contribute to the reduced myocardial contractility observed in these animals.

Introduction

Urotensin II (UII) is a somatostatin-like cyclic 11-amino acid vasoconstrictor peptide, first identified in the teleost fish caudal-neuro-secretory system [7]. The active moiety of UII is the cyclic domain, which is well conserved across all species [8]. The actions of UII are mediated by a single G-protein coupled receptor, GPR14, now renamed UT [9]. UII is the most potent of all vasoconstrictors acting on cardiovascular, renal, central nervous system, and endocrine systems.

The identification of UII and its receptor in the heart has generated considerable interest in this peptide in the field of cardiovascular physiology and pathophysiology [1]. Together with the knowledge that other vasoconstrictor systems, such as the renin-angiotensin, endothelin and sympathetic nervous systems are important in the progression of cardiovascular diseases, emerging data on the role of UII suggest that this may be another system with a potentially important role in cardiovascular disease. Furthermore, studies have reported UII plasma levels to be elevated in many disease states, including chronic heart failure [11]. This review will focus on the cardiovascular actions of UII and its role in disease.

Section snippets

Cardiac fibrosis

Our group has recently demonstrated the presence of UII and its receptor in both myocytes and cardiac fibroblasts and a possible role of UII in fibrosis. Furthermore, in a rat model of heart failure following myocardial infarction (MI), both peptide and receptor expression are increased in both infarct and non-infarct regions of the left ventricle compared with sham-operated controls [31], suggesting an important role for UII in cardiac pathophysiology. Additionally, we have shown that in

Direct actions of urotensin II on the vasculature

UII is a potent vasoconstrictor in isolated tissue bath studies. The contractile activity of UII in rat thoracic aorta is 10- and 3-fold more potent than endothelin-1 and angiotensin-II, respectively [10]. Removal of the UT receptor gene in knockout mice selectively abolishes all vasoconstrictor responses to UII [2].

Many studies have examined the effects of UII on the vasculature and have reported large differences in responses to UII between species, different vascular beds and even within the

Systemic effects of urotensin II

The systemic effects of UII have been assessed in non-human primates and rats. Infusion of UII in cynomologus monkey demonstrated reductions in mean arterial pressure together with reduction in carotid and regional blood flow. This was accompanied by a reduced cardiac output-volume and +dP/dt as well as increases in left ventricular end-diastolic pressure and total peripheral resistance. The animals went into a state of cardiovascular collapse, thought to be related to either reduced cardiac

Effect of chronic urotensin II infusion in the rat

Our group has recently shown that, in vitro, UII stimulates collagen gene and protein expression in cardiac fibroblasts, implicating a role in cardiac fibrosis [31]. Given the dramatic effect of bolus UII infusion in anaesthetized monkeys [1], and the dose-dependent vasodilator response observed in conscious rat mesenteric and hindquarter vascular beds at 300 and 3000 pmol/kg [13], we chose the lower dose of UII, infused at an hourly rate into rats by osmotic mini-pump for 2 weeks. We examined

Role of urotensin II in human cardiovascular disease

UII has been implicated in several cardiovascular disease states, including chronic heart failure, kidney failure and diabetes mellitus.

We have shown that UII and its receptor are up-regulated in the post-MI setting in the rat [31]. Similar changes have been observed in human myocardium of patients with heart failure, where an increase in UII expression significantly correlated with a decrease in ejection fraction [11].

Several groups have examined plasma levels of UII in chronic heart failure

Urotensin II receptor antagonists as a therapeutic target

The development of inhibitors of neurohormonal systems, such as the renin-angiotensin, endothelin and sympathetic nervous systems, have provided beneficial therapies in the treatment of many cardiac diseases. To determine whether blockade of UII will be of benefit in cardiovascular disease, UII receptor antagonists, or compounds that inhibit the conversion of precursors to mature peptide, need to be examined in relevant disease models. Thus far, several compounds that act on different receptors

Conclusions

The role of UII in the regulation of the cardiovascular system is not fully understood. Further studies utilizing UT receptor antagonists in animal models of disease, and the generation of UT receptor transgenic and knockout animals, are required to determine whether UII has a major role in the pathophysiology of cardiovascular disease.

References (36)

A.P. Davenport et al.
Urotensin II: fish neuropeptide catches orphan receptor
Trends Pharmacol Sci.
(2000)
S.A. Douglas et al.
Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease
Trends Cardiovasc Med.
(2000)
S.A. Douglas et al.
Congestive heart failure and myocardial expression of urotensin II
Lancet
(2002)
T. Dschietzig et al.
Plasma levels and cardiovascular gene expression of urotensin-II in human heart failure
Regul. Pept.
(2002)
A. Gibson et al.
Cardiovascular effects of urotensin II in anesthetized and pithed rats
Gen. Comp. Endocrinol.
(1986)
G.A. Gray et al.
Human urotensin II increases coronary perfusion pressure in the isolated rat heart: potentiation by nitric oxide synthase and cyclooxygenase inhibition
Life Sci.
(2001)
P.R. Kalra et al.
Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure?
Int. J. Cardiol.
(2002)
K. Totsune et al.
Role of urotensin II in patients on dialysis
Lancet
(2001)
R.S. Ames et al.
Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14
Nature
(1999)
D.J. Behm et al.
Deletion of the UT receptor gene results in the selective loss of urotensin-II contractile activity in aortae isolated from UT receptor knockout mice
Br. J. Pharmacol.
(2003)

D.J. Behm et al.

Pharmacological characterization of SB-710411 (Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide), a novel peptidic urotensin-II receptor antagonist

Br. J. Pharmacol.

(2002)

F. Bohm et al.

Urotensin II evokes potent vasoconstriction in humans in vivo

Br. J. Pharmacol.

(2002)

F.E. Bottrill et al.

Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries

Br. J. Pharmacol.

(2000)

V. Camarda et al.

Effects of human urotensin II in isolated vessels of various species; comparison with other vasoactive agents

Naunyn Schmiedebergs Arch Pharmacol.

(2002)

S.A. Douglas et al.

Urotensin receptors

S.A. Douglas et al.

Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey

Br. .J Pharmacol.

(2000)

S.M. Gardiner et al.

Depressor and regionally selective vasodilator effects of human and rat urotensin II in conscious rats

Br. J. Pharmacol.

(2001)

G.S. Hassan et al.

Effect of human urotensin-II infusion on hemodynamics and cardiac function

Can. J. Physiol. Pharmacol.

(2003)

Cited by (39)

Study of urotensin-2 (T21M and S89N) gene polymorphisms in systemic sclerosis
2017, Meta Gene
Citation Excerpt :
Kompa et al., revealed the fibrotic effects of UTS2 in the myocardium. They infused UTS2 for 2 weeks and documented that UTS2 led to an increase in left ventricular end-diastolic pressure, which indicated myocardial fibrosis and increased the ratio of collagen types I and III (Kompa et al., 2004). Another study by Tran et al. also supported these data, with the finding of an association of chronic UTS2 infusion and fibrosis of the left ventricle and diastolic dysfunction caused by increasing collagen type I (Tran et al., 2010).
Systemic sclerosis (SSc) is an immune-mediated fibrotic disease. Urotensin II (UTS2) is a new peptide with vasoactive and fibrogenic features, an association of UTS2 gene polymorphisms with SSc has been reported in the Turkish population.
To study the possible association of UTS2 (T21M and S89N) gene polymorphisms with SSc in Egyptian patients.
41 SSc patients and 70 healthy control subjects were genotyped for UTS2 (T21M and S89N) polymorphisms by TaqMan real-time PCR and PCR-RFLP, respectively.
The frequency of the S/N genotype and N allele of UTS2 S89N were significantly higher in SSc patients as compared to the healthy controls (p = 0.037, OR 4.60; p = 0.041, OR 4.26, respectively). The Rodnan score was significantly higher in SSc patients carrying the combined (T/M + M/M) genotype of UTS2 T21M polymorphism as compared to those with the wild T/T genotype (p = 0.018).
UTS2 (T21M and S89N) gene polymorphisms may play an important role in the susceptibility and the clinical outcome of SSc in Egyptian patients.
Urotensin II alters vascular reactivity in animals subjected to volume overload
2010, Peptides
Citation Excerpt :
Animals were divided into 4 groups: control, UTII infused (UT II), volume overload only (VO) or volume overload + UTII (VO + UTII). Human Urotensin II (hUTII, American Peptide, Sunnyvale, CA) was administered using subcutaneous Alzet mini-osmotic pumps for 4 weeks at a rate of 300 pmol/kg/h. Infusion rates and concentration of UTII were based on those previously reported by Kompa et al. [23]. In animals in the VO + UTII group, UTII administration was begun immediately after aortocaval (A–V) shunt formation.
Congestive heart failure (CHF) alters vascular reactivity and up regulates in urotensin II (UTII), a potent vasoactive peptide. The aim of this study was to investigate the interaction between CHF and UTII in altering vascular reactivity in a rat model of volume overload heart failure. Animals were divided into 4 groups: control, UTII infused (UTII), volume overload only (VO) or volume overload + UTII (VO + UTII). Volume overload was established by the formation of an aortocaval fistula. Following fistula formation animals were administered UTII at a rate of 300 pmol/kg/h for 4 weeks subcutaneously with mini-osmotic pumps. Thoracic aorta rings, with/without endothelium, were subjected to cumulative dose–responses to phenylephrine, sodium nitroprusside (SNP), acetylcholine (ACH), UTII, and the Rho-kinase inhibitor HA-1077. Aortas from VO animals exhibited increased sensitivity to phenylephrine and UTII with a decreased relaxation response to ACH and HA-1077. Aortas from animals subjected to chronic UTII with volume overload (VO + UTII) retained their sensitivity to phenylephrine and UTII while they improved their relaxation to HA-1077 but not ACH. The constrictive response to UTII was dose-dependent and augmented at concentrations <0.01 μM in VO animals. The changes in vascular reactivity paralleled an elevation of both the UTII and α_1A-adrenergic receptor while the Rho and Rho-kinase signalling proteins were diminished. We found that volume overload increased sensitivity to the vasoconstrictor agents that was inversely related to changes in the Rho-kinase expression. The addition of UTII with VO reversed the constrictive vascular response through alterations in the Rho-kinase signalling pathway.
Chronic urotensin II receptor antagonist treatment does not alter hypertrophy or fibrosis in a rat model of pressure-overload hypertrophy
2010, Peptides
Urotensin II (UII) is a potential mediator in the pathogenesis of cardiovascular disease, and inhibition of its actions at the urotensin receptor (UT) has been shown to improve cardiac function and structural changes of the myocardium in a model of myocardial infarction. In this study we utilized a model of pressure-overload hypertrophy induced by abdominal aortic constriction (AAC) which resulted in hypertrophy, increased fibrosis and impaired diastolic and systolic function. These changes were associated with a 4-fold increase in UII protein expression in the myocardium. Treatment of animals with a selective UT (SB-657510) antagonist for 20 weeks at a dose of 1500 ppm did not improve cardiac function as assessed by echocardiography and pressure–volume loop analysis, nor did it inhibit left ventricular hypertrophy or fibrosis. We hypothesize that other neurohumoral pathways may have a greater involvement in the pathogenesis of this model. Targeting the UII system appears to be insufficient to observe a beneficial outcome.
Urotensin-II and cardiovascular remodeling
2008, Peptides
Urotensin-II (U-II), a cyclic undecapeptide, and its receptor, UT, have been linked to vascular and cardiac remodeling. In patients with coronary artery disease (CAD), it has been shown that U-II plasma levels are significantly greater than in normal patients and the severity of the disease is increased proportionally to the U-II plasma levels. We showed that U-II protein and mRNA levels were significantly elevated in the arteries of patients with coronary atherosclerosis in comparison to healthy arteries. We observed U-II expression in endothelial cells, foam cells, and myointimal and medial vSMCs of atherosclerotic human coronary arteries. Recent studies have demonstrated that U-II acts in synergy with mildly oxidized LDL inducing vascular smooth muscle cell (vSMC) proliferation. Additionally, U-II has been shown to induce cardiac fibrosis and cardiomyocyte hypertrophy leading to cardiac remodeling. When using a selective U-II antagonist, SB-611812, we demonstrated a decrease in cardiac dysfunction including a reduction in cardiomyocyte hypertrophy and cardiac fibrosis. These findings suggest that U-II is undoubtedly a potential therapeutic target in treating cardiovascular remodeling.
PPAR-γ expression in animals subjected to volume overload and chronic Urotensin II administration
2008, Peptides
Activation of PPAR-γ through the administration of glitazones has shown promise in preserving function following cardiac injury, although recent evidence has suggested their use may be contraindicated in the case of severe heart failure. This study tested the hypothesis that PPAR-γ expression increases in a time dependent manner in response to chronic volume overload (VO) induced heart failure. Additionally, we attempted to determine what effect 4 week administration of Urotensin II (UTII) may have on PPAR-γ expression. VO induced heart failure was produced in Sprague–Dawley rats (n = 32) by aorta-caval fistula. Animals were sacrificed at 1, 4, and 14 weeks following shunt creation. In a separate set of experiments, animals were administered 300 pmol/kg/h of UTII for 4 weeks, subjected to 4 weeks of volume overload, or given UTII + VO. Densitometric analysis of left ventricular (LV) protein demonstrated PPAR-γ expression was significantly (^*p < 0.05) upregulated at 4 and 14 weeks (31.5% and 37%, respectively) post-fistula formation compared to control values. PPAR-γ activation was decreased in the 4 and 14 week (39.16% and 42.4%, respectively), but not in the 1-week animals, and these changes did not correlate with NF-κB activity. Animals given UTII either with or without VO demonstrated increased expression of PPAR-γ as did animals subjected to 4 week VO alone. Animals given UTII either with or without VO had decreased activity vs. control. These data suggest PPAR-γ may play a role in the progression of heart failure, however, the exact nature has yet to be determined.
Hemodynamic effects of chronic urotensin II administration in animals with and without aorto-caval fistula
2007, Peptides
Urotensin II (UTII) is a potent vasoactive peptide. Recent studies have demonstrated increased expression of both UTII and its receptor (UTR) expression in end-stage congestive heart failure (CHF), but it is unclear whether UTII and UTR are late stage markers of decompensation, or earlier adaptive responses. The purpose of this study was to measure the effects of chronic UTII administration in normal and volume overloaded animals. Chronic 4 weeks administration of UTII produced decreases in hemodynamic function in animals not subjected to volume overload while returning function to control levels in animals with overload. Expression levels of calcium regulatory proteins phospholamban (PLN), sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2), and Na⁺/Ca²⁺ exchanger (NCX) were measured to determine if administration of UTII resulted in aberrant Ca²⁺ handling. Changes in protein expression revealed that UTII influenced Ca²⁺ handling proteins in normal animals although these changes are not seen in the volume overload.

View all citing articles on Scopus

View full text

ReviewCardiovascular role of urotensin II: effect of chronic infusion in the rat

Abstract

Introduction

Section snippets

Cardiac fibrosis

Direct actions of urotensin II on the vasculature

Systemic effects of urotensin II

Effect of chronic urotensin II infusion in the rat

Role of urotensin II in human cardiovascular disease

Urotensin II receptor antagonists as a therapeutic target

Conclusions

Trends Pharmacol Sci.

Trends Cardiovasc Med.

Lancet

Regul. Pept.

Gen. Comp. Endocrinol.

Life Sci.

Int. J. Cardiol.

Lancet

Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14

Nature

Deletion of the UT receptor gene results in the selective loss of urotensin-II contractile activity in aortae isolated from UT receptor knockout mice

Br. J. Pharmacol.

Pharmacological characterization of SB-710411 (Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide), a novel peptidic urotensin-II receptor antagonist

Br. J. Pharmacol.

Urotensin II evokes potent vasoconstriction in humans in vivo

Br. J. Pharmacol.

Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries

Br. J. Pharmacol.

Effects of human urotensin II in isolated vessels of various species; comparison with other vasoactive agents

Naunyn Schmiedebergs Arch Pharmacol.

Urotensin receptors

Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey

Br. .J Pharmacol.

Depressor and regionally selective vasodilator effects of human and rat urotensin II in conscious rats

Br. J. Pharmacol.

Effect of human urotensin-II infusion on hemodynamics and cardiac function

Can. J. Physiol. Pharmacol.

Review
Cardiovascular role of urotensin II: effect of chronic infusion in the rat