Urocortin II

Urocortin 2 (Ucn2) is an endogenous peptide in the corticotrophin-releasing factor (CRF) family.^[1] Immunohistochemistry analysis of human myocytes has shown greater immunoreactivity of Ucn2 in myocytes of the failing heart compared to those of the healthy heart. Researchers suggest this is a result of an innate mechanism in which Ucn2 acts to improve function of the failing heart [2]. The pathophysiology of heart failure is often a consequence of improper calcium handling and relaxation resulting in a lower cardiac output, decreased blood flow and overall decreased heart function [3]. Infusion of Ucn2 in healthy humans has shown a dose dependent increase in cardiac output, heart rate and left ventricle ejection fraction and a decrease in systemic vascular resistance [4]. Ucn2 has been studied as potential treatment for individuals with heart failure.

Research findings

The cardiovascular function of Ucn2 was assessed by Meili-Butz and her team who used isolated hearts from a rat model for hypertension heart disease with severe left ventricle dysfunction and heart failure. Hearts were assessed for left ventricle function, MAPD and VFT before and after perfusion with Ucn2 and compared with a control group. Infusion of Ucn2 resulted in an immediate and significant improvement in left ventricle function, increased coronary flow, significantly altered intracellular calcium handling and increased SR calcium [5]. These relaxation effects can be explained by the increased calcium clearance into the SR would assist in relaxation of the cell. Increased calcium in the SR by Ucn2 was studied by Dr. Yand LZ et al. and shown to be a result of Ucn2 mediated production of cAMP and phosphokinase A (PKA) [8-10]. This is consistent Nishikimi T. et al. findings that Ucn2 to increases cAMP levels in myocytes and nonmyocytes [2]. The production of PKA results in the phosphorylation of phospholamban and inhibition of its block on the sarcoendoplasmic reticulum calcium ATPase (SERCA) [8-10]. Additional research Smani T et al. studied the production of PKA by Ucn2 on rat coronary vessels. It was determined PKA mediated inhibition of calcium-independent phospholipase A and calcium influx which resulted in relaxation of the vasculature [7]. This suggests Ucn2 may be beneficial in improving blood but these findings have less biological applicability to human medicine as they were completed on rats. In 2011 a similar relationship was found in human heart[10]. Ucn2 produced a dose dependent relaxation of coronary. It was confirmed that this correlation was a result of the cAMP/ PKA pathway and independent of endothelial function. The researches suggested Ucn2 may be a beneficial drug in damaged hearts where the endothelium is not intact.^[2]

Ucn2 and the CFR2 receptor

The activation of cAMP/PKA by Ucn2 gives similar effects to the β-adrenergic pathway. Research on receptor stimulation leading to the subsequent PKA production found Ucn2 increased left ventricular function independent of the β-adrenergic receptor but dependent on the binding of Ucn2 to CFR2 [6,8-10]. It is now known that Ucn2 is an agonist for the G-protein coupled CRF1 and CRF2 receptors. It is highly selective for CRF2 which is predominantly found in the myocardium, blood vessels and peripheral tissues. This association provides reason for its strong cardiovascular effects. When Ucn2 binds CRF2 it activates adenyl-cyclase to increase cAMP which activates PKA and results in the noted changes to cardiovascular function.^[3]

Future research

The ability of Ucn2 to produce PKA and alter calcium flux has led to the hypothesis that administration of Ucn2 may increase the risk of arrhythmias[8,10]. More research is needed on the molecular mechanism of Ucn2 and its long-term effects on the human heart.

Urocortin II is a 38-amino acid peptide that is a member of the CRF family of peptides. Unlike Urocortin I, Urocortin II is highly selective for the CRF2 receptor and does not show affintiy for the CRF binding protein.

Urocortin II has been shown to have anorexigenic effects and hypotensive effects similar to Urocortin, but does not induce secretion of ACTH.

Urocortin (UCN) II, also known as stresscopin-related peptide, is a 38 amino acid member of the mammalian corticotropin-releasing hormone (CRH) peptide family, which also includes CRH, UCN I, and UCN III [1;2]. CRH mainly binds to type 1 CRH receptors (CRH1), while UCN II and III bind primarily to type 2 CRH receptors, and UCN I binds to both (CRH2).^[4] Each of these hormones has distinctive distribution patterns in the central nervous system and the periphery, suggesting each peptide may have distinct behavioral and physiological effects, although all have been associated with anxiety [2–5]. In general, agonism of CRH1 receptors is posited to be anxiogenic and agonism of CRH2 receptors is posited to be anxiolytic [6].

References

2. Nishikimi T, Miyata A, Horio T, Yoshihara F, Nagaya N, Takishita S, Yutani C, Matsuo H, Matsuoka H, Kangawa K. 2000. Urocortin, a member of the corticotropin-releasing factor family, in normal and diseased heart. American Journal of Physiology-Heart and Circulatory Physiology 279: H3031-H3039.

3. Kumar V, Abbas AK, Fausto N, Mitchell RN, Burns D. From The Heart. In: Robbins Basic Pathology. 8th edition. Edited by Kumar V, Abbas AK, Fausto N, Mitchell RN. Philadelphia PA: Saunders; 2007: 379-419.

4. Davis ME, Pemberton CJ, Yandle TG, Fisher SF, Lainchbury JG, Frampton CM, Rademaker MT, Richards M. 2007. Urocortin 2 infusion in human heart failure. European Heart Journal 28: 2589-2597.

5. Meili-Butz S, Buhler K, John D, Buser P, Vale WW, Peterson KL, Brink M, Dieterle T. 2010. Acute effects of urocortin 2 on cardiac function and propensity for arrhythmas in an animal model of hypertesnison-induced left vetricular hypertrophy and heart faiure. European Journal of Heart Failure 12: 797-804.

6. Bale TL, Hoshijima M, Gu Y, Dalton N, Anderson KR, Lee KF, Rivier J, Chien KR, Vale WW, Peterson KL. 2004. The cardiovascular physiologic actions of urocortin II: Acute effects in murine heart failure. PNAS 101(10): 3697-3702.

7. Smani T, Dominguez-Rodgriguez A, Hmadcha A, Calderon-Sanchez E, Horrilo-Ledesma A, Ordonez A. 2007. Role of Ca2+-Independent Phospholipase A2 and Store-Operated Pathway in Urocortin-Induced Vasodilation of Rat Coronary Artery. Circulation Research 101: 1194-1203.

8. Yang LZ, Kockskämper J, Khan S, Suarez J, Walther S, Doleschal B, Unterer G, Khafaga M, Mächler H, Heinzel FR, Dillmann WH, Pieske B, Spiess J. cAMP- and Ca²(+) /calmodulin-dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes. Br J Pharmacol. 2011 Jan;162(2):544-56. doi:10.1111/j.1476-5381.2010.01067.x. PubMed PMID 20942811; PubMed Central PMC3031072.

9. Yang LZ, Tovote P, Rayner M, Kockskämper J, Pieske B, Spiess J. Corticotropin-releasing factor receptors and urocortins, links between the brain and the heart. Eur J Pharmacol. 2010 Apr 25;632(1-3):1-6. Epub 2010 Feb 2. Review. PubMed PMID 20132811.

10. Yang LZ, Kockskämper J, Heinzel FR, Hauber M, Walther S, Spiess J, Pieske B. Urocortin II enhances contractility in rabbit ventricular myocytes via CRF(2) receptor-mediated stimulation of protein kinase A. Cardiovasc Res. 2006 Feb 1;69(2):402-11. Epub 2005 Dec 28. PubMed PMID 16386238.