Copyright © 2004, European Society of Cardiology
On the cardiovascular activity of apelin
Sezione di Fisiologia, Università di Torino, Corso Raffaello, 30, 10125 Torino, Italy
* Tel.: +39 11 6707785; fax: +39 11 670 7708. Email address: gianni.losano{at}unito.it
Received 14 October 2004; accepted 21 October 2004
See article by Ashley et al. [8] (pages 73–82) in this issue.
Apelin, a peptide recently isolated from bovine stomach extracts, has been seen to act as an endogenous ligand of the orphan G-protein-coupled APJ receptor [1]. The structure of apelin preproteins was deduced from the sequences of the relevant cDNAs. The preproteins consist of 77 amino acid residues, with the apelin active sequence in the C-terminal regions [1]. Apelin mRNA expression was also found in the gastrointestinal tract, adipose tissue, brain, lung, kidney, liver, skeletal muscle, and cardiovascular system. In the cardiovascular system, it has been detected in endothelial cells of large conduit arteries, coronary vessels, and endocardium of the right atrium [2].
Apelin displays several activities on various systems. It has been seen to stimulate the proliferation of gastric cells in vitro and to increase the secretion of cholecystokinin in vivo [3]. A diuretic effect is consistent with its presence in the supraoptic nucleus of the hypothalamus, where it seems to inhibit the electrical activity of vasopressin-releasing neurons [4].
On the cardiovascular system, apelin exerts potent vasodilator and positive inotropic activities. Studies on mice revealed that apelin-induced hypotension is abolished by inhibition of nitric oxide (NO) synthase and that the angiotensin II hypertensive response is enhanced in APJ-deficient animals [5]. These results suggest not only that apelin vasodilatation is mediated by NO, but also that APJ receptors counteract the pressor effect of angiotensin II, possibly in response to a basal release of apelin from the vascular endothelial cells and in spite of a similarity between APJ and angiotensin II type-1 receptors.
The positive inotropic activity of apelin has been investigated in both isolated preparations and intact animals [6,7]. In isolated perfused rat hearts paced at a constant rate and contracting isovolumetrically, the peptide caused a dose-dependent increase in developed tension and dP/dtmax [6]. It also enhanced the increase of these variables obtained by an increase of preload. In anesthetized intact rats, apelin caused an increase of left ventricular systolic pressure, dP/dtmax, and stroke volume [7]. Since the increase in stroke volume was not accompanied by changes in end-diastolic ventricular volume, there was evidence of a positive inotropic effect. Infusion of apelin also improved ventricular diastolic relaxation as indicated by a reduction of dP/dtmin. It is remarkable that an increase in contractility has also been observed in failing hearts, suggesting the possibility of a therapeutic use of the compound [7].
In isolated rat hearts, the blockade of phospholipase C (PLC) significantly reduced by 68% the positive inotropic effect of apelin [6]. A similar result was obtained with the inhibition of protein kinase C (PKC), suggesting that both enzymes are involved in the activity of apelin on myocardium [6]. In fact, PLC can activate PKC with the mediation of diacylglycerol, released as a result of PLC-induced hydrolysis of phosphoinositides. In turn, activated PKC can phosphorylate the Na+–H+ exchanger, a protein that enables the exit of H+ from the cells and the entrance of Na+ into the cells. The increase of intracellular Na+ concentration can then activate a Ca2+–Na+ exchanger, leading to an increase in intracellular Ca2+ concentration, thus favoring the increase in contractility. In fact, it has been found that the inotropic effect of apelin can also be reduced by 60% or more with the blockade of either Na+–H+ or Na+–Ca2+ exchange. Although the blockade of the above-described pathway did not suppress, but simply reduced, the inotropic response, there is no doubt about its involvement in the myocardial response to the peptide.
The separate analysis of vascular and myocardial effects of apelin does not satisfy the need for a complete view of its integrated activity on the cardiovascular system. The paper of Ashley et al. [8], published in the present issue of Cardiovascular Research, has the merit of clarifying in intact animals (mice) the overall hemodynamic effect of apelin, i.e. the matching of the heart with changes in preload and afterload induced by the same peptide responsible for the increase in myocardial contractility after acute and chronic (over the course of 2 weeks) administration of the compound. It is also noteworthy that this is the first investigation that studies the chronic effects of apelin on the cardiovascular system.
The interaction between cardiac loading and contractility requires an awareness of the difference between the changes in the force (and energy) of contraction and the changes in contractility. Although changes in contractility always cause changes in the force and energy of contraction, as revealed by changes in dP/dtmax and stroke work, respectively, force and energy of contraction can vary in response to changes in preload (Starling mechanism) without changes in contractility. While increases in preload are revealed by increases in end-diastolic ventricular volume, increases in contractility at constant preload and afterload lead to a decrease in end-systolic volume. Moreover, if afterload is kept constant, the ejection fraction is affected by changes in contractility but not in preload. Thus, the pressure–volume loop is a reliable tool to assess which are the changes affecting the force of contraction.
In isovolumetrically beating hearts, increases in dP/dtmax take place after increases of the force of contraction in response to increases of either preload or inotropy. However, while increases in preload enhance dP/dtmax through an increase in developed pressure without changes in the time from ventricular diastolic to systolic pressure, increases in myocardial inotropy are also characterized by a reduction of that time.
Using pressure–volume loop and ejection fraction, Ashley and his coworkers saw that the short-term effect of acutely administered apelin resulted in a vasodilatation-induced decrease in preload and afterload and a potent increase in contractility accompanied by a trend to the decrease of cardiac output (CO) due to the decreased preload. On the contrary, the effect of chronic administration resulted in an increase in contractility accompanied by an increase in CO, which was likely to occur because the reduction in filling pressure was curtailed over the time of the chronic administration. Interestingly, no hypertrophy was seen after chronic administration.
Although dP/dtmax ratio was unchanged because of the opposite effect of increased inotropy and decreased preload, the use of pressure–volume loop allowed the authors to evidence the changes in contractility in the acutely treated animals, while the increase in the velocity of circumferential shortening was an indication that, in chronically treated hearts not affected by changes in preload and afterload, the increase in CO depended on an improved inotropy.
Like other authors before, Ashley and his coworkers are also of the opinion that apelin could have a therapeutic use in heart failure. Although their forecast may be correct, at the moment there are at least two reasons to wait for the results of further investigations: one is that acutely administered apelin may reduce CO if a reduction of preload is not required; the other is that its mode of action on inotropic activity is similar to that of angiotensin II and endothelin, which are far from being indicated in heart failure. Moreover, the absence of hypertrophy after 2 weeks of treatment does not exclude its appearance after a longer administration. On the other hand, in favor of a therapeutic use, it must be underlined that the involvement of some isoforms of PKC in the signaling cascade might also result in myocardial protection.
 |
References |
|---|
 Top References |
|---|
- Tatemoko K., Hosoya M., Habata Y., Fujii R., Kakegawa T., Zou M.X., et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem. Biophys. Res. Commun. (1998) 251:471–476.[CrossRef][ISI][Medline]
- Kleinz M.J., Davenport A.P. Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells. Regulatory Pept. (2004) 118:119–125.[CrossRef]
- Wang G., Anini Y., Wei W., Qi X., O'Carroll A.M., Mochizuki T., et al. Apelin: a new enteric peptide: localization in the gastrointestinal tract, ontogeny, and stimulation of gastric cell proliferation and of cholecystokinin secretion. Endocrinology (2004) 145:1342–1348.
[Abstract/Free Full Text] - De Mota N., Reaux-Le Goazigo A., El Messary S., Chartrel N., Roesch D., Dujardin C., et al. Apelin, a potent diuretic neuropeptide couteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Proc. Natl. Acad. Sci. U.S.A. (2004) 101:10464–10469.
[Abstract/Free Full Text] - Ishida J., Hashimoto T., Hashimoto Y., Nishiwaki S., Iguchi T., Harada S., et al. Regulatory role for APJ, a seven transmembrane receptor related to angitensin-type I receptor in blood pressure in vivo. J. Biol. Chem. (2004) 279:26274–26279.
[Abstract/Free Full Text] - Szokodi I., Tavi P., Földes G., Voutilainen-Myllyla S., Ilves M., Tokola H., et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ. Res. (2002) 91:434–440.
[Abstract/Free Full Text] - Berry M.F., Pirolli J., Jayasankar V., Burdick J., Morine K.J., Gardner T.J., et al. Apelin has in vivo inotropic effect on normal and failing hearts. Circulation (2004) 110(suppl. II):II-187–II-193.[ISI][Medline]
- Ashley E.A., Powers J., Chen M., Kundu R., Finsterbach T., Caffarelli A., et al. The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc. Res. (2005) 65:73–82.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||