Serum Apelin 13 Levels in Patients With Pulmonary Embolism

Introduction

A variety of adipokines have been reported in the recent years that contribute to many different systemic processes. One of these novel adipokines, apelin, has become popular in the past decades. Expression and peptide immunoreactivity of apelin messenger RNA (mRNA) have been described in a variety of tissues, including gastrointestinal tract, adipose tissue, brain, kidney, liver, cardiovascular system, and lungs. ^{1 –4} Interaction between apelin and its receptor APJ may have pathophysiologic effects in those tissues. Apelin-12, -13, -17, and -36 all originate from a common 77 amino acid precursor and are all bioactive forms of this adipokine. ⁵ It has been suggested that apelin 13 is the final active product of apelin, as it is more resistant to enzymatic cleavage. ^6,7 However, it has not been determined which peptide is the best target for investigation. Pulmonary embolism (PE) is a common clinical entity and remains poorly understood, despite advanced diagnostic methods. Impaired gas exchange, hypoxia in particular, cannot be explained solely on the basis of mechanical obstruction of the pulmonary arteries. ^8,9 Different mediators have been reported that contribute to chemical vasoconstriction and gas exchange abnormalities, similar to serotonin and thromboxane in patients with PE. ^8,9

We hypothesized that serum concentrations of apelin may be correlated with PE, with this adipokine serving as a lung-derived marker in patients with PE. To date, only animal studies have examined apelin’s involvement in acute PE. ¹⁰

In an acute PE, apelin may possess either protective vasodilator or vasoconstrictor effects within the pulmonary vessels. ¹¹ This study aimed to investigate the possible involvement of the endogenous apelin within the pathophysiological events in patients with PE.

Material and Methods

Results

The median ages were 57 and 53 years in the PE and control groups, respectively. The difference was not statistically significant (P = .233). Female–male ratios were 30/23 and 20/15, and mean BMI values were 24.95 ± 2.99 and 26.25 ± 3.21 in the PE and control groups, respectively. There was no difference between the 2 groups in terms of gender distribution and mean BMI values (P = .960 and P = .846, respectively). The baseline laboratory parameters of patients with PE are given in Table 1. The mean serum apelin 13 levels were found to be 76.94 ± 10.70 and 50.01 ± 7.13 ng/mL in the PE and control groups, respectively. The difference was statistically significant (P < .001; Figure 1). There were no correlations between serum apelin levels and BNP levels (P = .108, r = −.224), troponin I levels (P = .225, r = −.170), oxygen saturation (P = .789, r = .038), partial oxygen pressure (P = .545, r = .085) in arterial blood gas analysis, and pulmonary artery maximum pressure in echocardiography (P = .096, r = .231).

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Figure 1.

Box plot showing serum apelin levels between patients with pulmonary embolism and control group.

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Table 1.

Baseline Laboratory Parameters of Patients With Pulmonary Embolism.^a

SAP, mm Hgb	117.56 ± 18.03
fC, beats/minb	100.3 ± 19.93
bSao 2, %b	89.86 ± 10.68
Pao 2, mm Hgb	65.58 ± 13.13
A–a gradientb	38.01 ± 13.76
BNP, pg/mLb	319.73 ± 315.80
Troponin I, ng/mLb	0.14 ± 0.24
PAPmax, mm Hgb	40.03 ± 17.40

Abbreviations: SAP, systolic systemic arterial pressure; fC, cardiac frequency; Sao ₂, arterial oxygen saturation; A–a gradient, alveolar–arterial oxygen gradient; BNP, brain natriuretic peptide; PAPmax, pulmonary arterial maximum pressure in echocardiography; SD, standard devıatıon.

^aResults are presented as mean ± SD.

^bAdmission values.

Discussion

This is the first study to investigate the serum apelin 13 levels in patients with PE. The results of the study showed that PE is associated with increased serum apelin 13 levels compared to healthy volunteers.

Recently, it has become apparent that adipose tissue is an active endocrine and paracrine organ that releases several bioactive mediators that produce metabolically active proteins, such as apelin, leptin, resistin, and adiponectin, termed adipocytokines. ¹³ Those substances influence bodyweight homeostasis, inflammation, insulin resistance, and diabetes. ¹⁴ However, their precise role in PE has not been fully elucidated. In 1993, O’Dowd et al identified a gene with a similar identity to the angiotensin II type 1 receptor and called it APJ. ¹⁵ This receptor was assumed to be an orphan, until 1998 when Tatemoto et al identified a selective endogenous ligand named apelin. ¹ Expression of apelin has been reported in large vessels, coronary arteries, and endothelial cells. ¹⁶ The vascular endothelial apelin expression is particularly high in pulmonary tissue. ⁴ Immunohistochemical studies were performed to further characterize the presence of apelin and APJ in the pulmonary tissue. ¹⁷ The highest apelin mRNA expression was reported in the lungs; these data suggest that the pulmonary system may be a major source of circulating apelin. ⁴ Apelin and APJ are synthesized in both the pulmonary artery and the airway. ¹⁸ This document suggests that apelin may directly affect the vasomotor and bronchomotor tones and thus influence pulmonary arterial pressure and gas exchange by altering regional ventilation and perfusion. ¹⁸ The effect of apelin on vasomotor tone is complicated, as it can cause differential changes in pulmonary and systemic arterial pressures under different physiological and pathological conditions. ¹⁰ However, the molecular mechanism as to how apelin affects arterial pressure in various disease states is still unclear. Apelin seems to be a positive inotropic agent and a potent vasodilator via a nitric oxide (NO)-dependent mechanism ^2,7,19 but also has been reported to have a direct vasoconstrictive action in both the endothelium-denuded arteries and the veins by inducing phosphorylation of the myosin light chains in vascular smooth muscle cells. ²⁰ A previous study demonstrated that administration of acute apelin in vivo causes NO-mediated arterial vasodilation but does not appear to affect peripheral venous tone. ²¹ The effect of apelin in pulmonary arteries has been examined in only a few in vitro studies. ^22,23 Sheikh at al suggested that the apelin-APJ pathway allows for systemic endothelial monitoring of tissue perfusion. ²⁴ Recently, some reports were published about the prophylactic role of apelin in chronic pulmonary hypertension and the in vitro effect of apelin on pulmonary vasomotion. ²⁵ The changes in plasma apelin levels in heart failure and pulmonary hypertension have brought forward the idea that apelin may serve as a biomarker for these diseases. ²⁶ All of these studies suggest that the blood apelin levels may change in PE and affect prognosis. In our study, we found significantly increased serum apelin levels in patients with PE compared with healthy participants. However, we did not perform a prognostic evaluation in this study.

Acute right heart failure due to the abrupt increase in pulmonary arterial pressure is the principal cause of death in PE. ²⁷ The current treatment of PE is focused on removing the mechanical obstruction in the pulmonary vessels. There is accumulating experimental evidence suggesting that pharmacological blockade of pulmonary vasoconstriction attenuates the hemodynamic changes associated with PE. ^27,28 A transgenic mouse expressing higher amounts of adiponectin in the blood was protected in a murine arterial thrombosis model, whereas the adiponectin knockout mice had enhanced thrombus formation. ²⁹ A previous study reported that there was no obvious role of the endogenous apelin—in the pulmonary arterial wall in the regulation of the pulmonary vascular tone in the acute phase of PE. ²² In another study, the level of endogenous apelin in the pulmonary arterial wall did not change significantly, whereas the expression of apelin in the bronchial epithelium was upregulated in the early stage of PE. ¹⁰ In the acute phase of PE, many vasoactive substances are released, and apelin may have an antagonistic effect on the vasoconstrictors via NO and prostanoid mechanisms. In addition, apelin may play a role by inhibiting reactive oxygen species and increasing constitutive NO synthase (NOS) and decreasing inducible NOS activities. ^25,30 Despite all of these data, the net effects of apelin on the vascular system and its mechanisms remain unclear.

The importance of apelin in the pathophysiology of hypoxic conditions has been a topic of discussion in recent years. ^24,31 However, the effect of hypoxia on apelin regulation in human adipocytes has yet to be clarified. Hypoxia has been shown to increase apelin expression in endothelial cells, adipocytes, and murine lung tissue. ^24,32,33 The decrease in arterial pH and Pao ₂ during PE may activate the hydrogen/sodium and sodium/calcium exchangers in the vasculature, which are involved in apelin-induced phosphorylation of the myosin light chains in vascular smooth cells and result in vasoconstriction. ²⁰ In this study, the lack of correlation between apelin and hypoxia suggest that there are many possible factors that influence serum levels of apelin. Furthermore, it is possible that mechanical strain and cardiac overload, additional features of pulmonary hypertension, may affect serum apelin levels. However in this study, lack of correlation between apelin and BNP, troponin I levels, and pulmonary arterial maximum pressure in echocardiography suggests that this adipokine increases independent of the right heart strain. The role of apelin in human body is still not fully understood. Numerous studies are available, and new studies in the works, regarding apelin’s pathophysiologic effects; however, many more studies are needed. With increased understanding, we may be able to develop novel apelinergic-based therapeutic targets, in addition to using this adipokine as a marker, thus bridging the gap between the basic science and the clinical world. It is uncertain whether apelin is a beneficial or harmful peptide in patients with PE.

We observed for the first time elevated levels of apelin 13 in patients with PE. In conclusion, the findings of this study intrigue idea for the possible regulatory role of apelin in PE. More experiments directly in PE model are essential to reveal the substantial role of apelin in the pathogenesis of PE. We hope that subsequent studies will establish background data on further investigations of the molecular mechanisms of the apelin in PE.