A novel peptide adropin in cardiovascular diseases

Clinica Chimica Acta 453 (2016) 107–113

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Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim

A novel peptide adropin in cardiovascular diseases Liang Li a,b,1, Wei Xie a,c,1, Xi-Long Zheng d, Wei-Dong Yin a,⁎, Chao-Ke Tang a,⁎ a Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, China b Department of Pathophysiology, University of South China, Hengyang 421001, Hunan, China c Department of Anatomy, University of South China, Hengyang 421001, Hunan, China d Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada

a r t i c l e

i n f o

Article history: Received 30 September 2015 Received in revised form 5 December 2015 Accepted 8 December 2015 Available online 10 December 2015 Keywords: Adropin Atherosclerosis Coronary artery disease Heart failure Hypertension

a b s t r a c t Cardiovascular diseases, such as atherosclerosis and hypertension, are the major cause of mortality and morbidity in the world. Adropin was first discovered in 2008 by Kumar and his coworkers. Adropin, encoded by the Energy Homeostasis Associated gene, is expressed in many tissues and organs, such as pancreatic tissue, liver, brain, kidney, endocardium, myocardium, and epicardium. In this review, we have summarized recent data suggesting the roles of adropin in several major cardiovascular diseases. Increasing evidence suggests that adropin is a potential regulator of cardiovascular functions and plays a protective role in the pathogenesis and development of cardiovascular diseases. However, further studies are needed to elucidate the specific mechanisms underlying the association between adropin and cardiovascular diseases. © 2015 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . Structure and characterization . . . . . Regulation of adropin expression . . . . Adropin-regulated signaling pathways . Roles of adropin in cardiovascular diseases 5.1. Atherosclerosis . . . . . . . . . 5.2. Coronary artery disease (CAD) . . 5.3. Cardiac syndrome X (CSX) . . . . 5.4. Heart failure . . . . . . . . . . 5.5. Hypertension . . . . . . . . . . 6. Conclusion and future directions . . . . Disclosure . . . . . . . . . . . . . . . . .

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Abbreviations: DIO, diet-induced obesity; HFD, high-fat diet; CR, calorie restriction; LXR, liver X receptors; FXR, farnesoid X receptor; STZ, streptozotocin; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; PUFAs, polyunsaturated fatty acids; MetS, metabolic syndrome; ECs, endothelial cells; eNOS, endothelial nitric oxide synthase; VEGFR2, vascular endothelial growth factor receptor 2; ERK1/2, extracellular signal-regulated kinase 1/2; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; SIRT1, silent information regulator 1; PGC-1α, peroxisome proliferators-activated receptor-γ coactivator-1α; Cpt1b, carnitine palmitoyltransferase 1B; Pdk4, pyruvate dehydrogenase kinase; PTEN, phosphatase and tensin homolog deleted on chromosome ten; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PDH, pyruvate dehydrogenase; GLUT4, glucose transporter 4; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; IP3, inositol trisphosphate; LPL, lipoprotein lipase; VSMC, vascular smooth muscle cell; AdrKO, adropin knockout mice; GDM, gestational diabetes mellitus; iNOS, inducible nitric oxide synthase; NAFLD, nonalcoholic fatty liver disease; CAD, coronary artery disease; SCAD, stable coronary artery disease; AMI, acute myocardial infarction; SAP, stable angina pectoris; CSX, cardiac syndrome X; HF, heart failure; ET-1, endothelin-1; BNP, brain natriuretic peptide; BMI, body mass index; SBP, systolic blood pressure. ⁎ Corresponding authors at: Institute of Cardiovascular Research, University of South China, Hengyang, Hunan 421001, China. E-mail addresses: [email protected] (W.-D. Yin), [email protected] (C.-K. Tang). 1 These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.cca.2015.12.010 0009-8981/© 2015 Elsevier B.V. All rights reserved.

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Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

3. Regulation of adropin expression

The incidence of cardiovascular diseases, the major cause of mortality and morbidity in the world, is influenced by the aging of the population, genetic predisposition, changing lifestyles, stress, hypercholesterolemia, dietary habits, diabetes and risky behaviors, including smoking, alcohol abuse, overnutrition and sedentary lifestyles. The increase in cardiovascular disease is already not some local or national phenomena, but a kind of universal existence, which severely impairs humanity health disease. Adropin was first discovered in 2008 by Kumar and his coworkers in mice [1,2]. It was named after two Latin words: one is “aduro” (set fire to), and the second is “pinquis” (fats or oils). In addition to pancreatic, liver, brain and kidney tissues, the expression of adropin was demonstrated immunologically in the endocardium, myocardium, and epicardium [3]. There is growing evidence suggesting that adropin is a potential regulator of cardiovascular functions and plays a protective role in the pathogenesis and development of cardiovascular diseases [2]. In the present review, we summarized the molecular characterization, regulation, cellular signaling pathways and cardiovascular physiological actions of adropin, and also explored its emerging pathogenetic significance and therapeutic potential in cardiovascular diseases.

When adropin was discovered by Kumar and his colleague, it was shown that hepatic Enho expression is influenced by fasting, and the macronutrient composition of the diet with high expression levels observed during short-term ingestion of high-fat diet (HFD). However, chronic exposure to HFD is associated with reduced expression of adropin, suggesting deregulation of liver Enho expression in obesity [1]. It was reported that high adropin levels have been observed in mice fed a high-fat low carbohydrate diet, whereas lower levels of adropin have been observed in mice fed a low fat high carbohydrate diet [4]. The lifelong calorie restriction (CR)-induced increase in adropin levels may provide additional protection for the liver against an ageassociated fat accumulation [12]. Taken together, this evidence suggests that adropin is associated with the fat in diets. In addition, liver Enho mRNA expression can be rapidly upregulated by macronutrient contents, suggesting an involvement of intracellular lipid sensors [4]. The liver X receptors (LXRα and LXRβ) and farnesoid X receptor (FXR) are nuclear receptors that are regulated by sterols and bile acids, and involved in carbohydrate and lipid homeostasis [13]. In HepG2 cells, Enho expression was reduced by the LXR agonist (GW3965), which can be blocked by an antisense RNA targeting LXRα [14]. In mice treated with GW3965, liver Enho mRNA was also significantly reduced. There was no change in Enho expression observed, when HepG2 cells were treated with the FXR agonist (GW4064) [1]. Taken together, these results indicate that liver Enho mRNA expression is regulated by LXRα, but not FXR, a nuclear receptor involved in cholesterol and triglyceride metabolism [13]. Evidence suggests that adropin is expressed in various rat tissues with potential tissue specificity. In the brain, the immunoreactivity of adropin is present in the vascular area, pia matter, neuroglial cells, Purkinje cells, granular layer, and neurons of the central nervous system. In other tissues, adropin was detected in the glomerulus, peritubular interstitial cells, and peritubular capillary endothelial cells (kidneys), endocardium, myocardium, and epicardium (heart), sinusoidal cells (liver), and serous acini (pancreas). Tissue adropin levels based on mg/wet weight tissues were as follows: Pancreas N liver N kidney N heart N brain N cerebellar tissue. The data showed that the levels of adropin were higher in streptozotocin (STZ)induced diabetic rats compared with the control rats [3]. However, the underlying mechanisms and potential effects remain to be further investigated. Fish oil is a commonly used supplemental source containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), 2n– 3 (v-3) polyunsaturated fatty acids (PUFAs) that have been shown to have a variety of protective effects against cardiometabolic diseases [15–17] It has been shown that a high-fructose diet in rhesus monkeys induces the features of MetS in humans, including obesity, dyslipidemia (particularly hypertriglyceridemia), and insulin resistance [18]. Administration of fish oil attenuates the decrease in circulating adropin concentrations in the monkeys [19], but the underlying mechanisms are unclear. In humans, it was shown that serum adropin levels do not differ between males and females, and there is also no correlation between adropin levels and age. Similarly, it was reported that there is no gender difference between adropin levels in the pediatric age groups [20]. In normal-weight individuals, however, women have lower plasma adropin levels than men [21]. In addition, it was observed that adropin levels in male newborns are lower than those in the female. Cord blood adropin levels are positively correlated with gestational age and

2. Structure and characterization Adropin is encoded by the Energy Homeostasis Associated gene (gene symbol: Enho) that is expressed in the liver and brain [1]. The Enho gene maps to chromosome 9p13.3 and consists of 25 exons. Adropin contains 76 amino acids and has a molecular weight of 4.5 kDa [4]. Bioinformatics analysis using SignalP 3.0 and experiments both suggested that the adropin is likely (87% probability) to be secreted [1]. In the brain of mice, however, adropin is a membrane-bound protein. The N-terminus from amino acids 1–9 is localized in the cytoplasm. Evidence suggests that the region of amino acids 9–30 is the transmembrane domain, and is enriched in hydrophobic residues (including seven leucine, three isoleucine, and three valine residues of 21 amino acids) with a very poorly defined protease cleavage site [5–8]. The Cterminus from amino acids 30–76 is localized outside of the surface of the plasma membrane [9]. These controversial findings regarding circulating adropin will require further investigation into its biochemical properties. Adropin amino acid sequences in human, mouse, and rat are completely identical. Porcine adropin cloned by the pEnho shows high overall identity (98%–99%) with other known adropins [10]. Adropin exerts various effects on the body system. In metabolic homeostasis, for example, adropin improves glucose homeostasis, fatty liver, and dyslipidemia resulting from obesity. When Kumar and his coworkers firstly discovered adropin, they revealed that adropin regulation of glucose homeostasis was independent of changes in body weight, food intake, and whole body energy expenditure. They also found that adropin delayed DIO (diet-induced obesity) in mice primarily due to altered metabolism. The Enho gene-encoded adropin was also expressed in several areas of the brain involved in metabolic regulation [1]. The expression of adropin in the central nervous system suggests a role as a neuropeptide. It is also possible that adropin has autocrine/paracrine effects in peripheral tissues. Adropin not only regulates angiogenesis but also increases blood flow and capillary density in the model of hind limb ischemia [2]. In a recent study, it was observed that adropin was increased in plasma in patients with heart failure [11], suggesting the relevance of adropin to cardiovascular health.

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Fig. 1. Schematic presentation of adropin-triggered intracellular signal transduction pathways. Adropin can regulate eNOS bioactivity and endothelial function by activating VEGFR2/PI3K/ Akt and VEGFR2/ERK1/2 pathways. Adropin reduces PGC-1α through inhibition of SIRT1 and downregulation of Cpt1b and Pdk4. Adropin increases insulin-induced Akt phosphorylation by downregulating PTEN with a potential increase in the basal level of PIP3 through Notch signal pathways in muscle. Adropin stimulates LPL gene expression through activation of cAMP/ PKA and PLC/IP3/PKC cascades in tilapia hepatocytes. Adropin stimulates the NB-3/Notch signaling pathway to modulate intercellular communications as a membrane-bound protein in the brain.

placental weight, but not with other fetal growth parameters [12]. The impact of obesity in men on plasma adropin levels is also far less severe than in women. Serum adropin levels in obese children were lower than those in healthy ones [22].

elevate cyclic adenosine monophosphate (cAMP) production and upregulate protein kinase A(PKA) and protein kinase C (PKC) activities. Through the activation of cAMP/PKA and phospholipase C (PLC)/inositol trisphosphate (IP3)/PKC cascade, adropin stimulated lipoprotein lipase (LPL) gene expression [30].

4. Adropin-regulated signaling pathways 5. Roles of adropin in cardiovascular diseases Adropin may trigger intracellular signal transduction pathways in endothelial cells (ECs). Adropin increases the expression level of endothelial nitric oxide synthetase (eNOS) through upstream activation of vascular endothelial growth factor receptor 2 (VEGFR2) with resultant activation of the PI3K-Akt and ERK1/2 pathways [2]. This finding suggests that adropin may possess nonmetabolic properties, such as the regulation of eNOS bioactivity and endothelial functions (Fig. 1). In addition, it was reported that the signaling pathways underlying adropin's metabolic actions involve SIRT1 and PGC-1α in muscle [23]. The data showed that adropin inhibits SIRT1 deacetylase activity. Given that PGC-1α is deacetylated and activated by SIRT1 [24,25], adropin treatment will result in hyperacetylation of PGC-1α [26], leading to downregulation of PGC-1α target genes, including Cpt1b and Pdk4 [27]. Cpt1b and Pdk4 through PDH play the gatekeeping roles in fatty acid oxidation and glucose oxidation [28]. It was also reported that adropin treatment increases insulin-induced Akt phosphorylation by downregulating PTEN (phosphatase and tensin homolog deleted on chromosome ten) with a potential increase in the basal level of phosphatidylinositol-3,4,5-trisphosphate (PIP3) and cell-surface expression of GLUT4. The Notch signaling might mediate the effect of adropin on PTEN expression [29]. All these findings indicate that adropin might be a promising candidate for developing treatments to improve insulin resistance in type 2 diabetes. More recently, a study suggests that adropin might be a membranebound protein in the brain that interacts with the NB-3/Notch signaling pathway to modulate intercellular signal transduction. Adropin controls energy expenditure by regulating physical activity and motor coordination via the signaling pathway [9]. In tilapia hepatocytes, adropin could

5.1. Atherosclerosis Atherosclerosis is one of the major underlying factors leading to dysfunctional cardiovascular events in patients with obesity, type 2 diabetes, heart attacks or strokes [31]. The development of atherosclerosis is a multifactorial and complex process with the involvement of endothelial dysfunction, vascular inflammation, VSMC proliferation, thrombus formation, infiltration of monocytes and their differentiation into macrophages, and the conversion of lesion-resident macrophages into foam cells [32]. The studies by Lovren et al. demonstrated that adropin may regulate eNOS bioactivity and endothelial functions. Because endothelial function plays an important role in the development and progression of atherothrombosis, it was proposed that adropin may represent a novel target to limit diseases characterized by endothelial dysfunction in addition to its favorable metabolic profile [2]. Gozal and his team observed that adropin concentration is reduced in children with obstructive sleep apnea who exhibit endothelial dysfunction [33]. In addition, Topuz et al. have investigated a total of 92 individuals with type 2 diabetes. It was found that adropin levels were lower in the group with the endothelial dysfunction [34]. All these findings suggest that adropin may be a new and effective marker for noninvasive evaluation of endothelial functions (Table 1). The pathogenesis of atherosclerosis involves many metabolic syndromes including hyperlipidemia, diabetes, and obesity. It is known that hyperinsulinemia, resulting from insulin resistance, induces endothelial cell apoptosis [35], vascular smooth muscle cell proliferation [36,37], and inflammatory signaling activation, all of which are involved

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Table 1 Effects of adropin on cardiovascular diseases. Diseases

Experimental models

Number of individuals

Mechanisms

Actions

References

Atherosclerosis

HUVECS Children plasma Human plasma Mice in vivo Mice in vivo knockout Pregnant women plasma Pregnant women plasma Mice in vivo Rats in vivo Human plasma Human plasma Human plasma Tilapia hepatocytes Human plasma Human plasma Rats in vivo Human plasma Human plasma Human plasma ? Human plasma

None 71 92 ? ? 40 80 ? 21 392 64 113 no 356 116 36 327 86 76 ? 123

↑ PI3K-Akt, ↑ERK1/2 ? ? ↑Lipid metabolism, ↑glucose homeostasis ↑Lipid metabolism, ↑glucose homeostasis ? ? ↑PDH↓SIRT1/PDK4 ? ? ? ? ↑cAMP/PKA, ↑PLC/IP3/PKC ? ? ? ? ? ? ? ↓ET-1

Protection No Protection Protection Protection ? ? Protection Protection Protection Protection ? ? Protection Protection Protection Protection Protection ? ? Protection

[2] [33] [34] [1] [4] [39] [40] [23] [42] [43] [20] [48] [30] [50] [51] [54] [55] [58] [11] [73] [77]

CAD

CSX Heart failure Hypertension

↑ Indicates activation or promotion. ↓ Indicates inhibition.

in the pathogenesis of atherosclerosis [38]. When Kumar and colleagues first discovered adropin, it was proposed that adropin is involved in peripheral glucose homeostasis and lipid metabolism in response to variable macronutrient consumption [1]. Thereafter, they have generated adropin knockout (AdrKO) mice on the C57BL/6J background in 2012. AdrKO mice also exhibited dyslipidemia and impaired suppression of endogenous glucose production in hyperinsulinemic–euglycemic clamp conditions. These data further suggested that adropin is involved in the improvement of insulin resistance, dyslipidemia, and adiposity [4]. In addition, Celik et al. demonstrated that maternal and neonatal serum adropin concentrations decrease in women with gestational diabetes mellitus (GDM) [39]. Beigi et al. also found low serum adropin concentrations in Iranian pregnant women with GDM [40]. However, it is still not clear whether low adropin level has a role in the pathogenesis of GDM or an impact on the emergence of insulin resistance. Because mitochondrial fatty acid overload in skeletal muscle may contribute to insulin resistance [41], the data from Gao and his colleagues suggest that adropin potentially enhances glucose utilization through regulating muscle substrate oxidation during the feeding and fasting cycle [23]. Kuloglu et al. have studied the variation of adropin and inducible nitric oxide synthase (iNOS) expression in the renal tissues of streptozotocin (STZ)-induced diabetic rats. The intensities of adropin and iNOS immunoreactivities were increased with the severity of diabetes [42], indirectly suggesting that adropin may be a promising candidate for developing treatments for insulin resistance and type 2 diabetes. Wu et al. examined the relationship between serum adropin levels and angiographic severity of coronary atherosclerosis in diabetic and non-diabetic patients. Serum adropin levels were significantly lower in type 2 diabetic patients than those in non-diabetic patients. Adropin levels were inversely and independently associated with angiographic severity of coronary atherosclerosis, suggesting that serum adropin may serve as a novel predictor of coronary atherosclerosis [43]. Demircelik et al. have carried out a study in patients undergoing coronary artery bypass grafting, and showed that lower plasma adropin level was associated with late saphenous vein graft occlusion. This finding provides evidence suggesting that adropin may have an effect on atherosclerotic progression. In addition, it is known that nonalcoholic fatty liver disease (NAFLD) is due to the accumulation of excess fat in the liver in the absence of alcohol consumption, which is commonly associated with obesity and increased risk of atherosclerosis. Obesity, insulin resistance, oxidative stress, dyslipidemia, and inflammation are known to play an important

role in the development and progression of NAFLD [44–47]. Sayin et al. demonstrated for the first time that serum adropin levels were decreased in obese adolescents with NAFLD and insulin resistance, and adropin was required for metabolic homeostasis, specifically for maintaining insulin sensitivity and preventing dyslipidemia. Therefore, a lower adropin level can be an independent risk factor for NAFLD in obese adolescents [20]. Butler and coworkers found that dietary glucose consumption lowers, while fructose increases, plasma adropin concentrations. The increase in serum adropin levels with fructose intake was most robust in individuals exhibiting hypertriglyceridemia. Furthermore, dietary fat intake might also increase circulating adropin concentrations. Diet coupled with systemic triglyceride (TG) metabolism was first suggested to have an important influence in the regulation of plasma adropin concentrations in humans [48]. Using primary cultured tilapia hepatocytes, Lian et al. showed that adropin could trigger LPL secretion and production and its gene expression via direct action at the cellular level. These findings provided the first evidence that adropin could stimulate LPL gene expression in tilapia hepatocytes through activation of multiple signaling mechanisms [30]. 5.2. Coronary artery disease (CAD) The incidence of CAD, the most common cardiovascular disease, increases in the elderly [49]. Zhang et al. have included 356 patients for a study to examine the correlation of serum adropin level with CAD, and found that serum adropin level is significantly lower in CAD group than that in the control group. The multivariate regression analysis revealed that adropin was an independent risk factor for CAD [50]. In addition, Zhao et al. have investigated the serum adropin levels of a cohort of patients with and without stable coronary artery disease (SCAD) to ascertain the association of adropin with SCAD. Their results showed that low serum adropin level was an independent predictor of SCAD, and significantly associated with high syntax score that indicates the more severe coronary atherosclerosis [51]. It is well known that acute myocardial infarction (AMI) will occur when the coronary artery in patients with CAD is completely blocked. AMI is one of the leading causes of morbidity and mortality worldwide [52,53]. Yu and colleagues have enrolled 138 AMI patients with 114 stable angina pectoris (SAP) patients and 75 controls. Adropin levels in all patients were measured by enzyme-linked immunosorbent assay (ELISA). The data showed that serum adropin levels were decreased in patients with AMI, and there was a negative correlation

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between adropin levels and the presence of AMI in CAD patients [55]. Aydin et al. observed in rats with isoproterenol-induced myocardial infarction that cardiac muscle cells, glomerular, peritubular and renal cortical interstitial cells, hepatocytes and liver sinusoidal cells synthesized adropin, and adropin synthesis was increased 1–24 h after MI except in the liver cells [54]. Taken together, these results have suggested that adropin might represent a novel biomarker for predicting AMI onset in CAD patients. 5.3. Cardiac syndrome X (CSX) The patients with CSX have a normal coronary angiogram, effortinduced angina pectoris, positive exercise stress test, and/or positive single-photon emission computed tomography study [56]. Celik and coworkers have investigated the relation between the levels of adropin and patients with CSX and found that CSX patients have lower levels of adropin. In addition, they found that serum nitrite/nitrate levels were also lower in patients with CSX as shown for adropin. Adropin increases nitric oxide release through activation of eNOS. Therefore, adropin may directly affect the endothelium and exert a protective role for endothelium via upregulating eNOS [2]. Among the suggested pathophysiological mechanisms, endothelial dysfunction of the coronary microcirculation is known to have a very important role in the development of CSX [57]. It has been hypothesized that lower levels of adropin might have a crucial role in the pathophysiology of CSX. The study by Celik et al. is the first one demonstrating the association between serum adropin levels and CSX. Adropin may be an independent risk factor for CSX [58]. Collectively, these results are very important to our understanding of the pathophysiology of CSX. 5.4. Heart failure Heart failure (HF) is considered a major public health problem worldwide [59–66]. HF is the outcome of some conditions with different etiologies. In 56 patients with HF and 20 control subjects, Lian et al. have found that plasma adropin levels were significantly increased corresponding to the severity of HF, and brain natriuretic peptide (BNP) and BMI had an independent impact on plasma adropin level. BNP is synthesized in the ventricular myocardium, indicating the severity of heart failure [67,68]. In addition, the plasma level of BNP appears to be inversely associated with BMI [69]. It was shown that the plasma adropin level had a positive correlation with the plasma level of BNP. These findings suggest that the augmented release of adropin may be involved in the pathogenesis of HF. However, further research will be required to clarify the correlation between adropin and the severity of HF and determine whether a true cause-and-effect relationship exists or their correlation just reflects parallel changes in this population [11]. The study by Lian et al. is the first report to describe the abnormal levels of plasma adropin in patients with HF.

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have speculated that adropin may also have an important role in the regulation of hypertension. The underlying mechanism may be related to reducing obesity and insulin resistance, improving endothelial dysfunction, and modulating the activity of nervous system [73]. Gu and colleagues studied a total of 123 participants, who were diagnosed with primary hypertension according to World Health Organization criteria. The results showed that adropin had a negative correlation with blood pressure and endothelin-1 (ET-1) levels. ET-1 is a potential marker of endothelial dysfunction and a potent vasoconstrictor that increases systolic blood pressure (SBP) [74–76]. Adropin was an independent predictor of hypertension, and might influence blood pressure by protecting endothelial functions [77]. It needs to be further clarified whether the correlation between blood pressure and adropin represents a true cause-and-effect relationship or merely reflects parallel changes because of a common underlying etiology in this population. In addition, Altincik and coworkers evaluated the interrelationship between serum adropin levels and blood pressure in obese children, since little was known about adropin levels and blood pressure indexes in the pediatric age group. Unexpectedly, their results showed no significant association between blood pressure values and serum adropin levels [22]. 6. Conclusion and future directions Although the investigation regarding the effects of adropin is still in the early stage, increasing evidence has suggested a protective role for this hormone peptide in the development of cardiovascular diseases. However, our current knowledge on the cardiovascular protection of adropin mainly comes from animal studies through the overexpression and knockout of adropin or treatment with the putative secreted domain (adropin34-76). Whether the therapeutic effects of the adropin34-76 in animal studies can be transferable to clinical studies needs to be determined. Although several studies have been performed in some patients with cardiovascular diseases, the levels of adropin can be affected by lifestyle, eating habits, body mass and body size among individuals in different ethnic groups and countries. The source of adropin and the mechanism for its release have remained controversial, although several laboratories have reported adropin immunoreactivity present in plasma and sera of the mouse, nonhuman primate, and human. Further studies are also needed to elucidate the specific mechanism underlying the association between adropin and cardiovascular diseases. In summary, adropin may serve as a therapeutic candidate for the prevention of cardiovascular disease, and/or become a promising biomarker for cardiovascular risk stratification. Disclosure The authors have declared no conflict of interest.

5.5. Hypertension

Acknowledgments

Lovren et al. demonstrated that adropin had an endothelial protective effect via upregulation of eNOS expression [2]. It is well known that the endothelium plays a central role in the maintenance of vascular homeostasis, and impairment of endothelial function contributes to the occurrence and progression of cardiovascular diseases [70]. NO is a wellknown endogenous vasodilator. Some paracrine and neuroendocrine factors similar to adropin, such as adiponectin and leptin, have an effect on blood pressure by modulation of metabolic regulation, energy expenditure, endothelial dysfunction or cardiovascular, central nervous system [71,72]. However, adropin, which is also expressed in many brain cells, likely regulates the balance of central autonomic nervous system [3,9]. Therefore, according to the report by Lovren et al. in 2010, adropin had a potential capacity to protect endothelium by an increase in eNOS [2]. Nitric oxide is an endogenous vasodilator. Chen et al.

The authors gratefully acknowledge the financial support from the National Natural Sciences Foundation of China (81270269 and 81370377), and the Zhengxiang Scholar Program of University of South China (2014-004), and the construct program of the key discipline in Hunan Province, China (Basic Medicine Sciences in University of South China, Xiangjiaofa NO. [2011]76). References [1] K.G. Kumar, J.L. Trevaskis, D.D. Lam, G.M. Sutton, R.A. Koza, V.N. Chouljenko, K.G. Kousoulas, P.M. Rogers, R.A. Kesterson, M. Thearle, A.W. Ferrante Jr., R.L. Mynatt, T.P. Burris, J.Z. Dong, H.A. Halem, M.D. Culler, L.K. Heisler, J.M. Stephens, A.A. Butler, Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism[J], Cell Metab. 8 (6) (2008) 468–481.

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