Hypoxia inducible factor regulates the cardiac expression and secretion of apelin

Ronkainen, Veli‐Pekka; Ronkainen, Jarkko J.; Hänninen, Sandra L.; Leskinen, Hanna; Ruas, Jorge L.; Pereira, Teresa; Poellinger, Lorenz; Vuolteenaho, Olli; Tavi, Pasi

doi:10.1096/fj.06-7294com

Cited by 150 publications

(117 citation statements)

References 42 publications

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“…Endothelial dysfunction is well established in OSA (Atkeson & Jelic 2008) and is ameliorated by CPAP therapy (Jelic et al 2008). Hypoxia-induced myocardial/endothelial apelin expression has been demonstrated via hypoxia-inducible factor (HIF) pathways (Glassford et al 2007, Ronkainen et al 2007, and the HIF-1 pathway is activated in patients with OSA (Atkeson & Jelic 2008). The pulmonary apelin-producing endothelium is particularly sensitive to hypoxia (Sheikh et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Plasma apelin levels in obstructive sleep apnea and the effect of continuous positive airway pressure therapy

Henley¹,

Buchanan²,

Gibson³

et al. 2009

Journal of Endocrinology

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Apelin is a peptide hormone with cardiovascular and glucose homeostasis properties, and obstructive sleep apnea (OSA) is complicated by cardiovascular and metabolic comorbidities. Plasma apelin has not been previously assessed in OSA. We investigated the response of plasma apelin to a 2-h 75 g oral glucose tolerance test (OGTT) and the effect of 3 months compliant continuous positive airway pressure (CPAP) therapy in 15 obese males with newly diagnosed OSA. Plasma apelin and serum cortisol were recorded 10 minutely, while serum insulin and glucose were measured 30 minutely. Ten subjects had plasma apelin measured at intervals across a 24-h period to investigate for circadian variation in apelin levels, and this was repeated following 3 months compliant CPAP therapy. Fasting (0 . 342G0 . 038 vs 0 . 288 G0 . 024 ng/ml, PZ0 . 04), 30 min (0 . 399G0 . 035 vs 0 . 312 G0 . 036 ng/ml, PZ0 . 007) and 120 min (0 . 402G0 . 030 vs 0 . 259G0 . 024 ng/ml, P!0 . 001) apelin levels were reduced following CPAP. The area under curve for apelin OGTT response was lower post-CPAP (44 . 1G3 . 3 vs 35 . 8 G2 . 3 ng/ml per min, P!0 . 001). Mean OGTT apelin levels showed a significant treatment effect (PZ0 . 006) and a time effect (P!0 . 001), and the effect of time was different preversus post-CPAP (PZ0 . 005). No significant variability in apelin levels existed across the 24-h period at diagnosis. Lower levels were evident overnight following treatment (PZ0 . 004). Improvements in insulin and glucose parameters and reduced cortisol levels were found post-CPAP. In summary, untreated OSA was associated with elevated plasma apelin levels, altered apelin secretory dynamics in response to oral glucose and lack of an apparent circadian variability, which was restored following CPAP.

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Section: Discussionmentioning

confidence: 99%

Plasma apelin levels in obstructive sleep apnea and the effect of continuous positive airway pressure therapy

Henley¹,

Buchanan²,

Gibson³

et al. 2009

Journal of Endocrinology

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“…Mutagenesis, electrophoretic mobility shift assays and ChIP have also been used in vitro to determine whether upstream stimulatory factors 1 and 2 (USF1 and USF2) are involved in the expression of apelin in the breast, while in vitro ChIP analyses have shown that endogenous USF up-regulates the expression of apelin in the lactating rat breast (Wang et al 2006). Putative hypoxia response elements (HREs) are present in the apelin gene promoter and intron sequence of various species in silico (Cox et al 2006), and hypoxia has subsequently been found to up-regulate the expression of apelin in cardiac myocytes (Ronkainen et al 2007), and hypoxia-inducible factor 1a (HIF1a) has been reported to induce the expression of apelin in adipocytes (Glassford et al 2007). Additional studies have determined that hypoxia-inducible apelin up-regulation is mediated by HIF1a at a HRE within the APLN intron (conserved in rat and mouse apelin genes) between C813 and C826 bp (Eyries et al 2008), indicating that apelin may play a role in the homeostatic response to low oxygen levels.…”

Section: Gene Regulationmentioning

confidence: 99%

“…However, APJ mRNA is decreased in the weakened and enlarged heart of humans with idiopathic dilated cardiomyopathy (Foldes et al 2003). Apelin may have a cardioprotective role in hypoxia and ischaemia, where the cardiac levels of apelin and APJ respectively are increased (Atluri et al 2007, Ronkainen et al 2007, Zeng et al 2009). Apelin may also play a protective a role in ischaemia/reperfusion injury , Zeng et al 2009), although the method of signalling appears to be independent of the characteristic myocardial kinase cascade, termed the reperfusion injury salvage kinase pathway (Kleinz & Baxter 2008).…”

Section: Cardiovascular Roles Of Apelin/apjmentioning

confidence: 99%

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

O’Carroll

Lolait

Harris

et al. 2013

Journal of Endocrinology

282

216

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The apelin receptor (APJ; gene symbol APLNR) is a member of the G protein-coupled receptor gene family. Neural gene expression patterns of APJ, and its cognate ligand apelin, in the brain implicate the apelinergic system in the regulation of a number of physiological processes. APJ and apelin are highly expressed in the hypothalamo-neurohypophysial system, which regulates fluid homeostasis, in the hypothalamic-pituitary-adrenal axis, which controls the neuroendocrine response to stress, and in the forebrain and lower brainstem regions, which are involved in cardiovascular function. Recently, apelin, synthesised and secreted by adipocytes, has been described as a beneficial adipokine related to obesity, and there is growing awareness of a potential role for apelin and APJ in glucose and energy metabolism. In this review we provide a comprehensive overview of the structure, expression pattern and regulation of apelin and its receptor, as well as the main second messengers and signalling proteins activated by apelin. We also highlight the physiological and pathological roles that support this system as a novel therapeutic target for pharmacological intervention in treating conditions related to altered water balance, stress-induced disorders such as anxiety and depression, and cardiovascular and metabolic disorders.

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“…For this reason it has been suggested as a tool for the treatment of heart failure (HF) [76,70,24,67,77,78]. However, the results of various investigations arise some doubts about this proposal.…”

Section: Inotropic Effectmentioning

confidence: 99%

“…In particular, in the rat the elevation of apelin gene expression in vivo was seen to take place within 24 hours after MI, when an increased apelin release contributes to compensate the sudden HF [76]. Consistently, apelin deficiency in humans worsens the damage of ischemia-reperfusion (I/R), included extension of infarct size, related inflammation and mortality [54].…”

Section: Apelin In Heart Failurementioning

confidence: 99%

Effects of apelin on the cardiovascular system

et al. 2015

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Apelin is an endogenous peptide acting on the APJ receptor. It consists of several isoforms characterised by different numbers of aminoacids. The number of aminoacids in the active isoforms range from 36 to 12. Apelin-13 and, to a lesser extent, apelin-36 are considered the most active isoforms with the greatest activity on the cardiovascular homeostasis. The effects normally exerted by the basal level of endogenous apelin, can be enhanced not only by its up-regulation, but may also by its exogenous administration. The present review considers the effects of apelin on various aspects of the cardiovascular function, such as cardiac development, vasomotor tone, angiogenesis, myocardial inotropy in healthy and failing hearts as well as the prevention of ischemia-reperfusion injury, cardiac fibrosis and remodeling. Also the biphasic changes of apelin level during the evolution of heart failure are considered. Although the positive inotropic effect exerted by apelin in normal and failing hearts would suggest the use of this peptide in the treatment of heart failure, the limited duration and extent of its effect do not support this possibility, unless a long lasting (6 hours) infusion is performed to overcome the limit of its short life. However, although the data on the characteristics of the inotropic activity do not provide a strong support for the treatment of active heart failure, apelin may be used in the prevention of heart failure because of its activity in limiting the consequences of myocardial ischemia such as infarct size and cardiac remodeling. KeywordsApelin/APJ system, heart failure, ischemia-reperfusion injury, contractility, cardiac protection, Reninangiotensin system 2 The apelin/APJ system Apelin In 1998 Tatemoto et al. discovered the endogenous peptide capable of binding the G protein-coupled receptor (GPCR) APJ [1,2], which at that time was considered an orphan receptor becaue its ligand was unknown. The just discovered ligand was called, apelin e.g APj Endogenous LIgaNd. Apelin is expressed in hearts, lungs, kidneys, liver, adipose tissue, gastrointestinal tract, brain, adrenal glands, endothelium, and human plasma. The gene of apelin is located on chromosome X [3] and encodes a 77 aminoacid sequence called pre-pro-apelin [4]. Upon cleavage by a family of endopeptidases, pre-pro-apelin generates several C-terminal fragments of various size, which are classified on the basis of the number of aminoacids. The active isoforms range from 36 to 12 aminoacids. As fragments shorter than 12 aminoacids are biologically inactive, it appears evident that the Cterminal 12 aminoacids are essential for receptor binding, whereas the N-terminal sequence modulates the interaction with the receptor [5]. At present it is recognized that, although different isoforms display similar functions, active isoforms differ in tissue distribution, potency and receptor binding affinity [6]. Apelin-13 and, to a lesser extent, apelin-36 have been considered the most active isoforms with the greatest activity on the cardi...

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Hypoxia inducible factor regulates the cardiac expression and secretion of apelin

Cited by 150 publications

References 42 publications

Plasma apelin levels in obstructive sleep apnea and the effect of continuous positive airway pressure therapy

Plasma apelin levels in obstructive sleep apnea and the effect of continuous positive airway pressure therapy

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

Effects of apelin on the cardiovascular system

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