Identification of insulin-regulated aminopeptidase (IRAP) in the rat pineal gland and the modulation of melatonin synthesis by angiotensin IV

Abrahão, Mariana; Santos, Natália Fernanda Teixeira dos; Kuwabara, Wilson Mitsuo Tatagiba; Amaral, Fernanda Gaspar do; Buonfiglio, Daniella do Carmo; Peres, Rafael; Vendrame, Rafaela Fadoni Alponti; Silveira, Paulo Flávio; Cipolla‐Neto, José; Baltatu, Ovidiu Constantin; Afeche, Solange Castro

doi:10.1016/j.brainres.2018.09.015

Cited by 12 publications

(8 citation statements)

References 42 publications

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“…However, there are conflicting results about their presence on astrocytes (Greenland et al, 1996;Jackson et al, 2018;O'Connor and Clark, 2018). In a recent study, the presence of IRAP/AT 4 R was shown in both pinealocytes and astrocytes in the rat pineal gland (Abrahão et al, 2019).…”

Section: Angiotensin Receptors and Their Locations Within The Brainmentioning

confidence: 99%

“…Previous work suggested that actions of Ang IV are partially mediated by IRAP which codistributes with the insulin-regulated glucose transporter (GLUT 4) ( Albiston et al, 2001 , 2003 ). In this context, AT 4 Rs show some of their effects by inhibiting the catalytic activity of IRAP ( Lew et al, 2003 ; Singh and Karnik, 2016 ; Abrahão et al, 2019 ). With this inhibition, Ang IV extends the half-life of several pro-cognitive endogenous peptides such as vasopressin, oxytocin, somatostatin, and endothelial NOS, which have been shown to enhance memory consolidation and retrieval.…”

Section: Functions Of Renin–angiotensin System Receptorsmentioning

confidence: 99%

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Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

et al. 2020

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The renin-angiotensin system (RAS) was initially considered to be part of the endocrine system regulating water and electrolyte balance, systemic vascular resistance, blood pressure, and cardiovascular homeostasis. It was later discovered that intracrine and local forms of RAS exist in the brain apart from the endocrine RAS. This brainspecific RAS plays essential roles in brain homeostasis by acting mainly through four angiotensin receptor subtypes; AT 1 R, AT 2 R, MasR, and AT 4 R. These receptors have opposing effects; AT 1 R promotes vasoconstriction, proliferation, inflammation, and oxidative stress while AT 2 R and MasR counteract the effects of AT 1 R. AT 4 R is critical for dopamine and acetylcholine release and mediates learning and memory consolidation. Consequently, aging-associated dysregulation of the angiotensin receptor subtypes may lead to adverse clinical outcomes such as Alzheimer's disease and frailty via excessive oxidative stress, neuroinflammation, endothelial dysfunction, microglial polarization, and alterations in neurotransmitter secretion. In this article, we review the brain RAS from this standpoint. After discussing the functions of individual brain RAS components and their intracellular and intracranial locations, we focus on the relationships among brain RAS, aging, frailty, and specific neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and vascular cognitive impairment, through oxidative stress, neuroinflammation, and vascular dysfunction. Finally, we discuss the effects of RAS-modulating drugs on the brain RAS and their use in novel treatment approaches.

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Section: Angiotensin Receptors and Their Locations Within The Brainmentioning

confidence: 99%

Section: Functions Of Renin–angiotensin System Receptorsmentioning

confidence: 99%

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

et al. 2020

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“…A variety of positive and negative regulatory factors are involved in the regulation of rhythms depending on species. The positive regulatory factors including norepinephrine (NE), neutral amino acids, angiotensin II, and angiotensin IV promote melatonin synthesis and secretion. The negative regulatory factors such as anhydroecgonine methyl ester, β‐ N ‐methylamino‐ l ‐alanine, adenosine triphosphate, dexamethasone, and leptin have inhibitory effects on melatonin synthesis.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐7 inhibits melatonin synthesis by acting as a linking molecule between leptin and norepinephrine signaling pathways in pig pineal gland

Qiu

Zhang

Zhou

et al. 2019

Journal of Pineal Research

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MicroRNAs, including microRNA‐7 (miR‐7), are important modulators of numerous gene expressions and the related biological processes. Melatonin is a key hormone regulating daily and seasonal rhythms, in which a variety of positive and negative regulatory factors, such as norepinephrine (NE) and leptin, are involved. However, the interactions among these factors and the mechanisms remain to be elucidated. The aims of the present study were to identify the functions and the related mechanisms of miR‐7 in regulating melatonin synthesis and secretion through in vitro and in vivo experiments in pineal gland of pigs, which is an important animal model for agricultural and biomedical studies. Our results firstly show that miR‐7 is specifically expressed in porcine pinealocytes and negatively regulates melatonin synthesis. The further functional studies show that the dynamic expression levels of miR‐7 are contrary to the melatonin levels throughout the day, and the forced inhibition of endogenous miR‐7 in porcine pinealocytes sharply increases arylalkylamine N‐acetyltransferase (AANAT) expression by 80.0% (P = 0.0031) and melatonin levels by 81.0% (P = 0.0421), whereas miR‐7 over‐expression down‐regulates AANAT expression by 38.6% (P = 0.0004) and melatonin levels by 37.6% (P = 0.0212). In addition, the miR‐7 expression is up‐regulated by leptin through the JAK/STAT3 signaling pathway, and the in vivo intracerebroventricular injection of leptin increases miR‐7 expression by 80.0% (P = 0.0044) in porcine pineal glands and reduces melatonin levels by 57.1% (P = 0.0060) compared with the controls. This functional inhibition of melatonin synthesis by miR‐7 is accomplished by its binding to the 3′‐UTR of Raf1. Further, our results demonstrate that the RAF1/MEK/ERK signaling pathway mediates NE‐induced AANAT expression, whereas leptin attenuates NE's function through miR‐7. Taken together, the results demonstrated that leptin activates the JAK/STAT3 signaling pathway to increase the expression of miR‐7, which acts as a negative regulatory molecule inhibiting NE‐activated RAF1/MEK/ERK signaling pathway by targeting Raf1, resulting in decreased AANAT expression and melatonin synthesis. These findings suggest that miR‐7 is a novel negative regulator of melatonin synthesis and links leptin‐ and NE‐mediated signaling pathways in porcine pineal glands, which will contribute to our understanding in the establishment of the biological rhythms resulting from melatonin.

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“…In addition to synthesis in the pineal gland, the enzymes that convert serotonin into melatonin, serotonin N-acetyltransferase and N-Acetylserotonin O-methyltransferase, were found to be present not only in the pineal gland but also in the plasma [30] and the lung [31]. Melatonin synthesis can be activated by the activation of sympathetic system and renin-angiotensin system [32][33][34][35]. PH patients and the two rat models of PH have previously been shown to exhibit increased sympathetic activity (consistent with a higher heart rate in PH patients in the present study) as well as activation of the renin-angiotensin system [36][37][38][39][40].…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, PAH patients with the highest levels of endogenous melatonin seemed to have a high mortality in the present study. We believe that these high endogenous melatonin levels may be attributed to hyper-activation of sympathetic system and/or renin-angiotensin system [32][33][34][35], which are present in severe PAH patients and therefore contribute to a poor survival [40,45,46]. Therefore, whether exogenous melatonin supplements may be effective as a therapeutic strategy in patients with PH remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Lower plasma melatonin levels predict worse long-term survival in pulmonary arterial hypertension

Cai

Klein

Geenen

et al. 2020

European Heart Journal

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Background Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms may be involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve pulmonary arterial hypertension (PAH) patients and their clinical significance are still unknown. Methods and results Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in treatment-naïve PAH patients (n=43) and healthy controls (n=111). Melatonin levels were higher in PAH patients when compared with controls (Median 118.9 [IQR 109.3–147.7] versus 108.0 [102.3–115.2] pM, P<0.001) (Figure 1A). The overall mortality was 26% (11/43) during a median long-term follow-up of 42 [IQR: 32–58] months. When PAH patients were stratified into 4 groups according to the quartiles of melatonin levels, the mortality from below 1st quartile to above 4th quartile was 55% (6/11), 10% (1/10), 0% (0/12), and 40% (4/10), respectively (Figure 1B). Kaplan-Meier analysis further showed that patients with melatonin levels below the 1st quartile (<109.3 pM) had a worse long-term survival than patients with melatonin levels above the 1st quartile (Mean survival times were 46 [95% CI: 30–65] versus 68 [58–77] months, Log-rank, p=0.026) (Figure 1C). Conclusion Endogenous melatonin levels were increased in treatment-naïve PAH patients, and lower levels of melatonin were associated with worse long-term survival in patient with PAH, however, whether exogenous melatonin supplements may be effective as a therapeutic strategy in human PAH remains to be established. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): This work was supported by the China Scholarship Council (201606230252) as well as the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-11, RECONNECT), and German Center for Cardiovascular Research (DZHK81Z0600207). Instrumentation support was received from AB Sciex, ltd. for LC-MS/MS analyses performed in this study.

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Identification of insulin-regulated aminopeptidase (IRAP) in the rat pineal gland and the modulation of melatonin synthesis by angiotensin IV

Cited by 12 publications

References 42 publications

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

MicroRNA‐7 inhibits melatonin synthesis by acting as a linking molecule between leptin and norepinephrine signaling pathways in pig pineal gland

Lower plasma melatonin levels predict worse long-term survival in pulmonary arterial hypertension

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