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Nitric Oxide-Heat Shock Protein Axis in Menopausal Hot Flushes

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Nitric Oxide-Heat Shock Protein Axis in Menopausal Hot Flushes Human Reproduction Update, Vol.23, No.5 pp. 600–628, 2017 Advanced Access publication on July 18, 2017 doi:10.1093/humupd/dmx020 Nitric oxide-heat shock protein axis in menopausal hot flushes: neglected metabolic issues of chronic inflammatory diseases associated with deranged heat shock response Antônio Azambuja Miragem1,2 and Paulo Ivo Homem de Bittencourt Jr1 1Laboratory of Cellular Physiology, Department of Physiology, Federal University of Rio Grande do Sul, Rua Sarmento Leite 500, ICBS, 2nd Floor, Suite 350, Porto Alegre, RS 90050-170, Brazil 2Federal Institute of Education, Science and Technology ‘Farroupilha’, Rua Uruguai 1675, Santa Rosa, RS 98900-000, Brazil *Correspondence address. Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil. Tel: +55-51-33083151; Fax: +55-51-33084555; E-mail: [email protected] Submitted on March 24, 2016; resubmitted on June 11, 2017; editorial decision on June 27, 2017; accepted on June 28, 2017 .............................TABLE OF CONTENTS.............................................................................................. • Introduction The interplay between hot flushes, menopause-related chronic inflammatory diseases and deranged HSR The NO-HSP70 axis, thermoregulation and hot flushes • Methods • The Heat Shock Response Intracellular HSP70 and the antisenescent resolution of inflammation Proteotoxic stimuli, senescence and HSR Metabolic activation of HSR HSP70, thermoregulation and cytoprotective thermotolerance Extracellular HSP70 (eHSP70) as a danger signal and HSR indices Adrenergic stimulation Oestrogen-induced HSR and the NO-HSP70 axis • Temperature Control, Thermoneutral Zone, Oestrogen and Flushes: Clues for a Hidden HSR KNDy neurons, GnRH pulsatility and sexual steroid hormone feedback systems KNDy nuclei in thermoregulation and the shift of thermoneutral zone in menopause Termination of hot-flush period over menopause transition • KNDy Neuron Circuitry as a Backup System for Triggering HSR in the Absence of Oestrogen KNDy neurons and the NO-HSP70 axis HSR as a negative feedback for NKB and kisspeptin during hot flushes and its consequences in menopause • Predicted Interventions in Low-Grade Chronic Inflammatory Diseases Associated with Deranged HSR in Symptomatic Flushing Women Heat treatment Gut microbiota manipulation HSR inducers and co-inducers • Conclusion © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected] Nitric oxide-heat shock protein axis in hot flushes 601 BACKGROUND: Although some unequivocal underlying mechanisms of menopausal hot flushes have been demonstrated in animal mod- els, the paucity of similar approaches in humans impedes further mechanistic outcomes. Human studies might show some as yet unex- pected physiological mechanisms of metabolic adaptation that permeate the phase of decreased oestrogen levels in both symptomatic and asymptomatic women. This is particularly relevant because both the severity and time span of hot flushes are associated with increased risk of chronic inflammatory disease. On the other hand, oestrogen induces the expression of heat shock proteins of the 70 kDa family (HSP70), which are anti-inflammatory and cytoprotective protein chaperones, whose expression is modulated by different types of physio- logically stressful situations, including heat stress and exercise. Therefore, lower HSP70 expression secondary to oestrogen deficiency increases cardiovascular risk and predisposes the patient to senescence-associated secretory phenotype (SASP) that culminates in chronic inflammatory diseases, such as obesities, type 2 diabetes, neuromuscular and neurodegenerative diseases. OBJECTIVE AND RATIONALE: This review focuses on HSP70 and its accompanying heat shock response (HSR), which is an anti- inflammatory and antisenescent pathway whose intracellular triggering is also oestrogen-dependent via nitric oxide (NO) production. The main goal of the manuscript was to show that the vasomotor symptoms that accompany hot flushes may be a disguised clue for important neuroendocrine alterations linking oestrogen deficiency to the anti-inflammatory HSR. SEARCH METHODS: Results from our own group and recent evidence on hypothalamic control of central temperature guided a search on PubMed and Google Scholar websites. OUTCOMES: Oestrogen elicits rapid production of the vasodilatory gas NO, a powerful activator of HSP70 expression. Whence, part of the protective effects of oestrogen over cardiovascular and neuroendocrine systems is tied to its capacity of inducing the NO-elicited HSR. The hypothalamic areas involved in thermoregulation (infundibular nucleus in humans and arcuate nucleus in other mammals) and whose neurons are known to have their function altered after long-term oestrogen ablation, particularly kisspeptin-neurokinin B-dynorphin neu- rons, (KNDy) are the same that drive neuroprotective expression of HSP70 and, in many cases, this response is via NO even in the absence of oestrogen. From thence, it is not illogical that hot flushes might be related to an evolutionary adaptation to re-equip the NO- HSP70 axis during the downfall of circulating oestrogen. WIDER IMPLICATIONS: Understanding of HSR could shed light on yet uncovered mechanisms of menopause-associated diseases as well as on possible manipulation of HSR in menopausal women through physiological, pharmacological, nutraceutical and prebiotic inter- ventions. Moreover, decreased HSR indices (that can be clinically determined with ease) in perimenopause could be of prognostic value in predicting the moment and appropriateness of starting a HRT. Key words: menopause / hot flushes / heat shock response / chronic inflammatory diseases / cellular senescence / thermoregulation / heat therapy / obesity / insulin resistance / cardiovascular disease. Introduction et al., 1995) and surgical, (i.e. bilateral oophorectomised [Aksel et al., 1976]) menopausal patients present oestrogen levels that do not dif- Menopausal hot flushes (also known as hot flashes) alongside night fer between symptomatic and asymptomatic women (Freedman, sweats comprise a set of vasomotor symptoms (VMS) and other 2005). Conflicting results, however, suggest that oestrogen levels autonomic responses which lead to an uncomfortable trait of heat- may be indeed lower in symptomatic postmenopausal women (Erlik defence responses, including skin vasodilation and sweating. These et al., 1982) as well as in premenopausal patients presenting hot VMS are related to changes in hypothalamic processing of thermo- flushes (Kronenberg, 1990). Progesterone, which importantly drives regulation and are accompanied by an abrupt and huge feeling of sex-hormone elicited modulation of thermoregulation, has also heat, usually following a tiny rise in core temperature. Although hot shown to reduce VMS scores and frequencies in women within 10 flushes are the most common complaint that leads this group of years after last menstruation (Hitchcock and Prior, 2012). women to seek clinical support, little has been added to our knowl- Even though some animal studies have pointed out unequivocal edge on their clinical approach in almost 20 years (Stearns et al., mechanisms on which hot flushes rely (Dacks and Rance, 2010; 2002). The only irrefutable evidence is that oestrogen replacement Dacks et al., 2011; Mittelman-Smith et al., 2012; Rance et al., 2013), therapy virtually eliminates hot flushes, while some non-hormonal the paucity of similar approaches in humans has been impeding fur- treatments are currently under evaluation (Freedman, 2014). Even in ther mechanistic outcomes. More specifically, oestrogen possesses relation to oestrogen, its involvement is not completely settled, as it the ability to induce the expression of HSP72 (Olazábal et al., 1992a, is not the absolute level of oestrogen, but rather the pace of 1992b; Knowlton and Sun, 2001; Hamilton et al., 2004a, 2004b; Stice decrease in oestrogen plasma levels that determines the onset of the et al., 2011), a member of the 70 kDa family of heat shock proteins flushing time span (Kronenberg, 1990, 2010; Rance et al., 2013). It is (HSP70), which are anti-inflammatory and cytoprotective (i.e. cardio- intriguing that all menopausal women have low circulating oestrogen protective, vasculoprotective, neuroprotective, antiatherosclerotic levels, yet not all of them exhibit hot flushes. The appearance of hot and antidiabetic) protein chaperones (detailed in ‘The Heat Shock flushes always coincides with oestrogen withdrawal, but this does not Response’ section) whose expression is modulated by different types entirely explain the phenomenon because both natural (Freedman of physiologically stressful situations, including exercise and heat 602 Miragem and Homem de Bittencourt stress (Newsholme and Homem de Bittencourt, 2014). Hence, it is for both pharmacological and non-pharmacological interventions in not surprising that, during perimenopause, several homoeostatic middle-aged women. In fact, hot flushes are strongly associated with functions based on oestrogen-dependent HSP70 expression start to low-grade inflammation. For instance, obesity is a major factor for collapse. the appearance of hot flushes (Thurston and Joffe, 2011), whereas This is noteworthy because reduced production of HSP70, and its hot flushes directly correlate with the risk of insulin
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