MECHANISMS OF REDOX CONTROL IN ONTOGENY: CONTRIBUTION OF STRESS HORMONES AND PROTEINS

INTRODUCTION

At present there is no doubt any more, as to the important role of stress hormones, and first of all, glucocorticoids (GC) and catecholamines, and stress proteins, principally, heat shock proteins (HSP), in ontogenetic regulation, as well as in pathogeny of age-related diseases. What for their role in aging, earlier we have warned against attributing to GC the main contribution to this process [11]. Nevertheless, a possibility remains on participation of GC in aging mechanisms in combinations with other bioregulators, e.g., insulin and cytokines [10]. Besides, a number of evidence favor the necessity of considering biphasic GC action [6, 21, 27]. In the present work we decided to analyze how GC and other hormones, as well as stress proteins could participate both in aging and ontogenetic regulation, as well as in pathogeny of age-related diseases. In order to perform this task, we have evaluated their contribution to redox-control and oxidative stress, considering the importance of these mechanisms in aging and age-related pathology [27].

MATERIALS AND METHODS

The search of bibliographic evidence was performed in a number of commercial databases (Science Direct, Wiley, Springer, Karger, Ebsco), as well as in public internet domain, by means of Scholar Google, preferably in English, during the last 45 years, using the indicated key words. Special attention was payed to works performed in the frame of DOHaD (Developmental Origins of Health and Diseases) paradigm.

RESULTS AND DISCUSSION

The analysis of world literature has shown clearly the capacity of GC to cause oxidative stress in the body and target organs. Indeed, according to [13], synthetic GC dexamethasone increased the production of H₂O₂ and intracellular level of peroxynitrite in cultured endothelial cells. Dexamethasone increased also H₂O₂ production by skeletal muscle cells in culture [24]. On the other hand, administration of cortisol, noradrenaline and adrenaline to the culture of mouse 3T3 cells caused accumulation of DNA damage, whereas RU486 and propranolol, i.e., specific blockers of GC receptors and beta-adrenoreceptors, prevented the damaging influence of stress hormones [8].

In accord with [17], injections of dexamethasone increased oxidative stress in skeletal muscles and blood plasma of chicken. The adverse pro-oxidant action of dexamethasone could be prevented by vitamin E [7]. The administration of corticosterone increased the levels of peroxidation products of lipids and proteins in rat hippocampus and at the same time, it decreased the activities of antioxidative enzymes: superoxide dismutase, catalase and glutathione peroxidase [31]. According to [14], hyperoxia enhanced hormonal activity in HPA axis and decreased the level of GC receptors in rat hippocampus; these alterations were prevented by vitamin E. As shown in [15], the rats maintained on a diet deficient in vitamin E, were more susceptible to cataract development under the influence of locally applied synthetic GC prednisolone.

Not only data of original studies in vitro and in vivo, but also review papers support the idea on pro-oxidant GC action. For example, according to [32], GC possess such adverse action, in contrast to estrogens that have antioxidant activity. The meta-analysis [4] confirmed that in general, GC increase oxidative stress, however, among various organs, the brain was more sensitive to this adverse GC action, whereas the heart was more resistant. Besides, this meta-analysis has shown that pro-oxidant GC action was higher in young animals and in females. Finally, the evidence presented in world literature does not leave any doubt on pro-oxidant action of stress via the increase in metabolic rate, resulting in accelerated aging [18, 25].

Considering the important role of mitochondria in generation of peroxidation products, it was necessary to analyze, if GC can directly influence these organelles. In fact, mitochondria possess GC receptors [29] and besides, these hormones are involved in regulation of mitochondrial biogenesis [27]. Finally, it is important that GC possess biphasic action on mitochondria [6, 21].

During the last years the works appeared on important contribution of oxidative stress to programming / imprinting phenomena. Indeed, intrauterine growth retardation was associated with oxidative stress in the fetus, especially in beta-cells of pancreatic islets of Langerhans. Besides, the content of mitochondrial DNA was diminished in offspring of rats maintained on low protein diet during gestation and lactation [33]. In accord with [35], prenatal administration of dexamethasone in sheep caused increased H₂O₂ production by mitochondria of their offspring. On the other hand, high fat diet during gestation in rats was able to provoke decreased mitochondrial DNA content in kidneys of their offspring [34]. According to [16], mitochondria of skeletal muscles in rats with intrauterine growth retardation demonstrated lower levels of O₂ consumption and ATP production. On the other hand, the offspring of rats maintained on low protein diet during gestation and lactation, has shown decreased mitochondrial DNA content in the liver, pancreas and skeletal muscles. Other articles also support the idea on the role of mitochondria and oxidative stress in programming / imprinting phenomena. In fact, according to [26], undernutrition early in ontogeny can provoke long-term alterations in mitochondria that cause insulin resistance. Moreover, regulation not only of insulin action, but also of blood pressure could be the target of programming / imprinting under the influence of oxidative stress [19].

The most interesting works in this sense are those evidencing the capacity of antioxidants to prevent the programming / imprinting phenomena. Indeed, a combination of vitamins C and E prevented the capacity of dexamethasone administered to rats in neonatal period, to increase vasoconstrictory action of phenylephrine and thromboxane [12]. The same combination of vitamins prevented also the capacity of neonatally administered dexamethasone to diminish the survival rate and HSP90 content in left ventricle of the heart [1]. Besides, the combination of vitamins C and E prevented the capacity of dexamethasone administered in neonatal period, to decrease the total brain volume, as well as the volumes of several hippocampal regions [3]. Finally, in accord with [2], the antioxidant lazaroid prevented hypertension in rat offspring after maintaining their mothers on low protein diet during gestation.

What for stress proteins, the direct involvement in redox-regulation is established for thioredoxin and heme oxygenase [22, 30]. Besides, normal functioning of GC receptors depends on HSP90 and thioredoxin [5, 20, 28].

CONCLUSION

Turning back to aging theories based on peroxidation of macromolecules, it is pertinent to note that bibliographic analysis performed by us greatly enhances the probability of the involvement of GC and other stress hormones and proteins in aging mechanisms and pathogeny of age-related diseases. Moreover, the suggestion made by us earlier on GC capacity to cause in perinatal period the programming / imprinting of aging process [9], gains now possible interpretation, if to consider that the action of GC and / or stress in perinatal period can influence the regulation of endogenous GC already in adult state and perhaps, even in senescence. Finally, for new antioxidants like SkQ1 [23] the plausible (but not proved yet) possibility opens for partial prevention of aging and age-related diseases already in early development, confirming in this way high importance of DOHaD paradigm for modern and, especially, future studies.

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Von Bergen N.H., Koppenhafer S.L., Spitz D.R. et al. Fetal programming alters reactive oxygen species production in sheep cardiac mitochondria // Clin. Sci. – 2009. – V.116. – P.659-668.[schema type=»book» name=»MECHANISMS OF REDOX CONTROL IN ONTOGENY: CONTRIBUTION OF STRESS HORMONES AND PROTEINS» description=»The participation of stress hormones and proteins in ontogenetic regulation is a theme of earlier and recent research. However, the mechanisms underlying such participation are far from clear yet. The present work aimed at establishing the importance of redox control and oxidative stress in regulatory mechanisms involving stress hormones and proteins. In order to localize the studies of interest, we performed bibliographic search utilizing the indicated key words. Various databases, as well as Public Domain of Internet were explored using Scholar Google, preferably in English, during the last 45 years. Literature data confirm that glucocorticoids can provoke oxidative stress in the body and target organs. Besides, the importance of various stress proteins in redox control is increasingly established. Since one of the theories of aging is based on oxidative damage to mitochondria and macromolecules, the role of stress hormones and proteins in pathogeny of age-related disorders becomes better justified. In this respect, the use of antioxidants like vitamins C and E, SkQ1, etc. for diminution of adverse effects of glucocorticoids and their contribution to programming / imprinting phenomena is a promising avenue of future investigations.» author=»Prokhorov Leonid Yurievich, Goudochnikov Viktor Ivanovitch» publisher=»БАСАРАНОВИЧ ЕКАТЕРИНА» pubdate=»2017-03-30″ edition=»ЕВРАЗИЙСКИЙ СОЮЗ УЧЕНЫХ_30.04.2015_04(13)» ebook=»yes» ]

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