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Summary - Феномен адаптационной стабилизации структур и защита сердца

Феномен адаптационной стабилизации структур и защита сердца
Основные механизмы долговременной адаптации
Роль HSP70
Кардиопротекторные эффекты адаптации к стрессу
Динамика становления и обратного развития ФАСС коррелирует с изменением содержания hsp70 в миокарде
Формирование феномена адаптационной стабилизации структур
Роль инозитол-фосфатного цикла в кардиопротекторном эффекте адаптации к повторным стрессорным воздействиям
Феномен адаптационной стабилизации структур при адаптации организма к периодической гипоксии
Адаптация к гипоксии по сравнению с адаптацией к стрессу сопровождается меньшим накоплением стресс-белков
Биологическое значение белков теплового шока
Клеточная локализация и функции hsр70 в стрессированных клетках
Функции hsp 70, локализованных вдоль актиновых миофиламентов
Механизмы транскрипции и стресс-индуцированной активации синтеза hsp70
Роль hsp70 в адаптивных реакциях на примере развития термотолерантности и гипертрофии сердца
Компенсаторная гипертрофия и роль белков теплового шока в ее механизме
Механизм адаптационного накопления белков теплового шока
Роль белков теплового шока в механизме формирования феномена адаптационной стабилизации клеточных структур
Место защитной системы, связанной с hsp70 среди других клеточных систем защиты
Перспективы использования активации системы белков теплового шока в адаптационной медицине
Другие механизма феномена адаптационной стабилизации структур
Возможности воспроизведения ФАСС и его использование для защиты сердца
Механизмы ФАСС участвуют в повышении устойчивости организма к тяжелой гипоксии

In 1989-1990 a phenomenon of adaptive stabilization of structures (PhASS) was discovered. The phenomenon is in that adaptation to stress exposure strikingly increases the resistance not only of the organism as a whole but also of isolated organs and first of all of the heart to a wide spectrum of harmful factors from toxic catecholamine concentrations to the reperfusion paradox. There is a simultaneous increase in resistance to autolysis of such cytoplasmic structures as sarcoplasmic reticulum, mitochondria and nuclei. The monograph summarizes recent results of investigations of molecular, cellular and neurogenic mechanisms which participate in the formation of PhASS. Furthermore, the central place i$ occupied by the consideration of basic mechanisms related to the activation of synthesis and accumulation of cellular stress proteins of the hsp70 family, the activation of ITP-DAG regulatory cascade and the increase in cholinergic system tone. In addition, principal possibilities of PhASS reproduction using physiotherapeutic procedures as well as of PhASS application to protect the heart and the organism as a whole are discussed.
The first chapter of the monograph states the following:

  1. Adaptation of the organism to intermittent immobilization stress exerts a pronounced cardioprotective effect and protects isolated heart against reperfusion damage. For instance, in reperfusion following total ischemia, the degree of restoration of the contraction amplitude was 50% in the hearts from adapted animals while in control it was only 20%. The contracture magnitude was 6 times less and the duration of severe arrhythmias and the release of creatine kinase into the perfusate were reduced in 2 and 2.5 times respectively as compared to the control. In addition, preliminary adaptation to stress enhanced the resistance of isolated heart to high concentrations of catecholamines and calcium, the "calcium paradox" and thermal injury. These results correspond to the concept that the cardioprotective effect of adaptation is realized both at the central level and at the level of regulatory mechanisms of the heart itself. It appeared that the capacity of such adaptation to limit disturbances of cardiomyocyte electric stability as well as intracellular calcium overload is an important PhASS component which plays a key role in the anti-arrhythmic effect of adaptation. For instance, under the action of low-sodium solution on rat papillary muscle, the contracture was 5 times reduced and the depression of resting potential was twofold less pronounced in adaptation than in control group. Adaptation to stress provides more lengthy action potential and limits the depression of membranous potential under a high frequency pacing and a high Ca2+ in papillary muscle.
  2. Preliminary adaptation of animals to stress provides an increased resistance both of cytoplasmic structures like SR and mitochondria and of nuclear DNA to damaging actions. For instance, the addition of single strand DNA which induced proteolysis resulted in degradation of as little as 8% of nuclear DNA in adapted animals versus 43% in control. Therefore the phenomenon of adaptive stabilization of structures (PhASS) can be formed not only at the level of cytoplasmic structures but also at the level of DNA, the genetic matrix.
  3. In adaptation of the organism to intermittent stress, the PhASS is accompanied by an accumulation of heat shock protein of the hsp70 family in organ cells. For instance, in adaptation to stress, the cardiomyocyte cytoplasm accumulates 5 hsp70 isoforms and the nucleoplasm accumulates 2 isoforms; potent cardioprotective effects are formed simultaneously. It was shown that the dynamics of direct and reverse development of protective effects of PhASS correlated to the content of myocardial hsp70 during and after adaptation to stress. In the process, the dynamics of hsp70 accumulation was nonlinear and characterized with a definite lag period of 6-8 days. Following this period the increase in synthesis of these proteins and the formation of protective effects of adaptation to stress proceed very rapidly. On the whole, these results allowed to put forward a hypothesis that heat shock proteins of hsp70 family present one PhASS mechanism and play an important role in the development of protective effects of adaptation to ambient factors .

The second chapter is devoted to the analysis of the dependence of adaptation protective effects upon the duration and regime of stress exposure, it was shown that cardioprotective effects of adaptation to long-term continuous stress are formed as a result of alternating increase in cholinergic tone and activation of cellular mechanisms. Among cellular mechanisms which contribute to the PhASS formation the ITP-DAG regulatory cascade plays the most important role. For instance, a 15-day course of adaptation to short-term stress exposure results in a pronounced activation of phospholipase c* the key link of ITP-DAG regulatory cascade. Furthermore, there is an increase in Primary short-term and delayed stable positive inotropic responses of the heart to phenylephrine stimulation due to the ITP and DAG accumulation in the myocardium. In the process the PhASS is maximum pronounced. The disappearance of phospholipase c activation and increased responses to phenylephrine by the 30 day of adaptation is accompanied by a considerable suppression of PhASS. Therefore, the activation of ITP-DAG regulatory cascade plays an important role in the PhASS formation.
The third chapter of the monograph deals with the peculiarities of PhASS development and the role of of heat shock proteins in adaptation to hypoxia. It was established that the PhASS is considerably less pronounced in adaptation of the organism to intermittent hypoxia than in adaptation to stress, namely, adaptation to hypoxia increased the resistance of heart to thermal but not to reperfusion injury. In injuries associated with calcium overload like under the action of high concentrations of catecholamines or calcium, the anti-arrhythmic effect of adaptation to hypoxia was low in comparison with that of adaptation to stress. This may be related with the fact that adaptation to stress is more effective than adaptation to hypoxia in limiting the arrhythmogenic shifts of cardiomyocyte bioelectric activity, namely, the reduced amplitude and duration of action potential and the depression of resting potential along with the probability of trigger arrhythmias and delayed afterpotential.
Besides, the resistance of cytoplasmic structures and nuclei to damaging factors did not increase in adaptation to hypoxia as distinct from adaptation to stress. Thus there are profound differences between protective effects of these two types of adaptation both at the level of whole organ and at the level of cellular structures. Further it appeared that, in adaptation to hypoxia, the cardiomyocyte cytoplasm accumulated only 2 hsp70 isoforms of 5 ones detected in adaptation to stress while there was no increase at all in nuclear hsp70. Thus the differences between cardioprotective effects of these two forms of adaptation may be associated with peculiarities of accumulation, isoformic pattern and subcellular distribution of myocardial hsp70.
In studying the role of phosphoinositide metabolism in adaptation to hypoxia it was found that the activity of ITP-DAG regulatory cycle was reduced in myocardium by the 20th day of adaptation. The regulatory inositolphosphate cycle became activated only in 40 days after the onset of adaptation to intermittent hypoxia. This activation manifested itself in an enhancement of positive inotropic responses of the heart to o^-agonist stimulation and an increase in Ca2+-dependent phospholipase C activity. This enzyme activation was less pronounced than in adaptation to stress. On the whole this corresponds to the fact that cardioprotective effects of long-term adaptation to hypoxia as well as many components of PhASS are less pronounced than in adaptation to stress.
The fourth chapter of the book based on our own data and on the data of literature analyzes the biological significance of heat shock proteins and their role in the development of PhASS. As a result a hypothesis has been put forward that the activation of heat shock protein synthesis induced by adaptation to ambient factors may be related to three principal receptor-dependent mechanisms, namely 1) activation of Ca2+-mobilizing receptors, increase in intracellular ITP and DAG and subsequent activation of genetic apparatus via pH change and phosphorylation of transcription factor by protein kinase c, 2) adrenoceptor activation, increase in cellular cAMP and phosphorylation of heat shock protein gene transcription factor by cAMP-dependent protein kinase, and, finally, 3) activation of heat shock protein gene transcription following the binding of activated steroid receptors to DNA.
It was shown that the protective role of heat shock proteins in adaptation and PhASS development may be supposingly related to the following mechanisms: binding of fatty acids and thus limitation of their detergent action, increased potency of cellular antioxidant systems and prevention of free-radical damage to membranes and DNA; destruction of anomalous protein-to -protein aggregates with subsequent renaturation of protein molecules; providing normal protein biosynthesis in unfavorable conditions; limitation of protein proteolysis by shielding of damaged sites; and, finally, limitation of harmful effects of calcium overload by the binding of calmodulin, one principal Ca2+ receptor.
Taken together, these data allowed to define the protective system of heat shock proteins as the new local stress-limiting system which plays an important role in the adaptive stabilisation of cellular structures along with already known stress-1imiting systems - antioxidant, adenosinergic, prostaglandin systems and others. On this basis, the conclusion of the fourth chapter considers the prospects of using the activation of heat shock protein system in adaptive medicine.
The fifth chapter is completely devoted to a theoretical analysis of other PhASS mechanisms divorced from heat shock proteins as well as the role of PhASS in the common mechanism of long-term adaptation of the organism.
The sixth chapter being the most interesting for clinic present data that PhASS can be reproduced with routine physiotherapeutic methods to be applied for the protection of heart in infarction and of the whole organism in severe hypoxia. For instance it has been shown that a course of adaptation to short-term stress exposure exerted no effect on the volume of ischemic zone 5 min following the ligation of left coronary artery in rat. However, the volume of necrotic tissue measured two days following the coronary ligation was reduced by more than 40% in hearts from adapted animals because a considerably less part of initially ischemic tissue was subsequently subjected to necrosis than in control. It is interesting that, in adaptation to hypoxia, when the PhASS was significantly less pronounced in comparison with adaptation to stress, the cytoprotective effect was utterly absent and the anti-ischemic effects was determined mainly by the growth of coronary vessels. Thus adaptation to stress, as distincts from adaptation to hypoxia lacks the anti-ischemic effect though possesses a strong cytoprotective effect. When estimating the effect of a course of physiotherapeutic procedures (transauricular electric stimulation: 0.8-2 mA, 1.5 ms, 3 Hz for 20 min daily during 12 days) on the volume of initially developed ischemic zone with subsequent necrosis induced by coronary ligation, the following appeared. The course of such procedures as adaptation to repeated stress exposure, did not affect the ischemic zone immediately after the coronary ligation. At the same time it more than twice increased the restoration zone which was not subsequently subjected to necrosis. Therefore, the PhASS developing under the physiotherapeutic action like in adaptation to stress exposure lacks any anti-ischemic effect but possesses a pronounced cytoprotective effect. However the most effect has been achieved in combining the physiotherapeutic procedures with with adaptation to intermittent hypoxia produced in an altitude chamber. It was shown that this combination reproduced both the anti- ischemic effect of adaptation to hypoxia and the cytoprotective effect of physiotherapeutic actions. As a result, the final necrotic zone was more than threefold reduced as compared with the control. This effect appeared to be greater than in separate application of adaptation to hypoxia and the course of physiotherapeutic procedures. It is of no less clinical importance that the PhASS may be applied not only to increase the resistance of individual organs but, what is more important, the PhASS can become a basis for the protection of whole organism against factors which are a threat to life, in particular, against sublethal hypoxia, it was shown that adaptation of the organism to repeated stress resulted in a decrease in lethality from inspiration of gas mixture containing 6% of oxygen by 6.5 times. The major mechanism underlying this phenomenon is an increased capacity of tissues to utilize oxygen delivered with blood. This important shift may be due to at least two factors. First, the membranous barrier between and cell is better preserved and, therefore, provides a higher rate of oxygen diffusion. This point of view is in agreement with the fact of adaptive limitation of membrane-damaging processes, namely, lipolysis activation and lipid peroxidation. Second, in adapted animals, the higher oxygen consumption may be caused by a better preservation of mitochondrial processes of oxygen utilization and oxidative phosphorylation. It is presently known that adaptation to repeated immobilization stress results in the development of PhASS manifests itself in an increased resistance of plasmic membrane, sarcoplasmic reticulum, mitochondria, and nuclei to autolysis and lipid peroxidation. One may assume that, in the conditions of our experiment, the PhASS development has played its role in the preservation of cellular structures under severe hypoxia and thus saved a high rate of oxygen diffusion and consumption by cells.
Thus the increased resistance of adapted to stress organism is likely caused by two main factors, namely, regulatory economization of oxygen transport and PhASS. Theoretical significance of this concluding part of investigation is that the data obtained demonstrate with a high degree of probability that the PhASS is in fact not a local but a general phenomenon which embraces the organism as a whole and is able to protect it even against such in most cases fatal factors as deep and lengthy hypoxia.

Thus the problem of PhASS appears to be incommensurably more broad than a mere studying of mechanisms of enhanced resistance of cellular structures. It remains to be estimated in full measure the PhASS significance in the development of new methods in adaptive medicine. Judging from the first experimental data, these methods may appear no less effective for protection of the heart and the whole organism than the medicamentous therapy.

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