F. Z. Meerson

The role of high-energy phosphate compounds in the development of cardiac hypertrophy

Abstract A number of diverse causes of cardiac hypertrophy are considered: a prolonged increase in work; prolonged hypoxia or ischaemia; the administration of sympathomimetic drugs; a congenital defect of mitochondrial function; and exposure to cold. The common factor preceding the activation of nucleic acid and protein synthesis in each of these forms of cardiac hypertrophy appears to be a decreased concentration of high energy phosphate compounds. It is suggested that such a deficiency of high energy phosphate compounds is the signal which gives rise to the activation of the genetic apparatus of the cell.

Differences in adaptive stabilization of structures in response to stress and hypoxia relate with the accumulation of hsp70 isoforms.

The phenomenon of adaptive stabilization of structures (PhASS) develops during adaptation of the organism to intermittent restraint stress. The PhASS manifests itself in a considerably increased resistance of the heart to a broad spectrum of harmful factors. In the present work, the content of hsp70 and their role in the development of PhASS during adaptation to intermittent restraint stress and to intermittent hypoxia were studied. In adaptation to restraint stress, five hsp70 isoforms with pI ranging from 5.7 to 6.3 were accumulated in the myocardium. The heart simultaneously became strikingly resistant to reperfusion paradox and heat shock. In adaptation to hypoxia, only two hsp70 isoforms with pI about 5.8 were accumulated. The resistance to reperfusion paradox was not increased and the resistance to heat shock was increased only moderately. These data suggest a role of different hsp70 isoforms in the mechanism of PhASS as well as adaptive protection of the heart.

Adaptation to stress increases the heart resistance to ischemic and reperfusion arrhythmias

Adaptation to repeated stress prevents or limits ischemic and reperfusion arrhythmias in the whole organism. In studying mechanism of this phenomenon, we have investigated the effect of local ischemia and subsequent reperfusion on the function of isolated hearts of rats adapted to the stress of repeated immobilization. We established that such adaptation limited the depression of the amplitude and velocity of contraction and velocity of relaxation of the heart in ischemia and subsequent reperfusion. Simultaneously this adaptation limited reperfusion-induced arrhythmias to a considerable extent; in particular, the duration of reperfusion-induced fibrillation was reduced two-fold. Thus the cardioprotective antiarrhythmic effect of adaptation of the organism to stress exposure depends not only on adaptive alterations of central regulation, but to a considerable extent, is determined by processes occurring at the level of the heart itself.

Phenomenon of the adaptive stabilization of sarcoplasmic and nuclear structures in myocardium

In adaptation of rats to repeated stress exposure, a mechanism gradually forms at the level of heart to provide a considerable increase in the organ resistance to reperfusion paradox and toxic concentrations of catecholamines and Ca2+. Sarcoplasmic reticulum and mitochondria isolated from the hearts of adapted animals are highly resistant to autolysis, and nuclei to the damaging action of one-chain DNA. These changes are named phenomenon of the adaptive stabilization of structures (PhASS). An important role of myocardial heat shock protein (HSP) accumulation in the mechanism of PhASS is shown. The development of PhASS is accompanied by an increased resistance of myocardium to ischemic necrosis.

Adaptation to stress exposure prevents arrhythmogenic and contractural effects of the excess of Ca2+ on the heart by the increased activity of sarcoplasmic reticulum

SummaryAdaptation of rats to repcated short-term stress exposure prevents, to a considerable extent, contractural and arrhythmogenic effects of high concentrations of extracellular Ca2+ on isolated heart. Increased efficiency of SR Ca2+-pump functioning and a significant increase in Ca2+ pump resistance to autolysis are proved to play the main role in this effect.

Adaptive protection of the heart and stabilization of myocardial structures

SummaryAdaptation of animals to short-term stress exposure (ASE) protected the heart against arrhythmias in acute ischemia and reperfusion and eliminated the decrease in threshold of fibrillation and arrhythmias in acute myocardial infarction and postinfarction cardiosclerosis. Cardioprotective effect of ASE was provided not only by the activation of GABAergic, opioidergic and cholinergic stress-limiting system but also by a mechanism formed at the level of heart itself. Isolated hearts of animals adapted to short-term stress exposure possessed a strikingly enhanced resistance to toxic doses of catecholamines, Ca2+, and to reperfusion damage following total ischemia. Contracture-inducing and arrhythmogenic effects of these factors and the release of CK into the perfusate were manifold reduced in ASE. Mitochondria and elements of SR Ca-pump isolated from the hearts of adapted animals were much more resistant to autolysis. This phenomenon of adaptive stabilization of structures (PhASS) was accompanied by the accumulation of HSP 71 and a simultaneous increase in the heart thermal stability. In the coronary artery ligation the PhASS lacked the anti-ischemic effect, but it provided a decrease of the necrotic zone by more than 40 %, the ischemic zone being unchanged, due to its cytoprotective effect.

BIPHASIC CHARACTER OF THE PHENOMENON OF ADAPTIVE STABILIZATION OF STRUCTURES DURING LONG-TERM ADAPTATION OF THE ORGANISM TO STRESS

In 198%1990 [2,9], the phenomenon of adaptive stabilization of structures (PASS), manifested in an increased resistance not only of the whole organism but also of isolated organs (primarily, of heart) to a broad spectrum of damaging factors, ranging from toxic concentrations of catecholamines to reperfusion and heat injury [2,3,9], was discovered for adaptation of the organism to stress. Simultaneously, the resistance of such cell structures as the sarcoplasmic reticulum, mitochondria [3,8], and nucleus [1] to autolysis increases. PASS has been found to be realized against the background of a significant increase of the content of heat shock proteins (hsp 70) in the myocardium [1,9]. Thus, PASS emerged as the cellular component of adaptation, boosting the resistance of structures to damaging factors due to the activation of the genetic apparatus [3]. A marked PASS has been shown to appear as soon as after a 14-day course of adaptation to stress [1,2,3,8]. However, the possibility of maintaining PASS on a high level by prolonging the course of adaptation has not been studied; in other words, the dynamics of PASS is still to be clarified in long-term adaptation to stress. Accordingly, the aim of the present study was, first, to compare the magnitude of PASS judging by the changes in the resistance of the isolated

Isoform composition of inducible hsp 70 in the rat myocardium after heat shock

Organisms ranging from prokaryotes to the higher eukaryotes respond in a remarkably varied manner to environmental stress. Meanwhile a general characteristic feature of the cellular response to stress in many cases is rapid synthesis of what are called heat shock proteins (hsp) [9, 10]. The principal representatives of this family are heat shock proteins with molecular weight of about 70 kilodaltons (hsp 70) [9, 10]. We know that hsp are involved in the repairing of stress-induced injuries through disaggregation of abnormal protein-protein interactions [9, 10, 13]. Expression of individual genes coding for isoforms of inducible hsp has been shown to depend on the strength and character of the stressor [1, 6, 12, 13]. It has also been shown that the content of inducible hsp 70 in cells depends on the time elapsing after exposure to stress and, in particular, in the case of rat cardiomyocytes, two phases in the accumulation of hsp 70 have been found after pressure loading [3]. Meanwhile, the important question of how the isoform spectrum of hsp 70 depends on the time after stress has not yet been answered, i.e., essentially it remains unclear in what order expression of the genes of particular hsp 70 isoforms takes place after stress. The aim of this investigation was to study the isoform spectrum of hsp 70 accumulating in the rat myocardium at different times after heat shock.

Adaptation to stress increases the resistance of heart cell nuclei to the damaging action of single-stranded exogenous DNA

During the last decade it has been shown that in response to repeated exposures to short-term stress situations the body develops adaptation which not only increases its resistance to severe stress, but also possesses a broad spectrum of crossed protective effects, i.e., it protects the body against direct ischemic [3], chemical [15], cold [9], and even radiation-induced damage [4]. This adaptive protection has been shown to be realized not only at the level of neuroendocrine mechanisms, but also at the level of the target organs themselves. Thus it has been shown that the isolate heart of adapted animals possesses sharply increased resistance to reperfUsion injuries [11], to high Ca 2+ concentrations [5], and to toxic doses of catecholamines [2], whereas organelles isolated from it, namely elements of the sarcoplasmic reticulum and mitochondria -differ from the controls in their higher degree of resistance to autolysis [5]. This combination of phenomena has been described as the phenomenon of adaptive stabilization of structures (PASS) [6]. However, until recently one fundamental question remained open: is PASS realized only in cytoplasmic structures or does it develop also at the level of the genetic template (DNA). When this problem is studied it must be recalled that induction of nuclear proteases by single-stranded DNA regions can lead to irreversible damage to DNA [14]. It has been shown that such single-stranded DNA regions may arise as a result of free-radical injury to DNA during jschemia or severe stress [3]. The aim of this investigation was to assess the effect of preliminary adaptation of the body to stress on resistance of heart cell nuclei to the damaging action of exogenous single-stranded DNA.

Adaptation to stress prevents the cardiotoxic effect of rifampicin but not that of polymyxin B

Adaptation to stress has been shown to increase the resistance of the isolated heart to reperfusion injury and heat shock [4], to high Ca z+ concentrations and toxic doses of catecholamines [1, 8], and cellular structures (elements of the sarcoplasmic reticulum of the mitochondrion and nucleus), isolated from the myocardium of adapted animals, have been found to differ from the controls in having high resistance to damaging factors [5, 9]. This combination of phenomena has been called adaptive stabilization of structures (ASS) [3, 9]. An important role in the mechanism of the ASS phenomenon has been shown to be played by accumulation of heat shock proteins (hsp 70) in the cells of the organ [10]. Investigations have shown [11, 15] that hsp 70, by their disaggregating effects, protect cell proteins and, in particular, enzymes against damaging factors. However, the problem whether the resistance of the heart to the toxic effects of enzyme inhibitors is increased during adaptation to stress has not previously been studied. The aim of this investigation was to assess, on the basis of physiological criteria, the effect of adaptation to stress on the resistance of the heart to the toxic action of the RNA-polymerase inhibitor rifampicin [13] and the protein kinase C inhibitor polymyxin B [14].