Features of the Development of Postinfarction Heart Failure in Rats of Different Genetic Lines

The investigation is devoted to the study of features of postinfarction heart failure development in rats of two genetic lines — August and Wistar. The work analyzes cardiac contractile and pumping function in the dynamics following myocardial infarction, sympathetic nervous system activity based on catecholamine levels, nitric oxide system function, the state of myocardial β-adrenergic receptor complexes, and the level of stress proteins. Comparison of animals with inherently different neurohumoral regulation makes it possible to identify genetically determined mechanisms governing cardiac resistance or vulnerability to ischemic injury and subsequent decompensation.

Research Relevance. Ischemic heart disease and its complications in the form of postinfarction heart failure (HF) are the leading cause of mortality in developed countries. It is well established in clinical practice that individual, i.e., genetically determined, differences exist in disease course and survival in the postinfarction period. However, the mechanisms underlying this phenomenon remain far from clear. In particular, the features of regulatory systems determining cardiac resistance (or, conversely, vulnerability) to this severe disease are insufficiently studied. The most critical role in the pathogenesis of heart failure is played by hyperactivation of the sympathetic nervous system (SNS), as a result of which catecholamines cause disturbances of cardiac function and rhythm, myocardial hypertrophy (Simpson R.S. et al., 1991; Yamazaki T. et al., 1998), and apoptosis (Communal et al., 1999). Another consequence of elevated circulating catecholamine levels is decreased adrenoreactivity of the myocardium, which is associated with reduced β-adrenergic receptor density (Bristow M.R. et al., 1992; Steinfath M. et al., 1992; Bohm M., 1995) and their desensitization (Bohm M., 1996; Kompa A.R. et al., 1999), leading to disruption of cAMP-dependent mechanisms of Ca2+-channel activation and suppression of the inotropic response to agonist action.

In existing approaches to studying the mechanisms of adrenergic injury, SNS activation is modeled by various methods: chronic norepinephrine infusion (Urasawa K. et al., 1992; Brouri F. et al., 2002), overexpression of the β-adrenergic receptor-coupled stimulatory protein Gas in transgenic mice (Iwase M. et al., 1996), or the α-adrenergic receptor-coupled protein Gq (Adams J.W. et al., 2001). At the same time, animals possessing innate heightened SNS activity and correspondingly elevated catecholamine levels in the blood are of great interest for studying this problem. Such a feature is possessed by August-line rats compared with Wistar population rats (Kvetnanský R. et al., 1981; Pertsov S.S. et al., 1997). In this regard, August rats exhibit decreased parasympathetic nervous system activity and baroreflex sensitivity (Belkina L.M. et al., 2007), which is considered a risk factor for myocardial infarction and heart failure (Lown B. et al., 1976; Vanoli E. et al., 1990). However, contrary to this notion, it was found that August rats are more resistant to acute myocardial infarction than Wistar rats, as evidenced by lower mortality and less pronounced disturbances of cardiac rhythm and contractile function (Belkina L.I.M. et al., 2001; Pshennikova M.G. et al., 2001). It has been established that one of the mechanisms of enhanced resistance of August rats to acute ischemia is decreased, compared with Wistar rats, myocardial adrenoreactivity (Belkina L.I.M. et al., 2001), as well as heightened activity of the NO system characteristic of these animals (Mikoyan V.D. et al., 1996). As is known, NO is not only a potent vasodilator but also regulates the SNS, limiting its activity both at the CNS level (Patel K.R. et al., 1996; Sakai K. et al., 2005) and at the peripheral level (Kau D.M. et al., 1991; Schwarz P. et al., 1995). Furthermore, NO activates protective systems at the cellular level, participating in the induction of synthesis of stress proteins possessing cardioprotective properties. At the same time, the features of postinfarction heart failure development, neurohumoral regulation, and activation of protective systems in August and Wistar rats in remote periods after myocardial infarction have not been studied. The features of functioning of myocardial adrenergic receptor complexes in animals of different genetic lines and their role in the pathogenesis of HF also remain unknown.

The aim of this study is to investigate the features of heart failure development and neurohumoral regulation in remote periods after myocardial infarction in rats of genetically different populations — August-line rats and Wistar population rats.

In accordance with the stated aim of the investigation, the following tasks were addressed:

1. To evaluate cardiac contractile and pumping function in the dynamics of postinfarction heart failure development in Wistar population and August-line rats.

2. To study sympathetic nervous system activity based on catecholamine levels in the brain, adrenal glands, and blood in the dynamics of heart failure development in Wistar and August rats.

3. To assess NO-system activity based on nitrate and nitrite content in blood during postinfarctive cardiosclerosis in Wistar and August rats.

4. To determine adenylate cyclase activity and the ratio of mRNA expression of β1- and β2-adrenergic receptors in the myocardium under control conditions and during postinfarctive cardiosclerosis in Wistar and August rats.

5. To determine the level of stress proteins hsp32 (heme oxygenase-1) and hsp70 in the heart during postinfarctive cardiosclerosis in Wistar and August rats.

The scientific novelty of the investigation is determined by the following obtained results.

For the first time, the development of heart failure in remote periods after myocardial infarction was studied in rats with innate heightened SNS activity, namely, in August-line rats compared with Wistar population rats. It was established that postinfarction heart failure developed to a lesser degree in August rats than in Wistar rats, as evidenced by lower mortality in the postinfarction period and lower left ventricular end-diastolic pressure in August rats.

For the first time, it was established that in August-line rats with long-standing postinfarctive cardiosclerosis, the efficiency of cardiac function under loads (maximum isometric load and adrenaline administration) is higher than in Wistar rats.

For the first time, a comparative analysis of postinfarction heart failure development with SNS activity and the nitric oxide (NO) system was conducted in rats of genetically different populations. It was established that SNS activation is less pronounced and NO-system activation is greater in August rats than in Wistar rats.

For the first time, a comparative analysis of postinfarction heart failure development with the function of β-adrenergic receptor complexes was conducted in rats of genetically different populations. It was established that August rats do not differ from Wistar rats in the level of basal and isoproterenol-stimulated adenylate cyclase activity.

It was established that the relative content of β2-adrenergic receptor (AR) mRNA in August rats under control conditions is higher than in Wistar rats. During postinfarctive cardiosclerosis, against the background of a general decrease in β-adrenergic receptor mRNA levels, changes occur in their relative content — the ratio of β2-AR mRNA to β1-AR mRNA sharply increases in Wistar rats, whereas in August rats the ratio of mRNA for these two types of β-ARs equalizes.

For the first time, it was demonstrated that during long-standing postinfarctive cardiosclerosis, less pronounced myocardial dysfunction in August rats with 3-month postinfarctive cardiosclerosis is accompanied by greater activation of stress protein hsp32 (heme oxygenase-1) synthesis in the left and right ventricles of the heart compared with Wistar rats, while no activation of stress protein hsp70 synthesis occurs in either comparative line.

The theoretical significance of the work is determined by the fact that, firstly, for the first time the relationship between the development of postinfarction heart failure and the features of neurohumoral regulation in rats of different genetic lines — August and Wistar rats — has been studied; secondly, it has been established that the innate heightened SNS activity characteristic of August rats does not aggravate the development of postinfarction heart failure, as it is compensated by decreased activation of the sympathoadrenal system and heightened activation of the nitric oxide system and heme oxygenase-1 synthesis.

The practical significance of the work is determined by the fact that, based on the identified genetically determined features of postinfarction heart failure development and neurohumoral regulation, new approaches for the correction of this disease are being opened. The following statements are presented for defense:

1. In remote periods after myocardial infarction, heart failure develops to a lesser degree in August-line rats than in Wistar rats. This is evidenced by greater survival of August rats and less pronounced disturbances of cardiac contractile function in the postinfarction period compared with Wistar population rats.

2. Less pronounced heart failure in August rats with 3-month postinfarctive cardiosclerosis is associated with decreased activation of the sympathoadrenal system and heightened activation of the NO system compared with Wistar rats.

3. During long-standing postinfarctive cardiosclerosis in August and Wistar rats, no activation of stress protein hsp70 synthesis occurs in the myocardium, whereas the degree of activation of stress protein hsp32 (heme oxygenase-1) synthesis is greater in August rats than in Wistar rats.