Bakteriális lipopoliszachariddal kiváltott késői kardioprotekció az iszkémia/reperfúziós károsodással szemben = Late cardioprotection against ischemia-reperfusion injury induced by bacterial lipopolysaccharides

Hazánkban és a civilizált társadalmakban egyaránt, az iszkémiás szívbetegség az egyik leggyakoribb halálokok közé tartozik. A szivizom endogén adaptációs mechanizmusainak támogatása, illetve vizsgálata ezért nagy jelentőségű. Kísérleteink bizonyítják, hogy ez a mechanizmus emberben is hatásos védelmet jelent. Kimutattuk továbbá, hogy a farmakológiai prekondícionálás hatékonyan véd az iszkémiás károsodás ellen. A kis dózisú (0,5 mg/kg) bakteriális lipopoliszachariddal (LPS) előkezelt patkányok szíve 24 órával a kezelés után fokozottabb mértékben áll ellen az iszkémiát követő szívfunkciós károsodásnak. A 24 órás LPS előkezelés megnövelte a szívizom nitrogén-monoxid tartalmát az indukálható nitrogén oxid szintáz fokozott aktivitása révén. A LPS előkezelés hatására szignifikánsan emelkedett a szívizom szuperoxid termelése is a fokozott xantin oxidoreduktáz aktivitás miatt. A szérum nitrotirozin szintje ugyancsak emelkedett az LPS előkezelés hatására, jelezvén a NO és szuperoxid anion reakciója révén képződő peroxinitrit fokozott képződését a szervezetben. A LPS előkezelés növelte a miokardiális cGMP tartalmat is. Eredményeink szerint az oxidatív és nitrozatív stressz, valamint az NO-cGMP szignalizációs út fontos szerepet játszhat a szívizom farmakológiai prekondícionálásában. | Ischemic heart disease is one of the most frequent cause of death in the civilized societies, therefore investigation of cardioprotective mechanisms to prevent ischemic damage is essential. We have shown that this protective mechanism is effective in humans. We have also shown that pharmacological preconditioning effectively protects against ischemia/reperfuson injury. 24h pretreatment of rats with bacterial polysaccharides (LPS) has resulted in a protection against ischemia-induced deterioration of cardiac function. A 24h LPS pretreatment increased cardiac nitric oxide content via the induction of the inducible isoform of nitric oxide synthase. LPS pretreatment also increased cardiac superoxide production via an increase in the activity of xanthin oxidoreductase. LPS increased serum nitrotyrosine levels showing increased formation of peroxynitrite from NO and superoxide. In addition, LPS pretreatment increased myocardial cGMP level. Our results suggest, that both oxidative and nitrosative stress play an important role in pharmacological preconditioning of the heart

The effect of electrical stimulation of skeletal muscle on cardioprotection and on muscle-derived myokine levels in rats: A pilot study

Electrical muscle stimulation (EMS) is a widely used method in sports and rehabilitation therapies to simulate physical exercise. EMS treatment via skeletal muscle activity improves the cardiovascular functions and the overall physical condition of the patients. However, the cardioprotective effect of EMS has not been proven so far, therefore, the aim of this study was to investigate the potential cardiac conditioning effect of EMS in an animal model. Low-frequency 35-min EMS was applied to the gastrocnemius muscle of male Wistar rats for three consecutive days. Their isolated hearts were then subjected to 30 min global ischemia and 120 min reperfusion. At the end of reperfusion cardiac specific creatine kinase (CK-MB) and lactate dehydrogenase (LDH) enzyme release and myocardial infarct size were determined. Additionally, skeletal muscle-driven myokine expression and release were also assessed. Phosphorylation of cardioprotective signaling pathway members AKT, ERK1/2, and STAT3 proteins were also measured. EMS significantly attenuated cardiac LDH and CK-MB enzyme activities in the coronary effluents at the end of the ex vivo reperfusion. EMS treatment considerably altered the myokine content of the stimulated gastrocnemius muscle without altering circulating myokine levels in the serum. Additionally, phosphorylation of cardiac AKT, ERK1/2, and STAT3 was not significantly different in the two groups. Despite the lack of significant infarct size reduction, the EMS treatment seems to influence the course of cellular damage due to ischemia/reperfusion and favorably modifies skeletal muscle myokine expressions. Our results suggest that EMS may have a protective effect on the myocardium, however, further optimization is required

The effect of electrical stimulation of skeletal muscle on cardioprotection and on muscle-derived myokine levels in rats: A pilot study

Electrical muscle stimulation (EMS) is a widely used method in sports and rehabilitation therapies to simulate physical exercise. EMS treatment via skeletal muscle activity improves the cardiovascular functions and the overall physical condition of the patients. However, the cardioprotective effect of EMS has not been proven so far, therefore, the aim of this study was to investigate the potential cardiac conditioning effect of EMS in an animal model. Low-frequency 35-min EMS was applied to the gastrocnemius muscle of male Wistar rats for three consecutive days. Their isolated hearts were then subjected to 30 min global ischemia and 120 min reperfusion. At the end of reperfusion cardiac specific creatine kinase (CK-MB) and lactate dehydrogenase (LDH) enzyme release and myocardial infarct size were determined. Additionally, skeletal muscle-driven myokine expression and release were also assessed. Phosphorylation of cardioprotective signaling pathway members AKT, ERK1/2, and STAT3 proteins were also measured. EMS significantly attenuated cardiac LDH and CK-MB enzyme activities in the coronary effluents at the end of the ex vivo reperfusion. EMS treatment considerably altered the myokine content of the stimulated gastrocnemius muscle without altering circulating myokine levels in the serum. Additionally, phosphorylation of cardiac AKT, ERK1/2, and STAT3 was not significantly different in the two groups. Despite the lack of significant infarct size reduction, the EMS treatment seems to influence the course of cellular damage due to ischemia/reperfusion and favorably modifies skeletal muscle myokine expressions. Our results suggest that EMS may have a protective effect on the myocardium, however, further optimization is required

Piroptózis, PANoptózis és ferroptózis a szív iszkémia/reperfúziós károsodásában

Az intenzív kutatások ellenére továbbra sem rendelkezünk olyan kardioprotektív gyógyszerekkel, amelyek a szív iszkémia/reperfúziós (I/R) károsodásával járó infarktusméretet hatásosan csökkentenék. Ennek egyik magyarázata, hogy az I/R-t kísérő sejtelhalás összetett folyamata teljesen még nem tisztázott. A mechanizmus részletesebb megismerése javíthatja a kardioprotektív gyógyszerfejlesztések transzlálhatóságát. A klasszikus szabályozott (apoptózis, autofágia-mediálta sejthalál) és nem szabályozott (nekrózis) sejthalálfolyamatok mellett olyan programozott sejthalálformákat és mechanizmusokat ismertünk meg az elmúlt években, mint például a piroptózis, a PANoptózis vagy a ferroptózis. Jelen összefoglaló közleményünkben ezen folyamatokat kívánjuk röviden bemutatni a szív I/R károsodásában, valamint kitérünk a lehetséges modulálási stratégiákra is

Effect of Eccentric Exercise on Metabolic Health in Diabetes and Obesity

There is a growing body of evidence showing the importance of physical activity against civilization-induced metabolic diseases, including type 2 diabetes (T2DM) and obesity. Eccentric contraction, when skeletal muscles generate force by lengthening, is a unique type of skeletal muscle activity. Eccentric contraction may lead to better power production characteristics of the muscle because eccentric contraction requires less energy and can result in higher tension. Therefore, it is an ideal tool in the rehabilitation program of patients. However, the complex metabolic effect (i.e., fat mass reduction, increased lipid oxidation, improvement in blood lipid profile, and increased insulin sensitivity) of the eccentric contraction alone has scarcely been investigated. This paper aims to review the current literature to provide information on whether eccentric contraction can influence metabolic health and body composition in T2DM or obesity. We also discussed the potential role of myokines in mediating the effects of eccentric exercise. A better understanding of the mechanism of eccentric training and particularly their participation in the regulation of metabolic diseases may widen their possible therapeutic use and, thereby, may support the fight against the leading global risks for mortality in the world

A szívizom sztressz-adaptációja: a peroxinitrit, a mátrix metalloproteinázok, és a hiperlipidémia szerepe = Stress adaptation of the myocardium: role of peroxynitrite, matrix metalloproteinases, and hyperlipidemia

A hiperlipidémia talaján kialakuló iszkémiás szívbetegség a leggyakoribb halálokok közé tartozik. A 4 éves project során a szívizom iszkémiának és az iszkémiás stressz adaptációs képességének (iszkémiás pre- és posztkondíció) celluláris mechanizmusait vizsgáltuk állatkísérletekben, különösképpen a peroxinitrit és celluláris targetjének, az MMP2-nek a szerepét. Új eredményeink közül néhányat emelünk ki. Kimutattuk, hogy hiperlipidemiában a szívben a peroxitrit képződés és ezáltal az MMP-2 aktivitása fokozódik, ami különösen hiperlipidmémiában jelentős, és ezt a folyamatot a prékondíció gátolja. DNA-chip vizsgálattal feltérképeztük hiperlipidémia hatására a génkifejeződés változásait a szívizomban. Kimutattuk, hogy az alacsony mértékű peroxinitrit képződés a stessz adaptáció kiváltásában igen fontos szerepet tölt be, hiszen olyan mechanizmusokat aktivál, melyek az iszkémiás stressz során túlzott mértékű peroxinitrit-MMP aktivitást csökkenti. Leírtuk, hogy nemspecifikus MMP gátlókkal az infarktus területe csökkenthető még hiperlipidémiás állatban is. Humán ApoB100 transzgenetikus eger modelleken megfigyeltük, hogy az oxidatív/nitrozatív stressz oka a hiperkoleszterinémia, és nem a hipertrigliceridémia. Kimutattuk továbbá, hogy a fiziológiás peroxinitrit szint, melyet a szívizom kapszaicin-érzékeny neuronjai szabályoznak, a normális szívizom relaxációt tartja fent. A project futamideje alatt az adott témában összesen 16 nemzetközi cikket (impakt faktor >70) közöltünk. | Ischemic heart disease developing due to hyperlipidemia is the number one killer in civilized societies. The present 4-year project was aiming at exploration of cellular mechanisms underlying stress adaptation of the myocardium, i.e. pre- and postconditioning, focusing on the role of peroxynitrite and its cellular target matrix metalloproteinase-2 (MMP2). Here we emphasize only some of the most important results of the project. We have shown that in hyperlipidemia, myocardial peroxynitrite formation and thereby MMP2 activity is increased, which is attenuated by preconditioning. We have mapped the changes in gene expression due to hyperlipidemia by the use of DNA-microarray assay. We have observed that moderate peroxynitrite formation is necessary to trigger the stress adaptation mechanisms, which in turn will decrease the pathological activation of the peroxynitrite-MMP2 signaling. We have shown that nonspecific MMP inhibitors are able to reduce infarct size even in the presence of hyperlipidemia. In human ApoB-100 transgene mice, we have observed that oxidative/nitrosative stress is due to hypercholesterolemia and not hypertriglyceridemia. Furthermore, we have shown that baseline physiological peroxynitrite formation, which is regulated by myocardial capsaicin-sensitive sensory nerves, plays an important role in the maintenance of normal relaxation of the myocardium. The present project yielded altogether 16 peer-reviewed papers (impact factor >70)

Acetylation State of Lysine 14 of Histone H3.3 Affects Mutant Huntingtin Induced Pathogenesis

Huntington’s Disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polyglutamine-coding CAG repeat in the Huntingtin gene. One of the main causes of neurodegeneration in HD is transcriptional dysregulation that, in part, is caused by the inhibition of histone acetyltransferase (HAT) enzymes. HD pathology can be alleviated by increasing the activity of specific HATs or by inhibiting histone deacetylase (HDAC) enzymes. To determine which histone’s post-translational modifications (PTMs) might play crucial roles in HD pathology, we investigated the phenotype-modifying effects of PTM mimetic mutations of variant histone H3.3 in a Drosophila model of HD. Specifically, we studied the mutations (K→Q: acetylated; K→R: non-modified; and K→M: methylated) of lysine residues K9, K14, and K27 of transgenic H3.3. In the case of H3.3K14Q modification, we observed the amelioration of all tested phenotypes (viability, longevity, neurodegeneration, motor activity, and circadian rhythm defects), while H3.3K14R had the opposite effect. H3.3K14Q expression prevented the negative effects of reduced Gcn5 (a HAT acting on H3K14) on HD pathology, while it only partially hindered the positive effects of heterozygous Sirt1 (an HDAC acting on H3K14). Thus, we conclude that the Gcn5-dependent acetylation of H3.3K14 might be an important epigenetic contributor to HD pathology

Metabolic syndrome influences cardiac gene expression pattern at the transcript level in male ZDF rats

Background: Metabolic syndrome (coexisting visceral obesity, dyslipidemia, hyperglycemia, and hypertension) is a prominent risk factor for cardiovascular morbidity and mortality, however, its effect on cardiac gene expression pattern is unclear. Therefore, we examined the possible alterations in cardiac gene expression pattern in male Zucker Diabetic Fatty (ZDF) rats, a model of metabolic syndrome. Methods: Fasting blood glucose, serum insulin, cholesterol and triglyceride levels were measured at 6, 16, and 25 wk of age in male ZDF and lean control rats. Oral glucose tolerance test was performed at 16 and 25 wk of age. At week 25, total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 14921 genes. Expression of selected genes was confirmed by qRT-PCR. Results: Fasting blood glucose, serum insulin, cholesterol and triglyceride levels were significantly increased, glucose tolerance and insulin sensitivity were impaired in ZDF rats compared to leans. In hearts of ZDF rats, 36 genes showed significant up-regulation and 49 genes showed down-regulation as compared to lean controls. Genes with significantly altered expression in the heart due to metabolic syndrome includes functional clusters of metabolism (e.g. 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2; argininosuccinate synthetase; 2-amino-3ketobutyrate-coenzyme A ligase), structural proteins (e.g. myosin IXA; aggrecan1), signal transduction (e. g. activating transcription factor 3; phospholipase A2; insulin responsive sequence DNA binding protein-1) stress response (e.g. heat shock 70kD protein 1A; heat shock protein 60; glutathione S-transferase Yc2 subunit), ion channels and receptors (e.g. ATPase, (Na+)/K+ transporting, beta 4 polypeptide; ATPase, H+/K+ transporting, nongastric, alpha polypeptide). Moreover some other genes with no definite functional clusters were also changed such as e. g. S100 calcium binding protein A3; ubiquitin carboxy-terminal hydrolase L1; interleukin 18. Gene ontology analysis revealed several significantly enriched functional inter-relationships between genes influenced by metabolic syndrome. Conclusions: Metabolic syndrome significantly alters cardiac gene expression profile which may be involved in development of cardiac pathologies in the presence of metabolic syndrome