Koncsos G, Varga ZV, Baranyai T, Boengler K, Rohrbach S, Li L, Schlüter KD, Schreckenberg R, Radovits T, Oláh A, Mátyás C, Lux Á, Al-Khrasani M, Komlódi T, Bukosza N, Máthé D, Deres L, Barteková M, Rajtík T, Adameová A, Szigeti K, Hamar P, Helyes Z, Tretter L, Pacher P, Merkely B, Giricz Z, Schulz R, Ferdinandy P. Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress. Am J Physiol Heart Circ Physiol. 2016 Oct 1;311(4):H927-H943. doi: 10.1152/ajpheart.00049.2016. Epub 2016 Aug 12. PMID: 27521417; PMCID: PMC5114470.

In this publication, we investigated the effect of prediabetes in rats on the development of diastolic dysfunction and pathological remodeling. Despite the fact that the link between contractile dysfunction and CaMKII activity was not demonstrated, at the level of calcium management, we showed that there was a decrease in phospholamban phosphorylation and thus a potential decrease in the function of the SERCA2a pump. In addition, it was shown that diastolic dysfunction and remodeling was associated with reduced markers of mitophagy (removal of damaged mitochondria) and increased oxidative stress, along with the aforementioned reduction in PKA kinase-regulated phospholamban phosphorylation.

Szobi A, Rajtik T, Carnicka S, Ravingerova T, Adameova A. Mitigation of postischemic cardiac contractile dysfunction by CaMKII inhibition: effects on programmed necrotic and apoptotic cell death. Mol Cell Biochem. 2014 Mar;388(1-2):269-76. doi: 10.1007/s11010-013-1918-x. Epub 2013 Dec 18. PMID: 24347176.

In this work, we investigated the effectiveness of the CaMKII inhibitor, substance KN-93, on the occurrence of contractile dysfunction and cell death in ischemia-reperfusion injury in rats. We presented the improvement of postischemic recovery of LVDP. Another original finding was that the inhibition of CaMKII reduced the expression of selected proteins involved in cascades and apoptotic and necroptotic cell death, thus we also indicated a link between CaMKII activity and cell death cascades, which until then, in the case of necroptosis, was not a known phenomenon and thus we indicated, that the normalization of calcium turnover also affects the necroptotic death of cardiomyocytes.

Lichý M, Szobi A, Hrdlička J, Horváth C, Kormanová V, Rajtík T, Neckář J, Kolář F, Adameová A. Different signalling in infarcted and non-infarcted areas of rat failing hearts: A role of necroptosis and inflammation. J Cell Mol Med. 2019 Sep;23(9):6429-6441. doi: 10.1111/jcmm.14536. Epub 2019 Jul 21. PMID: 31328381; PMCID: PMC6714220.

In the aforementioned publication, we evaluated the role of inflammation in the induction of necroptosis in a model of chronic heart failure, also taking into account the differentiation of damage zones after myocardial infarction in the left ventricles of rats. The results of the work indicate that in myocardial infarction, apoptotic cell death is not the main characteristic of damaged and at-risk tissue, but that the activation of inflammatory cascades in these zones leads to pathological remodeling associated with the activation of the signaling complex for necroptotic cell death.

Rajtik T, Goncalvesova E, Varga ZV, Leszek P, Kusmierczyk M, Hulman M, Kyselovic J, Ferdinandy P, Adameova A. Posttranslational modifications of calcium/calmodulin-dependent protein kinase IIδ and its downstream signaling in human failing hearts. Am J Transl Res. 2017 Aug 15;9(8):3573-3585. PMID: 28861149; PMCID: PMC5575172.

This publication characterizes multiple types of chronic heart failure in humans based on different etiologies (ischemic vs. non-ischemic; dilated vs. hypertrophic cardiomyopathy) with regard to calcium turnover cascades associated with CaMKII activity and the potential role of oxidative stress on its activity. We have shown that the post-translational activation of CaMKIIδ in HF varies depending on the etiology. Lower levels of downstream molecular targets of CaMKIIδ do not correlate with either CaMKIIδ activation or the expression of major protein phosphatases in HF, nor does its oxidative activation differ depending on the type of HF.

Rajtik T, Carnicka S, Szobi A, Giricz Z, O-Uchi J, Hassova V, Svec P, Ferdinandy P, Ravingerova T, Adameova A. Oxidative activation of CaMKIIδ in acute myocardial ischemia/reperfusion injury: A role of angiotensin AT1 receptor-NOX2 signaling axis. Eur J Pharmacol. 2016 Jan 15;771:114-22. doi: 10.1016/j.ejphar.2015.12.024. Epub 2015 Dec 13. PMID: 26694801.

In the aforementioned publication, we investigated whether the AT1 receptor blocker losartan can affect the oxidative activation of CaMKII, and thus whether such an action can underlie its pleiotropic action in the ischemia-reperfusion injury model. We differentiated its action by using a selective CaMKII inhibitor and also evaluated their concomitant use. Losartan was shown to be able to improve post-ischemic recovery of left ventricular function, but such recovery did not correlate with the expression of any of the active forms of CaMKII (oxidized/phosphorylated). Nevertheless, simultaneous blockade of AT1 receptors and the CaMKII inhibitor KN-93 abolished this cardioprotective effect, so we pointed out a possible clinical interaction between these two drugs.

Bartosova L, Horvath C, Galis P, Ferenczyova K, Kalocayova B, Szobi A, Duris-Adameova A, Bartekova M, Rajtik T. Quercetin alleviates diastolic dysfunction and suppresses adverse pro-hypertrophic signaling in diabetic rats. Front Endocrinol (Lausanne). 2022 Dec 8;13:1029750. doi: 10.3389/fendo.2022.1029750. PMID: 36568083; PMCID: PMC9772025.

In this publication, we dealt with the potential therapeutic effects of quercetin (Qct) on the heart of obese diabetic rats, we observed the anti-hypertrophic action of Qct, both at the molecular level and at the level of structural changes of the left ventricle. Qct inhibited the pro-hypertrophic cascade HDAC4/MEF2, calcineurin/NFAT as well as the upstream modulator Erk5 in diabetic animals. At the structural level, it reduced the thickness of the walls of the left ventricle and, on the contrary, potentiated the increase in the internal diameter. Qct further selectively reduced collagen content in the left ventricles of diabetic animals. Chronic Qct therapy also effectively reversed a marker of diastolic dysfunction (increased E/A ratio) in ZDF rats, while this effect was selective in diabetic animals. With these results, we showed cardioprotective potential of Qct and suggested its new potential role in reducing the pro-hypertrophic signalling.

Rajtik T, Galis P, Bartosova L, Paulis L, Goncalvesova E, Klimas J. Alternative RAS in Various Hypoxic Conditions: From Myocardial Infarction to COVID-19. Int J Mol Sci. 2021 Nov 26;22(23):12800. doi: 10.3390/ijms222312800. PMID: 34884604; PMCID: PMC8657827.

The aim of this review is to bring a comprehensive view of the mechanisms of different forms of hypoxic insults on the activity of alternative branches of the RAAS system, based on different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical significance of the studied phenomenon (experimental vs. clinical condition). In addition, in this publication we provide new insights into future strategies using the alternative RAAS as a diagnostic tool as well as a promising pharmacological target in severe cardiovascular and cardiopulmonary diseases related to hypoxia and ischemia.

Lichý M, Szobi A, Hrdlička J, Horváth C, Kormanová V, Rajtík T, Neckář J, Kolář F, Adameová A. Different signalling in infarcted and non-infarcted areas of rat failing hearts: A role of necroptosis and inflammation. J Cell Mol Med. 2019 Sep;23(9):6429-6441. doi: 10.1111/jcmm.14536. Epub 2019 Jul 21. PMID: 31328381; PMCID: PMC6714220.

In the aforementioned publication, we monitored the role of inflammation in the induction of necroptosis in a model of chronic heart failure, also taking into account the differentiation of damage zones after myocardial infarction in the left ventricles of rats. The results of the work indicate that in myocardial infarction, apoptotic cell death is not the main characteristic of damaged and at-risk tissue, but that the activation of inflammatory cascades in these zones leads to pathological remodeling associated with the activation of the signaling complex for necroptotic cell death.

Rajtik T, Goncalvesova E, Varga ZV, Leszek P, Kusmierczyk M, Hulman M, Kyselovic J, Ferdinandy P, Adameova A. Posttranslational modifications of calcium/calmodulin-dependent protein kinase IIδ and its downstream signaling in human failing hearts. Am J Transl Res. 2017 Aug 15;9(8):3573-3585. PMID: 28861149; PMCID: PMC5575172.

This publication characterizes multiple types of chronic heart failure in humans based on different etiologies (ischemic vs. non-ischemic; dilated vs. hypertrophic cardiomyopathy) with regard to calcium turnover cascades associated with CaMKII activity and the potential role of oxidative stress on its activity. We have shown that the post-translational activation of CaMKIIδ in HF varies depending on the etiology. Lower levels of downstream molecular targets of CaMKIIδ do not correlate with either CaMKIIδ activation or the expression of major protein phosphatases in HF, nor does its oxidative activation differ depending on the type of HF.

Giricz Z, Koncsos G, Rajtík T, Varga ZV, Baranyai T, Csonka C, Szobi A, Adameová A, Gottlieb RA, Ferdinandy P. Hypercholesterolemia downregulates autophagy in the rat heart. Lipids Health Dis. 2017 Mar 23;16(1):60. doi: 10.1186/s12944-017-0455-0. Erratum in: Lipids Health Dis. 2017 Jul 5;16(1):133. PMID: 28330474; PMCID: PMC5363032.

This is the first comprehensive analysis of autophagy and programmed cell death pathways of apoptosis and necroptosis in hypercholesterolemic rat hearts. This study showed that isolated hypercholesterolemia suppresses basal cardiac autophagy and that the decrease in autophagy may result from an activated mTOR pathway. Decreased autophagy was accompanied by increased apoptosis, whereas cardiac necroptosis was not modulated by isolated hypercholesterolemia. Decreased basal autophagy and increased apoptosis may be responsible for the loss of cardioprotection in hypercholesterolemic animals.

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VEGA 1/0500/25 - The role of TRPV channels and their pharmacological modulation in a model of cardiac volume overload leading to chronic heart failure and in myocardial ischemia-reperfusion injury

Principal investigator

TRPV (transient receptor potential vanilloid) channels are an important element of Ca2+ signaling in the cardiovascular system (CVS) and are essential for the development of blood vessels and heart. In case of disruption of their signaling severe phenotypes occur, from deterioration of myocardial contractile function to induction of inflammation associated with remodeling, fibrosis and cell death. The goal of the project is to characterize the pharmacological potential and role of TRPV channels using selected agonists and antagonists in an experimental model of aortocaval fistula in rats leading to volume overload and heart failure (HF) which still doesn’t have sufficiently effective pharmacotherapy. We will further characterize the influence of these modulations and TRPV-associated cascades in the ischemia-reperfusion injury model on isolated rat hearts. The acquired data will help in the understanding of TRPV-mediated signaling in CVS, as well as in the research of novel drugs for HF and other CV diseases.

VEGA 1/0775/21 - Cardioprotective potential of TRP channels: role in remodeling, inflammation and calcium dysregulation.

Principal Investigator

The role of TRP channels (TRP) has been confirmed in several cardiac pathologies such as ischemia-reperfusion injury (IR), remodeling and heart failure (HF). Similarly, the role of calmodulin-dependent kinase II (CaMKII) in the heart is considered an important part of the development of IR and HF, but there are still discrepancies in its action, manifested in clinical studies, limiting the possibilities of its modulation in a real scenario. It is not investigated whether there is a direct connection between TRP function and CaMKII-associated cascades in the development of severe phenotypes such as IR or SZ. The development of new TRP modulators, some of which are already in clinical trials as potential therapies for improving HF symptoms, represents a pharmacological tool to elucidate the link between these channels and CaMKII-associated pathways. Together with the use of modulators of TRP channels relevant for HF and IR, we want to establish the role of such a connection in the development of IR and HF in in vitro/in vivo models of heart damage and clarify their cardioprotective potential.

APVV-24-0619 Cardioprotective Effects of Novel Antidiabetic and Anti-Obesity Drugs in Aged Diabetic Obese Rats: A Comprehensive Analysis of Sex Differences

Deputy investigator (Faculty of Pharmacy, Comenius University Bratislava)

In recent decades, significant progress has been made in understanding cardioprotective mechanisms. With the rising prevalence of serious cardiovascular diseases (CVD) globally, the need for novel cardioprotective tools remains crucial. While various pharmacological and non-pharmacological interventions have been identified, translating these findings into clinical practice is challenging due to advanced age and comorbidities in patients. Type 2 diabetes (T2DM) and obesity are major metabolic diseases that increase CVD risk. Recent research highlights promising cardioprotective effects of new antidiabetic and anti-obesity drugs designed for T2DM and obesity. Evaluating these drugs' potential cardioprotective effects in relevant animal models of both sexes and older age is essential, as these conditions reflect real clinical scenarios. The aim of the project is to obtain new insights into the effects of antidiabetic/anti-obesity drugs—GLP-1 receptor agonists (e.g., semaglutide) and dual GLP-1/GIP receptor agonists (e.g., tirzepatide)—in models of acute myocardial infarction (MI) and chronic heart failure (CHF) in both sexes of aged diabetic obese ZDF rats. Myocardial infarction will be induced by coronary artery ligation, replicating clinical scenarios with reperfusion strategies and allowing study of both acute MI effects and CHF development post-MI. The project's originality lies in evaluating functional, molecular, and biochemical changes in heart damage models in response to therapy, focusing on the drugs' effects on cardiac function, cardioprotection, survival, metabolism, cell death, oxidative stress, remodeling, and vascular functions. Additionally, the project will assess sex differences in therapy, a less common focus in basic research. Results may clarify cardioprotective mechanisms related to age and/or sex differences, offering potential for individualized therapy and clinical guidelines.