Peter Bencsik

University of Szeged · Cardiovascular Research Group

Aims: Remote ischemic preconditioning (RIPC) is a robust cardioprotective intervention in preclinical studies. To establish a working and efficacious RIPC protocol in our laboratories, we performed randomized, blinded in vivo studies in three study centres in rats, with various RIPC protocols. To verify that our experimental settings are in good a...

Volume-induced hypertrophy is one of the risk factors for cardiac morbidity and mortality. In addition, mechanical and metabolic dysfunction, aging, and cellular redox balance are also contributing factors to the disease progression. In this study, we used volume overload (VO), which was induced by an aortocaval fistula in 2-month-old male Wistar r...

Hypoxia upregulates PCSK9 expression in the heart, and PCSK9 affects the function of myocytes. This study aimed to investigate the impact of PCSK9 on reperfusion injury in rats and mice fed normal or high-fat diets. Either the genetic knockout of PCSK9 (mice) or the antagonism of circulating PCSK9 via Pep2-8 (mice and rats) was used. Isolated perfu...

Aims: Volume overload (VO) induced hypertrophy is one of the hallmarks to the development of heart diseases. Understanding the compensatory mechanisms involved in this process might help preventing the disease progression. Methods and results: Therefore, the present study used 2 months old Wistar rats, which underwent an aortocaval fistula to de...

Bone grafting procedures during the use of dental implants may be avoided by the use of tilted implants in the maxilla and the mandible; advantages of angled implants are associated with the extension of the distal cantilever, leading to better implant survival rates. However, the bending effect on the single tilting implants may increase the margi...

Besides the health benefits of regular exercise, high-level training - above an optimal level -may have adverse effects. In this study, we investigated the effects of long-term vigorous training and its potentially detrimental structural-functional changes in a small animal athlete’s heart model. Thirty-eight 4-month-old male guinea pigs were rando...

Purpose Matrix metalloproteinases (MMPs) are identified as modulators of the extracellular matrix in heart failure progression. However, evidence for intracellular effects of MMPs is emerging. Pro- and anti-hypertrophic cardiac effects are described. This may be due to the various sources of different MMPs in the heart tissue. Therefore, the aim of...

Background: We recently developed novel matrix metalloproteinase-2 (MMP-2) inhibitor small molecules for cardioprotection against ischemia/reperfusion injury and validated their efficacy in ischemia/reperfusion injury in cardiac myocytes. The aim of the present study was to test our lead compounds for cardioprotection in vivo in a rat model of acu...

Cardiovascular diseases, including coronary artery disease, ischemic heart diseases such as acute myocardial infarction and postischemic heart failure, heart failure of other etiologies, and cardiac arrhythmias, belong to the leading causes of death. Activation of capsaicin-sensitive sensory nerves by the transient receptor potential vanilloid 1 (T...

There is some recent evidence that cardiac ischemia/reperfusion (I/R) injury induces intestinal damage within days, which contributes to adverse cardiovascular outcomes after myocardial infarction. However, it is not clear whether remote gut injury has any detectable early signs, and whether different interventions aiming to reduce cardiac damage a...

Swiprosin-1 (EFhD2) is a molecule that triggers structural adaptation of isolated adult rat cardiomyocytes to cell culture conditions by initiating a process known as cell spreading. This process mimics central aspects of cardiac remodeling, as it occurs subsequent to myocardial infarction. However, expression of swiprosin-1 in cardiac tissue and i...

Ischaemic post‐conditioning (IPoC) is a clinical applicable procedure to reduce reperfusion injury. Non‐responsiveness to IPoC possibly caused by co‐morbidities limits its clinical attractiveness. We analysed differences in the expression of mitochondrial proteins between IPoC responder (IPoC‐R) and non‐responder (IPoC‐NR). Eighty rats were randoml...

During the last decades, mortality of acute myocardial infarction has been dramatically improved, however, the incidence of post‐infarction heart failure is still increasing. Cardioprotection by ischemic conditioning have been discovered more than 3 decades ago, however, its clinical translation is still an unmet need, mainly due to the disrupted c...

Background: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease hallmarked by irreversible damage of cartilage and bone. Matrix metalloproteinases (MMPs) involved in connective tissue remodeling play an important role in this process. Numerous MMPs have been examined in humans and animals, but their functions are still not fully under...

(A) Cytosolic phospholipase A2 activity and (B) prostaglandin E2 levels of tibio-tarsal joint homogenates. Data are shown as mean ± S.E.M. of n = 3–7/group, ∗∗p < 0.01 vs. respective non-arthritic controls (one-way ANOVA followed by Bonferroni’s multiple comparison test).

(A) Water consumption (mL/day/mouse) and (B) percentage change of body weight (%). Data are shown as means ± S.E.M. of n = 3–13 mice/group, ∗p < 0.05 vs. respective non-arhritic control mice, ###p < 0.001 vs. tap water consuming arthritic mice (two-way ANOVA followed by Bonferroni’s multiple comparison test).

Doxycycline in high concentration (200 μg/mL), but not in lower ones inhibits in vitro MMP-9 activity in the arthritic joint homogenates. Changes of in vitro gelatinolytic activity of (A) 57–60 kDa, (B) 72 kDa, (C) 75 kDa, and (D) 92 kDa MMP isoforms in the arthritic and the non-arthritic control joint homogenates incubated with 0.2, 2, 20, and 200...

Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Methods: Male Wistar rats were treated with vehicle or capsaicin for 3 day...

Chronic kidney disease (CKD) is a public health problem that increases the risk of cardiovascular morbidity and mortality. Heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction is a common cardiovascular complication of CKD. MicroRNA-212 (miR-212) has been demonstrated p...

The aim of this study was to describe the potential associations of the expression of matricellular components in adverse post-infarction remodeling of the geriatric heart. In male geriatric (OM, age: 18 months) and young (YM, age: 11 weeks) OF1 mice myocardial infarction (MI) was induced by permanent ligation of the left anterior descending corona...

Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate t...

The transcriptional regulator JDP2 (Jun dimerization protein 2) has been identified as a prognostic marker for patients to develop heart failure after myocardial infarction. We now performed in vivo studies on JDP2-overexpressing mice, to clarify the impact of JDP2 on heart failure progression. Therefore, during birth up to the age of 4 weeks cardi...

The objective of our present study is to develop novel inhibitors for MMP-2 for acute cardioprotection. In a series of pilot studies, novel substituted carboxylic acid derivatives were synthesized based on imidazole and thiazole scaffolds and then tested in a screeening cascade for MMP inhibition. We found that the MMP-inhibiting effects of imidazo...

Table S1. Functional and Morphological Data Assessed by Echocardiography Figure S1. The validity of TnI as a marker to determine the infarct size. Figure S2. Expression pattern of β‐ARs in left ventricular tissue. Figure S3. The effect of GRK2 and β‐arrestin on the contraction of isolated ventricular cardiomyocytes. Figure S4. The functional re...

Background: Ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) are currently among the most efficient strategies protecting the heart against ischemia/reperfusion injury. However, the effect of IPC and IPoC on functional recovery following ischemia/reperfusion is less clear, particularly with regard to the specific receptor-mediat...

Whereas high amounts of reactive oxygen species (ROS) contribute to cardiac damage following ischemia and reperfusion (IR), low amounts function as trigger molecules in the cardioprotection by ischemic preconditioning (IPC). The mitochondrial translocation and contribution of the hydrogen peroxide-generating protein p66shc in the cardioprotection b...

Matrix metalloproteinases (MMP) belong to a distinguished class of zinc-dependent endopeptidases. Zymography is a semi-quantitative tool for determining the activity of different MMP isoenzymes in a variety of biological samples. In substrate gel zymography, protein samples of different origin (tissue, cell lysates, plasma/serum, perfusates, other...

Cigarette smoke-triggered inflammatory cascades and consequent tissue damage are the main causes of chronic obstructive pulmonary disease (COPD). There is no effective therapy and the key mediators of COPD are not identified due to the lack of translational animal models with complex characterization. This integrative chronic study investigated car...

Administration of low-dose endotoxin (lipopolysaccharide, LPS) 24 h before a lethal ischemia induces pharmacological late preconditioning. The exact mechanism of this phenomenon is not clear. Here we aimed to investigate whether low-dose LPS exerts late effects on peroxynitrite formation and activation of Akt, Erk, and STAT3 in the heart. MaleWista...

Besides their deleterious action on cardiac muscle, anthracycline-type cytostatic agents exert significant neurotoxic effects on primary sensory neurons. Since cardiac sensory nerves confer protective effects on heart muscle and share common traits with cutaneous chemosensitive nerves, this study examined the effects of cardiotoxic doses of adriamy...

Nitric oxide (NO) deficiency is common in pulmonary diseases, but its effect on pulmonary remodelling is still controversial. As pulmonary parathyroid hormone-related protein (PTHrP) expression is a key regulator of pulmonary fibrosis and development, the effect of chronic NO deficiency on the pulmonary PTHrP system and its relationship with oxidat...

Context • The activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of congestive heart failure, which is the reason that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin 2 receptor blockers (ARBs) have become established therapies for heart failure. However, it is still not kno...

Recently, Ceron CS and Luison MR critically commented on our paper entitled "Serum lipids and cardiac function correlate with nitrotyrosine and MMP activity in CAD patients" (published in Eur J Clin Invest in 2015) in two major points. Here we respond to their letter in details and comment their criticisms on suitability of MMP activity assays in s...

AimsPeroxynitrite – matrix metalloproteinase (MMP) signaling has been shown to contribute to myocardial ischemia/reperfusion injury and heart failure and to be influenced by hyperlipidemia in preclinical models. Therefore, here we investigated the correlation between the markers of peroxynitrite – MMP signaling and hyperlipidemia in patients with s...

Ischemic heart disease including myocardial infarction is developing on the basis of several risk-factors and co-morbidities such as obesity, diabetes, hypertension, and hypercholesterolemia. Ischemic heart disease is the leading cause of mortality worldwide, therefore, identification of novel drug targets for cardioprotection is of great importanc...

Nitroglycerin exerts a direct myocardial anti-ischemic effect even in the state of vascular nitrate tolerance. To examine the potentially diverse molecular responses in vascular and cardiac tissues, we investigated the gene expression profile of the heart and the aorta by DNA microarray in male Wistar rats that were previously made tolerant to the...

Cardiac ischaemia and reperfusion leads to irreversible injury and subsequent tissue remodelling. Initial reperfusion seems to shift arginine metabolism from nitric oxide (NO) to polyamine formation. This may limit functional recovery at reperfusion. The hypothesis was tested whether ischaemia/reperfusion translates such a shift in arginine metabol...

Although multivitamin products are widely used as dietary supplements, the effects of these products were not investigated in hypercholesterolemia which is a major risk factor of cardiovascular diseases. Therefore, here we investigated if a preparation of different minerals, vitamins, phytosterols and trace elements (MVT) developed for human use af...

Background: Gelatinase-type matrix metalloproteinases (MMP-2 and -9) have crucial role in inflammatory diseases, e.g. chronic obstructive pulmonary disease as well as in cardiovascular pathology. It is known that chronic smoke exposure increases MMP-2 and -9 activities in the lung. However, the smoke-induced alterations in MMP-2 and -9 activities i...

Although the physiological regulatory function of the gasotransmitter nitric oxide (NO, a diatomic free radical) has been discovered decades ago, NO is still in the frontline research in biomedicine. NO has been implicated in a variety of physiological and pathological processes, therefore, pharmacological modulation of NO level in various tissues...

We aimed to characterize early changes in microRNA expression in acute cardioprotection by ischemic pre- and postconditioning in rat hearts. Hearts isolated from male Wistar rats were subjected to i) time-matched non-ischemic perfusion, ii) ischemia/reperfusion (30 min coronary occlusion and 120 min reperfusion), iii) preconditioning (3x5 min coron...

To profile changes in gene expression in response to ischemic postconditioning, isolated rat hearts were subjected to 30 min of regional ischemia followed by 120 min of reperfusion with or without postconditioning. At the end of reperfusion, cardiac RNA was assayed by DNA microarrays (31,000 format), verified by quantitative real-time polymerase ch...

Unlabelled: Ischaemic heart disease, stroke and their pathological consequences are life-threatening conditions that account for about half of deaths in developed countries. Pathology of these diseases includes cell death due to ischaemia/reperfusion injury, vascular stenosis and cardiac remodelling. The growth factor midkine plays a pivotal role...

It has been previously shown that hyperlipidemia interferes with cardioprotective mechanisms. Here we investigated the interaction of hyperlipidemia with cardioprotection induced by pharmacological activators of ATP-sensitive potassium channels (KATP). Hearts isolated from rats fed 2% cholesterol-enriched diet or normal diet for 8 weeks were subjec...

Although complex multivitamin products are widely used as dietary supplements to maintain health or as special medical food in certain diseases, the effects of these products were not investigated in hyperlipidemia which is a major risk factor for cardiovascular diseases. Therefore, here we investigated if a preparation developed for human use cont...

Diet-induced hypercholesterolemia leads to oxidative/nitrative stress and subsequent myocardial dysfunction. However, the regulatory role of microRNAs in this phenomenon is unknown. We aimed to investigate, whether hypercholesterolemia-induced myocardial microRNA alterations play a role in the development of oxidative/nitrative stress and in subseq...

Organic nitrates play an important role in the therapy of ischemic heart disease, however, their clinical application is limited by the development of vascular nitrate tolerance. We have previously shown attenuation of the cardioprotective effect of preconditioning in vascular nitrate tolerance. Here we studied whether the development of vascular n...

Pharmacological inhibition of matrix metalloproteinase-2 (MMP-2) is a promising target for acute cardioprotection against ischemia/reperfusion injury. Therefore, here we investigated if the MMP inhibitor ilomastat administered either before ischemia or before reperfusion is able to reduce infarct size via inhibition of MMP-2, the most abundant MMP...

Background: The development of erythropoiesis-stimulating agents (ESAs) with extended serum half-lives has allowed marked prolongation of the administration intervals. The level of oxidative stress is increased in chronic kidney disease, and is reportedly decreased after long-term ESA treatment. However, the effect of different dosing regimens of...

Metabolic diseases such as hyperlipidemia and diabetes attenuate the cardioprotective effect of ischemic preconditioning. In the present study, we examined whether another metabolic disease, prolonged uremia, affects ischemia/reperfusion injury and cardioprotection by ischemic preconditioning. Uremia was induced by partial nephrectomy in male Wista...

Cardioprotection by ischemic preconditioning (IP) was abolished in connexin 43 (Cx43)-deficient mice due to loss of Cx43 located in mitochondria rather than at the sarcolemma. IP is lost in hyperlipidemic rat hearts as well. Since changes in mitochondrial Cx43 in hyperlipidemia have not yet been analyzed, we determined total and mitochondrial Cx43...

We have previously shown that the inhibition of myocardial nitric oxide (NO) and peroxynitrite-matrix metalloproteinase (MMP) signaling by early preconditioning (PC) is involved in its cardioprotective effect. Therefore, in the present study, we investigated the role of NO and peroxynitrite-MMP signaling in the development of late PC. PC was perfor...

Ischemic heart disease is a major cause of morbidity and mortality worldwide. Myocardial ischemia followed by reperfusion results in tissue injury termed ischemia/reperfusion injury which is characterized by decreased myocardial contractile function, occurrence of arrhythmias, and development of tissue necrosis (infarction). These pathologies are a...

Cardiac expression of cytoprotective gene heme oxygenase-1 (HO-1) is modulated by ischaemia and reperfusion (I/R). We therefore hypothesized that pretreatment with hemin, an inductor of HO-1, would precondition the heart against post-ischaemic dysfunction and ventricular fibrillation (VF). Male Wistar rats were given either hemin or HO enzyme inhib...

Sensory neuropathy develops in the presence of cardiovascular risk factors (e.g. diabetes, dyslipidemia), but its pathological consequences in the heart are unclear. We have previously shown that systemic sensory chemodenervation by capsaicin leads to impaired myocardial relaxation and diminished cardiac nitric oxide (NO) content. Here we examined...

We have previously shown that cholesterol diet-induced hyperlipidemia (marked hypertriglyceridemia and moderate hypercholesterolemia) increases cardiac formation of peroxynitrite and results in a moderate cardiac dysfunction in rats. Here our aim was to further clarify the mechanism of hyperlipidemia-induced nitrosative stress in a transgenic mouse...

3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, has been shown to protect against ischemic injury in the brain and in the heart via a preconditioning-like effect; however, the cellular mechanism is not known. The aim of the present study was to investigate if 3-NP pretreatment reduces infarct size and if altered...

We have previously shown that capsaicin-sensitive sensory nerves contribute to the regulation of normal cardiac function and to the development of cardiac adaptation to ischemic stress; however, the underlying molecular mechanisms remain unknown. Therefore, here we assessed cardiac functional alterations and relative gene expression changes by DNA...