Sedentary Behavior Patterns of the Hungarian Adult Population.

BACKGROUND AND AIM: Nowadays, a high level of sedentary behavior (SB) is an important health issue. Many studies have focused on evaluating the physical activity (PA) level, while evaluation of SB has received less attention. The main goal of the present study is to describe the sedentary lifestyle of the Hungarian adult population and identify the vulnerable groups with high amount of sitting time and the patterns of SB. Another aim of this study is to compare the two types of questionnaires (International Physical Activity Questionnaire-IPAQ and Sedentary Behavior Questionnaire-SBQ) related to sitting time. METHODS: This study analyzed cross-sectional primary data using self-reported questionnaires collected by a Hungarian research market company among the adult population in Hungary. The final sample of this study consisted of 1295 participants with a mean age of 45.9 years (SD = 15.2). Analysis of variance (ANOVA) test with post-hoc (Tukey) analysis were used to analyze the link between sitting time and socio-demographic variables (sex, age, BMI, settlement type, education level, marital status, work category, working hours, employment status, sport activity) and body mass index (BMI). RESULTS AND CONCLUSIONS: According to the SBQ, on average, Hungarians sit for 469.53 min per day (7.81 h) on weekdays and 421.25 min per day (7.01 h) on weekends, which suggested a significant difference compared to IPAQ data: 287.82 min per day (4.79 h) on weekdays and 224.30 min per day (3.73 h) on weekends. Young people (aged between 18 and 29) were reported to have the highest average sitting time, i.e., 545 min per day (more than 9 h), and are showing the highest prevalence (53%) of sitting at least 480 min (8 h) per day. Sitting workers also had a high average sitting time, i.e., 514.82 min per day, and a high prevalence (49.3%) of sitting at least 480 min (8 h) per day. People who live in the capital city had higher sitting time, especially on working days. Men sat longer than woman, i.e., 19 min on working days and 45 min on weekends. The most frequent sedentary activities are: working on computer (126 min) on working days and watching TV (130 min) on weekends. Our results clearly show that the self-report single-item measure (IPAQ) significantly underestimates sedentary time compared to the multi-item questionnaire (SBQ). We identified vulnerable groups with high sitting times: men, young adults, inhabitants of the capital city and sitting workers. Consequently, these groups should be continuously surveyed, and requires specific interventions and strategies that particularly counteract the increased sitting time.

The correlation between the cardiovascular instability and the size of the developed ischaemic lesions in patients who underwent carotid stenting.

AIMS: In this study we investigated the relationship between cardiovascular instability and the size of the developed ischaemic lesions during carotid stent implantation by diffusion-weighted (DWI) magnetic resonance (MR) examination. MATERIAL AND METHODS: We retrospectively analyzed anaesthesia reports and follow-up MR examinations after stent implantation of 192 patients in a 3-year period. Nineteen aspects of cardiovascular status were analyzed. We registered the duration of the intervention, low and high blood pressure (BP) values during anaesthesia and heart rates. The fluctuations of BP and heart rate and the time of their compensations after the stent expansion were also recorded. Values were compared with the number and the size of ischaemic lesions on DWI scans. We used Spearman and Kendall rank correlations and Welch's tests for statistical analysis. Values of p ≤ 0.05 were considered as statistically significant. RESULTS: Decreased heart rate significantly correlated with the number (p = 0.0123) and size (p = 0.00323) of ischaemic lesions during stent expansion. Other cardiovascular parameters did not show any significant correlations. CONCLUSIONS: Our results indicate that only heart rate attenuation affects the size of ischaemic lesions; thus the prevention of bradycardia is highly important.

Increased symmetric dimethylarginine, but not asymmetric dimethylarginine, concentrations are associated with transient myocardial ischemia and predict outcome.

OBJECTIVE: Asymmetric and symmetric dimethylarginines (ADMA and SDMA) are endothelial dysfunction markers. ADMA inhibits synthesis of nitric oxide. We aimed to analyze both markers in patients with coronary artery disease (CAD) who were referred for stress/rest myocardial perfusion scintigraphy (MPS). METHODS: All patients underwent a 2-day dipyridamole (DP) stress/rest protocol. Thereafter, patients with transient myocardial perfusion abnormality were followed up and their coronary blood flow was quantitatively assessed. Venous blood was taken before and after DP stress to measure markers. RESULTS: Baseline ADMA and SDMA concentrations were significantly higher in patients with CAD compared with healthy subjects. Pre- and post-stress SDMA concentrations were significantly higher in patients with transient myocardial perfusion abnormality compared with those with negative MPS results. However, ADMA and L-arginine concentrations were not significantly different between the two groups. None of the markers were significantly different between patients with angiographically proven low coronary flow and those with normal coronary flow. Pre-stress SDMA concentrations were an independent predictor of cardiovascular mortality during a 8-year follow-up. CONCLUSIONS: Elevated serum SDMA concentrations may be helpful for selecting high-risk patients with CAD if there is any doubt in interpreting MPS. SDMA concentrations may also predict cardiovascular outcome.

[Modern imaging of liver and pancreatic neoplasms]. / A máj és a hasnyálmirigy daganatainak korszeru radiológiai vizsgálata.

Modern imaging modalities play an outstanding role in the detection, characterization, staging, therapy planning, treatment outcome evaluation and follow-up of patients with liver and pancreatic neoplasms. Diagnostic performance and accuracy of the available modalities are continuously improving therefore, it is necessary to overview from time to time the diagnostic protocols and algorithms.

PARP-inhibitor treatment prevents hypertension induced cardiac remodeling by favorable modulation of heat shock proteins, Akt-1/GSK-3ß and several PKC isoforms.

Spontaneously hypertensive rat (SHR) is a suitable model for studies of the complications of hypertension. It is known that activation of poly(ADP-ribose) polymerase enzyme (PARP) plays an important role in the development of postinfarction as well as long-term hypertension induced heart failure. In this study, we examined whether PARP-inhibitor (L-2286) treatment could prevent the development of hypertensive cardiopathy in SHRs. 6-week-old SHR animals were treated with L-2286 (SHR-L group) or placebo (SHR-C group) for 24 weeks. Wistar-Kyoto rats were used as aged-matched, normotensive controls (WKY group). Echocardiography was performed, brain-derived natriuretic peptide (BNP) activity and blood pressure were determined at the end of the study. We detected the extent of fibrotic areas. The amount of heat-shock proteins (Hsps) and the phosphorylation state of Akt-1(Ser473), glycogen synthase kinase (GSK)-3ß(Ser9), forkhead transcription factor (FKHR)(Ser256), mitogen activated protein kinases (MAPKs), and protein kinase C (PKC) isoenzymes were monitored. The elevated blood pressure in SHRs was not influenced by PARP-inhibitor treatment. Systolic left ventricular function and BNP activity did not differ among the three groups. L-2286 treatment decreased the marked left ventricular (LV) hypertrophy which was developed in SHRs. Interstitial collagen deposition was also decreased by L-2286 treatment. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2(Thr183-Tyr185), Akt-1(Ser473), GSK-3ß(Ser9), FKHR(Ser256), and PKC ε(Ser729) and the level of Hsp90 were increased, while the activity of PKC α/ßII(Thr638/641), ζ/λ(410/403) were mitigated by L-2286 administration. We could detect signs of LV hypertrophy without congestive heart failure in SHR groups. This alteration was prevented by PARP inhibition. Our results suggest that PARP-inhibitor treatment has protective effect already in the early stage of hypertensive myocardial remodeling.

Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury: a randomized, controlled, experimental study.

INTRODUCTION: We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: Following 40% of total body surface area, third degree flame burn and 4 × 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas. RESULTS: Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day. CONCLUSIONS: Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.

Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis.

Vasopressin analogs are used as a supplement to norepinephrine in septic shock. The isolated effects of vasopressin agonists on sepsis-induced vascular dysfunction, however, remain controversial. Because V(2)-receptor stimulation induces vasodilation and procoagulant effects, a higher V(1a)- versus V(2)-receptor selectivity might be advantageous. We therefore hypothesized that a sole, titrated infusion of the selective V(1a)-agonist Phe(2)-Orn(8)-Vasotocin (POV) is more effective than the mixed V(1a)-/V(2)-agonist AVP for the treatment of vascular and cardiopulmonary dysfunction in methicillin resistant staphylococcus aureus pneumonia-induced, ovine sepsis. After the onset of hemodynamic instability, awake, chronically instrumented, mechanically ventilated, and fluid resuscitated sheep were randomly assigned to receive continuous infusions of either POV, AVP, or saline solution (control; each n = 6). AVP and POV were titrated to maintain mean arterial pressure above baseline - 10 mmHg. When compared with that of control animals, AVP and POV reduced neutrophil migration (myeloperoxidase activity, alveolar neutrophils) and plasma levels of nitric oxide, resulting in higher mean arterial pressures and a reduced vascular leakage (net fluid balance, chest and abdominal fluid, pulmonary bloodless wet-to-dry-weight ratio, alveolar and septal edema). Notably, POV stabilized hemodynamics at lower doses than AVP. In addition, POV, but not AVP, reduced myocardial and pulmonary tissue concentrations of 3-nitrotyrosine, VEGF, and angiopoietin-2, thereby leading to an abolishment of cumulative fluid accumulation (POV, 9 ± 15 ml/kg vs. AVP, 110 ± 13 ml/kg vs. control, 213 ± 16 ml/kg; P < 0.001 each) and an attenuated cardiopulmonary dysfunction (left ventricular stroke work index, PaO(2)-to-FiO(2) ratio) versus control animals. Highly selective V(1a)-agonism appears to be superior to unselective vasopressin analogs for the treatment of sepsis-induced vascular dysfunction.

Nebulization with γ-tocopherol ameliorates acute lung injury after burn and smoke inhalation in the ovine model.

We hypothesize that the nebulization of γ-tocopherol (g-T) in the airway of our ovine model of acute respiratory distress syndrome will effectively improve pulmonary function following burn and smoke inhalation after 96 h. Adult ewes (n = 14) were subjected to 40% total body surface area burn and were insufflated with 48 breaths of cotton smoke under deep anesthesia, in a double-blind comparative study. A customized aerosolization device continuously delivered g-T in ethanol with each breath from 3 to 48 h after the injury (g-T group, n = 6), whereas the control group (n = 5) was nebulized with only ethanol. Animals were weaned from the ventilator when possible. All animals were killed after 96 h, with the exception of one untreated animal that was killed after 64 h. Lung g-T concentration significantly increased after g-T nebulization compared with the control group (38.5 ± 16.8 vs. 0.39 ± 0.46 nmol/g, P < 0.01). The PaO(2)/FIO(2) ratio was significantly higher after treatment with g-T compared with the control group (310 ± 152 vs. 150 ± 27.0, P < 0.05). The following clinical parameters were improved with g-T treatment: pulmonary shunt fraction, peak and pause pressures, lung bloodless wet-to-dry weight ratios (2.9 ± 0.87 vs. 4.6 ± 1.4, P < 0.05), and bronchiolar obstruction (2.0% ± 1.1% vs. 4.6% ± 1.7%, P < 0.05). Nebulization of g-T, carried by ethanol, improved pulmonary oxygenation and markedly reduced the time necessary for assisted ventilation in burn- and smoke-injured sheep. Delivery of g-T into the lungs may be a safe, novel, and efficient approach for management of acute lung injury patients who have sustained oxidative damage to the airway.

Regulation of kinase cascade activation and heat shock protein expression by poly(ADP-ribose) polymerase inhibition in doxorubicin-induced heart failure.

Cardiomyopathy is one of the most severe side effects of the chemotherapeutic agent doxorubicin (DOX). The formation of reactive oxygen species plays a critical role in the development of cardiomyopathies, and the pathophysiological cascade activates nuclear enzyme poly(ADP-ribose) polymerase (PARP), and kinase pathways. We characterized the effects of the PARP-inhibitor and kinase-modulator compound L-2286 in DOX-induced cardiac injury models. We studied the effect of the established superoxide dismutase-mimic Tempol and compared the effects of this agent with those of the PARP inhibitor. In the rat H9C2 cardiomyocytes, in which DOX-induced poly(ADP-ribosyl)ation, L-2286 protected them from the DOX-induced injury in a concentration-dependent manner. In the in vivo studies, mice were pretreated (for 1 week) with L-2286 or Tempol before the DOX treatment. Both the agents improved the activation of cytoprotective kinases, Akt, phospho-specific protein kinase C ϵ, ζ/λ and suppressed the activity of cell death promoting kinases glycogen synthase kinase-3ß, JNK, and p38 mitogen-activated protein kinase, but the effect of PARP inhibitor was more pronounced and improved the survival as well. L-2286 activated the phosphorylation of proapoptotic transcription factor FKHR1 and promoted the expression of Hsp72 and Hsp90. These data suggest that the mode of the cytoprotective action of the PARP inhibitor may include the modulation of kinase pathways and heat shock protein expression.

The Angiotensin-converting enzyme inhibitor captopril inhibits poly(adp-ribose) polymerase activation and exerts beneficial effects in an ovine model of burn and smoke injury.

We investigated the effect of the angiotensin-converting enzyme (ACE) inhibitor captopril in a clinically relevant ovine model of smoke and burn injury, with special reference to oxidative stress and activation of poly(ADP-ribose) polymerase, in the lung and in circulating leukocytes. Female, adult sheep (28-40 kg) were divided into three groups. After tracheostomy and under deep anesthesia, both vehicle-control-treated (n = 5) and captopril-treated (20 mg/kg per day, i.v., starting 0.5 h before the injury) (n = 5) groups were subjected to 2 × 20%, third-degree burn injury and were insufflated with 48 breaths of cotton smoke. A sham group not receiving burn/smoke was also studied (n = 5). Animals were mechanically ventilated and fluid resuscitated for 24 h in the awake state. Burn and smoke injury resulted in an upregulation of ACE in the lung, evidenced by immunohistochemical determination and Western blotting. Burn and smoke injury resulted in pulmonary dysfunction, as well as systemic hemodynamic alterations. Captopril treatment of burn and smoke animals improved PaO2/FiO2 ratio and pulmonary shunt fraction and reduced the degree of lung edema. There was a marked increase in PAR levels in circulating leukocytes after burn/smoke injury, which was significantly decreased by captopril. The pulmonary level of ACE and the elevated pulmonary levels of transforming growth factor ß in response to burn and smoke injury were significantly decreased by captopril treatment. Our results suggest that the ACE inhibitor captopril exerts beneficial effects on the pulmonary function in burn/smoke injury. The effects of the ACE inhibitor may be related to the prevention of reactive oxygen species-induced poly(ADP-ribose)polymerase overactivation. Angiotensin-converting enzyme inhibition may also exert additional beneficial effects by inhibiting the expression of the profibrotic mediator transforming growth factor ß.

Burn and smoke injury activates poly(ADP-ribose)polymerase in circulating leukocytes.

The nuclear enzyme poly(ADP-ribose)polymerase (PARP) plays a significant role in the pathogenesis of various forms of critical illness. DNA strand breaks induced by oxidative and nitrative stress trigger the activation of PARP, and PARP, in turn, mediates cell death and promotes proinflammatory responses. Until recently, most studies focused on the role of PARP in solid organs such as heart, liver, and kidney. We investigated the effect of burn and smoke inhalation on the levels of poly(ADP-ribosylated) proteins in circulating sheep leukocytes ex vivo. Adult female merino sheep were subjected to burn injury (2× 20% each flank, 3 degrees) and smoke inhalation injury (insufflated with a total of 48 breaths of cotton smoke) under deep anesthesia. Arterial and venous blood was collected at baseline, immediately after the injury and 1 to 24 h after the injury. Leukocytes were isolated with the Histopaque method. The levels of poly(ADP-ribosyl)ated proteins were determined by Western blotting. The amount of reactive oxygen species was quantified by the OxyBlot method. To examine whether PARP activation continues to increase ex vivo in the leukocytes, blood samples were incubated at room temperature or at 37°C for 3 h with or without the PARP inhibitor PJ34. To investigate whether the plasma of burn/smoke animals may trigger PARP activation, burn/smoke plasma was incubated with control leukocytes in vitro. The results show that burn and smoke injury induced a marked PARP activation in circulating leukocytes. The activity was the highest immediately after injury and at 1 h and decreased gradually over time. Incubation of whole blood at 37°C for 3 h significantly increased poly(ADP-ribose) levels, indicative of the presence of an ongoing cell activation process. In conclusion, PARP activity is elevated in leukocytes after burn and smoke inhalation injury, and the response parallels the time course of reactive oxygen species generation in these cells.

Enhancement of organ regeneration in animal models by a stem cell-stimulating plant mixture.

Adult stem cells play an important role in the regeneration of damaged organs. Attempts have already been made to enhance stem cell production by cytokines, in order to increase the improvement of cardiac functions after myocardial infarction. In our present study we investigated the possibility whether instead of cytokine injection dietary stimulation of stem cell production accelerates the organ regeneration in animals. A dietary supplement, Olimpiq StemXCell (Crystal Institute Ltd., Eger, Hungary), containing plant extracts (previously proved to increase the number of circulating CD34(+) cells) was consumed in human equivalent doses by the experimental animals. In the first experiment carbon tetrachloride was applied to CBA/Ca mice, to induce liver damage, and liver weights between StemXCell-fed and control animals were compared 10 days after the treatment. In the second model experimental diabetes was induced in F344 rats by alloxan. Blood sugar levels were measured for 5 weeks in the control and StemXCell-fed groups. The third part of the study investigated the effect of StemXCell on cardiac functions. Eight weeks after causing a myocardial infarction in Wistar rats by isoproterenol, left ventricular ejection fraction was determined as a functional parameter of myocardial regeneration. In all three animal models StemXCell consumption statistically significantly improved the organ regeneration (relative liver weights, 4.78 +/-0.06 g/100 g vs. 4.97 +/- 0.07 g/100 g; blood sugar levels at week 5, 16 +/- 1.30 mmol/L vs. 10.2 +/- 0.92 mmol/L; ejection fraction, 57.5 +/- 2.23 vs. 68.2 +/- 4.94; controls vs. treated animals, respectively). Our study confirms the hypothesis that dietary enhancement of stem cell production may protect against organ injuries and helps in the regeneration.

PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats.

AIMS: Oxidative stress followed by abnormal signalling can play a critical role in the development of long-term, high blood pressure-induced cardiac remodelling in heart failure (HF). Since oxidative stress-induced poly(ADP-ribose)polymerase (PARP) activation and cell death have been observed in several experimental models, we investigated the possibility that inhibition of nuclear PARP improves cardiac performance and delays transition from hypertensive cardiopathy to HF in a spontaneously hypertensive rat (SHR) model of HF. METHODS AND RESULTS: SHRs were divided into two groups: one received no treatment (SHR-C) and the other (SHR-L) received 5 mg/kg/day L-2286 (PARP-inhibitor) orally for 46 weeks. A third group was a normotensive age-matched control group (CFY) and a fourth was a normotensive age-matched group receiving L-2286 treatment 5 mg/kg/day (CFY+L). At the beginning of the study, systolic function was similar in both CFY and SHR groups. In the SHR-C group at the end of the study, eccentric hypertrophy with poor left ventricular (LV) systolic function was observed, while PARP inhibitor treatment preserved systolic LV function. Due to these favourable changes, the survival rate of SHRs was significantly improved (P < 0.01) by the administration of the PARP inhibitor (L-2286). The PARP inhibitor used did not affect the elevated blood pressure of SHR rats, but moderated the level of plasma-BNP (P < 0.01) and favourably influenced all the measured gravimetric parameters (P < 0.05) and the extent of myocardial fibrosis (P < 0.05). The inhibition of PARP increased the phosporylation of Akt-1/GSK-3beta (P < 0.01), ERK 1/2 (P < 0.01), and PKC epsilon (P < 0.01), and decreased the phosphorylation of JNK (P < 0.05), p-38 MAPK (P < 0.01), PKC pan betaII and PKC zeta/lambda (P < 0.01), and PKC alpha/betaII and delta (P < 0.05). CONCLUSION: These data demonstrate that chronic inhibition of PARP induces long-term favourable changes in the most important signalling pathways related to oxidative stress. PARP inhibition also prevents remodelling, preserves systolic function, and delays transition of hypertensive cardiopathy to HF in SHRs.

Alcohol-free red wine inhibits isoproterenol-induced cardiac remodeling in rats by the regulation of Akt1 and protein kinase C alpha/beta II.

There is increasing evidence that moderate consumption of red wine containing high amount of polyphenols and anthocyanins is associated with decreased incidence of cardiovascular morbidity and mortality. Therefore, we hypothesized that cardiac hypertrophy and fibrosis as well as Akt (protein kinase B, PKB) and protein kinase C (PKC) cascades can be beneficially influenced by an alcohol-free red wine (AFRW) extract rich in 14 types of polyphenols and 4 types of anthocyanins during cardiac remodeling. To test this assumption, rats were treated with isoproterenol (ISO) to induce postinfarction remodeling and were given tap water or AFRW ad libitum for 8 weeks. Control rats received vehicle instead of ISO. Heart mass/body mass and ventricle mass/body mass ratios, diameter of cardiomyocytes, phosphorylation of PKC alpha/beta II and protein kinase B/Akt, and deposition of collagen type III were determined from the hearts of all four groups of rats. All measured gravimetric parameters, myocyte diameters and the amount of collagen type III decreased, and the phosphorylation of PKC alpha/beta II was reduced in the ISO+AFRW group compared to the ISO group. AFRW induced activation of Akt, one of the best characterized cytoprotective pathways even without ISO treatment, and this activation was further increased in the ISO+AFRW group. These data suggest that AFRW treatment has a protective effect on hearts undergoing postinfarction remodeling by repressing hypertrophy-associated increased phosphorylation of PKC alpha/beta II and by activating Akt, providing a molecular mechanism for the cardioprotective effect of red wine polyphenols.

Effect of L-2286, a poly(ADP-ribose)polymerase inhibitor and enalapril on myocardial remodeling and heart failure.

Increased activation of poly(ADP-ribose) polymerase (PARP) enzyme has been implicated in the pathogenesis of acute and chronic myocardial dysfunction. We have demonstrated the protective effect of PARP inhibitors against postinfarction myocardial remodeling and heart failure. The primary aim of our recent work was to compare the effect and efficacy of a potent PARP-inhibitor (L-2286) to enalapril, a widely used angiotensin-converting enzyme (ACE) inhibitor. in experimental heart failure model. Both L-2286 and enalapril were tested in a rat model of chronic heart failure after isoproterenol-induced myocardial infarction. After a 12-week treatment period, echocardiography was performed, cardiac hypertrophy and interstitial collagen deposition were assessed, and the phosphorylation state of Akt-1/GSK-3beta pathway as well as the PKC and MAPK kinases were determined. Both PARP and ACE inhibition reduced the progression of postinfarction heart failure by attenuating cardiac hypertrophy and interstitial fibrosis. More importantly, PARP inhibition increased the activity of the prosurvival signal transduction factors (Akt-1/GSK-3beta pathway, PKCepsilon). Due to these effects, L-2286 improved the systolic left ventricular function. Enalapril treatment exerted a similar, but weaker protective effect against postinfarction myocardial remodeling and heart failure. In conclusion, we demonstrated in an experimental heart failure model that L-2286 decreased the postinfarction myocardial remodeling more effectively than enalapril treatment.

The role of Akt and mitogen-activated protein kinase systems in the protective effect of poly(ADP-ribose) polymerase inhibition in Langendorff perfused and in isoproterenol-damaged rat hearts.

Blocking poly(ADP-ribosyl)ation of nuclear proteins protects the heart from ischemia-reperfusion injury. In addition, activation of Akt and mitogen-activated protein kinase (MAPK) cascades also plays a pivotal role in the survival of cardiomyocytes during ischemia-reperfusion; however, the potential interplay between these pathways is yet to be elucidated. We therefore tested the hypothesis whether poly(ADP-ribose) polymerase (PARP) inhibition can modulate Akt and MAPK signaling of ischemic-reperfused rat hearts. A novel PARP inhibitor, L-2286 [2-[(2-piperidin-1-yletil)thio]quinazolin-4(3H)-one] was administered during ischemia-reperfusion in Langendorff perfused rat hearts and in isoproterenol-induced myocardial infarction. Thereafter, the cardiac energy metabolism, oxidative damage, and the phosphorylation state of Akt and MAPK cascades were monitored. L-2286 exerted significant protective effect against ischemia-reperfusion-induced myocardial injury in both experimental models. More importantly, L-2286 facilitated the ischemia-reperfusion-induced activation of Akt, extracellular signal-regulated kinase, and p38-MAPK in both isolated hearts and in vivo cardiac injury. By contrast, isoproterenol-induced rapid c-Jun N-termainal kinase activation was repressed by L-2286. Here, we provide evidence for the first time that PARP inhibition beneficially modulates the cardiac Akt and MAPK signaling in ex vivo and in vivo ischemia-reperfusion models. We therefore propose that this novel mechanism may contribute to the cardioprotective properties of PARP inhibitors.