The aim of the study was to evaluate the impact of simulated acute hyperglycemia (HG) on PI3K/Akt signaling in preconditioned and non -preconditioned isolated rat hearts perfused with Krebs -Henseleit solution containing normal (11 mmol/l) or elevated (22 mmol/l) glucose subjected to ischemia -reperfusion. Ischemic preconditioning (IP) was induced by two 5 -min cycle s of coronary occlusion followed by 5 -min reperfusion. Protein levels of Akt, phosphorylated (activated) Akt (P-Akt), as well as contents of BAX protein were assayed (Western blotting) in cytosolic fraction of myocardial tissue samples taken prior to and a fter 30 -min global ischemia and 40- min reperfusion. In “normoglycemic ” conditions (NG), IP significantly increased P -Akt at the end of long -term ischemia, while reperfusion led to its decrease together with the decline of BAX levels as compared to non- pre conditioned hearts. On the contrary, under HG conditions, P -Akt tended to decline in IP - hearts after long -term ischemia, and it was significantly higher after reperfusion than in non -preconditioned controls . No significant influence of IP on BAX levels at the end of I/R was observed under HG conditions . It seems that high glucose may influence IP -induced activation of Akt and its downstream targets, as well as maintain persistent Akt activity that may be detrimental for the heart under above conditions., M. Zálešák, P. Blažíček, I. Gablovský, V. Ledvényiová, M. Barteková, A. Ziegelhöffer, T. Ravingerová., and Obsahuje bibliografii
The aim of our study was to characterize resistance to ischemia/reperfusion (I/R) injury in Langendorff-perfused rat hearts and effectivity of ischemic preconditioning (PC) under condition of simulated acute hyperglycemia (SAHG) by perfusion of the hearts with Krebs-Henseleit (KH) solution with elevated glucose concentration (22 mmol/l). I/R injury was induced by 30- min coronary occlusion followed by 120-min reperfusion and PC by two cycles of 5-min occlusion/5-min reperfusion, prior to I/R. The severity of I/R injury was characterized by determination of the size of infarction (IS, expressed in % of area at risk size) and the amount of heart-type fatty acid binding protein (h-FABP, a marker of cell injury) released from the hearts to the effluent. Significantly smaller IS (8.8±1 %) and lower total amount of released h-FABP (1808±660 pmol) in PC group compared with IS 17.1±1.2 % (p<0.01) and amount of h-FABP (8803±2415 pmol, p<0.05) in the non-PC control hearts perfused with standard KH solution (glucose 11 mmol/l) confirmed protective effects of PC. In contrast, in SAHG groups, PC enhanced IS (21.4±2.2 vs. 14.3±1.3 %, p<0.05) and increased total amount of h-FABP (5541±229 vs. 3458±283 pmol, p<0.05) compared with respective non-PC controls. Results suggest that PC has negative effect on resistance of the hearts to I/R injury under conditions of elevated glucose in vitro., M. Zálešák, P. Blažíček, D. Pancza, V. Ledvényiová, M. Barteková, M. Nemčeková, S. Čarnická, A. Ziegelhöffer, T. Ravingerová., and Obsahuje bibliografii
Risk factors (RF) of cardiovascular diseases associated with modern lifestyle, such as stress, chronically increased blood pressure, hyperglycemia and dyslipidemia have a negative impact on the heart exposed to ischemia: their may facilitate its lethal injury (myocardial infarction) and occurrence of sudden death due to ventricular arrhythmias. On the other hand, some stressful stimuli related to RF including reactive oxygen species, transient episodes of ischemia (hypoxia), high glucose and other may play a dual role in the pathogenesis of ischemia/reperfusion (I/R) injury (IRI). Besides their deleterious effects, these factors may trigger adaptive processes in the heart resulting in greater resistance against IRI, which is also a characteristic feature of the female myocardium. However, sensitivity to ischemia is increasing with age in both genders. Current research indicates that comorbidity related to lifestyle may impair the cardiac response to acute ischemia not only by interference with pathophysiological mechanisms of IRI per se, but via suppression of intrinsic protective mechanisms in the heart and its ability to tolerate the ischemic challenges, although the role of RF has not been unequivocally proven. Moreover, even pathologically altered myocardium need not completely lose its adaptive potential. In addition, increased ischemic tolerance can be induced by the pleiotropic (independent of the primary) effects of some hypolipidemic and antidiabetic drugs, even in the diseased myocardium. This review addresses the issue of the impact of RF on cellular cardioprotective mechanisms and the possibilities to restore adaptive potential in subjects challenged with several RF. Reactivation of adaptive processes in the myocardium taking into consideration gender and age can contribute to optimalization of antiischemic therapy., T. Ravingerová, ... [et al.]., and Obsahuje seznam literatury
Genes encoding enzymes involved in fatty acids (FA) and glucose oxidation are transcriptionally regulated by peroxisome proliferator-activated receptors (PPAR), members of the nuclear receptor superfamily. Under conditions associated with O 2 deficiency, PPAR-α modulates substrate switch (between FA and glucose) aimed at the adequate energy production to maintain basic cardiac function. Both, positive and negative effects of PPAR-α activation on myoc ardial ischemia/reperfusion (I/R) injury have been reported. Moreover, the role of PPAR-mediated metabolic shifts in cardioprotective mechanisms of preconditioning (PC) is relatively less investigated. We explored the effects of PPAR-α upregulation mimicking a delayed “second window” of PC on I/R injury in the rat heart and potential downstream mechanisms involved. Pretreatment of rats with PPAR-α agonist WY-14643 (WY, 1 mg/kg, i.p.) 24 h prior to I/R reduced post-ischemic stunning, arrhythmias and the extent of lethal injury (infarct size) and ap optosis (caspase-3 expression) in isolated hearts exposed to 30-min global ischemia and 2-h reperfusion. Protection was associated with remarkably increased expression of PPAR- α target genes promoting FA utilization (medium-chain acyl-CoA de hydrogenase, pyruvate dehydrogenase kinase-4 and carnitine palmitoyltransferase I) and reduced expression of glucose transporter GLUT-4 responsible for glucose transport and metabolism. In addition, enhanced Akt phosphorylation and protein levels of eNOS, in conjunction with blunting of cardioprotection by NOS inhibitor L-NAME, were observed in the WY-treated hearts. Conclusions: upregulation of PPAR-α target metabolic genes involved in FA oxidation may underlie a delayed phase PC-like protection in the rat heart. Potential non-genomic effects of PPAR-α-mediated cardioprotection may involve activation of prosurvival PI3K/Akt pathway and its downstream targets such as eNOS and subsequently reduced apoptosis., T. Ravingerová ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy