Although both lipophilic and more hydrophilic statins share the same pathway of the inhibition of HMG-CoA reductase, their pleiotropic cardioprotective effects associated with the ability to cross cellular membranes, including membranes of heart cells, may differ. To test this hypothesis, isolated rat hearts were Langendorff-perfused either with simvastatin (S, 10 μ mol/l) or pravastatin (P, 30 μ mol/l), 15 min prior to ischemia. Control untreated hearts (C) were perfused with perfusion medium only. Postischemic contractile dysfunction, reperfusion-induced ventricular arrhythmias and infarct size were investigated after exposure of the hearts to 30- min global isch emia and 2-h reperfusion. Both lipophilic S and hydrophilic P reduced the severity of ventricular arrhythmias (arrhythmia score) from 4.3±0.2 in C to 3.0±0 and 2.7±0.2 in S and P, respectively, (both P<0.05), decreased the duration of ventricular tachycardia and suppressed ventricular fibrillation. Likewise, the extent of lethal injury (infarct size) determined by tetrazolium staining and expressed in percentage of risk area, was significantly lower in both treated groups, moreover, the effect of P was more pronounced (27±2 % and 10±2 % in S and P groups, respectively, vs. 42±1 % in C; P<0.05). In contrast, only S, but not P, was able to improve postischemic recovery of left ventricular developed pressure (LVDP; 48±12 % of preischemic values vs. 25±4 % in C and 21± 7 % in P groups; P<0.05). Our results suggest that differences in water solubility of statins indicating a different ability to cross cardiac membranes may underlie their distinct cardioprot ective effects on myocardial stunning and lethal injury induced by ischemia/reperfusion., S. Čarnická ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Acute streptozotocin diabetes mellitus (DM) as well as remote ischemic preconditioning (RPC) has shown a favorable effect on the postischemic-reperfusion function of the myocardium. Cardioprotective mechanisms offered by these experimental models involve the mitochondria with the changes in functional properties of membrane as the end-effector. The aim was to find out whether separate effects of RPC and DM would stimulate the mechanisms of cardioprotection to a maximal level or whether RPC and DM conditions would cooperate in stimulation of cardioprotection. Experiments were performed on male Wistar rats divided into groups: control, DM, RPC and DM treated by RPC (RPC+DM). RPC protocol of 3 cycles of 5-min hind limb ischemia followed by 5-min reperfusion was used. Ischemicreperfusion injury was induced by 30-min ischemia followed by 40-min reperfusion of the hearts in Langendorff mode. Mitochondria were isolated by differential centrifugation, infarct size assessed by staining with 1 % 2,3,5-triphenyltetrazolium chloride, mitochondrial membrane fluidity with a fluorescent probe DPH, CoQ9 and CoQ10 with HPLC. Results revealed that RPC as well as DM decreased the infarct size and preserved mitochondrial function by increasing the mitochondrial membrane fluidity. Both used models separately offered a sufficient protection against ischemic-reperfusion injury without an additive effect of their combination., M. Ferko, I. Kancirová, M. Jašová, I. Waczulíková, S. Čarnická, J. Kucharská, O. Uličná, O. Vančová, M. Muráriková, T. Ravingerová, A. Ziegelhöffer., and Obsahuje bibliografii
Remote ischemic preconditioning (RIP)-induced protection of myocardial energetics was well documented on the level of tissue, but data concerning the involvement of mitochondria were missing. We aimed at the identification of changes in membrane properties and respiratory functions induced in rat heart mitochondria by RIP. Experiments were performed on 46 male Wistar rats divided into control and RIP-treated groups of 21 animals each. Blood flow in the occluded area was recorded by MRI angiography in four animals. RIP protocol comprised of three successive 5-min occlusions each followed by 5-min reperfusions of descending branches of the right hind limb femoral artery. The efficacy of RIP was evaluated as the extent of RIP-induced protection against damage to the functions of mitochondria isolated by differential centrifugation after 30-min global ischemia followed by 40-min reperfusion of the hearts in Langendorff mode. Assessments: mitochondrial membrane fluidity with a fluorescent probe DPH, CoQ9 and CoQ10 with HPLC, mitochondrial respiration with the Oxygraph-2k (Oroboros). Results revealed that RIP was affecting the mitochondria. The immediate protection conferred by RIP involves beneficial and prognostically significant effects: a total elimination of ischemia/reperfusion-induced depression of mitochondrial membrane fluidity and a trend for better preservation of mitochondrial state 3 respiration., M. Ferko, I. Kancirová, M. Jašová, S. Čarnická, M. Muráriková, I. Waczulíková, Z. Sumbalová, J. Kucharská, O. uličná, T. Ravingerová, A. Ziegelhöffer., and Obsahuje bibliografii
Remote ischemic preconditioning (RIPC) is a novel strategy of protection against ischemia-reperfusion (IR) injury in the heart (and/or other organs) by brief episodes of non-lethal IR in a distant organ/tissue. Importantly, RIPC can be induced noninvasively by limitation of blood flow in the extremity implying the applicability of this method in clinical situations. RIPC (and its delayed phase) is a form of relatively short-term adaptation to ischemia, similar to ischemic PC, and likely they both share triggering mechanisms, whereas mediators and end-effectors may differ. It is hypothesized that communication between the signals triggered in the remote organs and protection in the target organ may be mediated through substances released from the preconditioned organ and transported via the circulation (humoral pathways), by neural pathways and/or via systemic anti-inflammatory and antiapoptotic response to short ischemic bouts. Identification of molecules involved in RIPC cascades may have therapeutic and diagnostic implications in the management of myocardial ischemia. Elucidation of the mechanisms of endogenous cardioprotection triggered in the remote organ could lead to the development of diverse pharmacological RIPC mimetics. In the present article, the authors provide a short overview of RIPC-induced protection, proposed underlying mechanisms and factors modulating RIPC as a promising cardioprotective strategy., T. Ravingerova, V. Farkasova, L. Griecsova, S. Carnicka, M. Murarikova, E. Barlaka, F. Kolar, M. Bartekova, L. Lonek, J. Slezak, A. Lazou., 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
a1_Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are most frequently used drugs in the prevention of coronary artery disease due to their cholesterol- lowering activity. However, it is not exactly known whether these effects of statins or those independent of cholesterol decrease account for the protection ag ainst myocardial ischemia- reperfusion (I/R) injury. In this study, we investigated the effect of 5-day treatment with simvastatin (10 mg/kg) in Langendorff- perfused hearts of healthy control (C) and diabetic- hypercholesterolemic (D-H; strept ozotocin + high fat-cholesterol diet, 5 days) rats subjected to 30-min global ischemia followed by 40-min reperfusion for the examination of postischemic contractile dysfunction and reperfusion-induced ventricular arrhythmias or to 30-min (left anterior descending) coronary artery occlusion and 2-h reperfusion for the infarct size determination (IS; tetrazolium stai ning). Postischemic recovery of left ventricular developed pressu re (LVDP) in animals with D-H was improved by simvastatin therapy (62.7±18.2 % of preischemic values vs. 30.3±5.7 % in the untreated D-H; P<0.05), similar to the values in the simvastatin-treated C group, which were 2.5-fold higher than those in the untreated C group. No ventricular fibrillation occurred in the simvastatin-treated C and D-H animals during reperf usion. Likewise, simvastatin shortened the duration of ventri cular tachycardia (10.2±8.1 s and 57.8±29.3 s in C and D-H vs. 143.6±28.6 s and 159.3±44.3 s in untreated C and D-H, respectively, both P<0.05). The decreased arrhythmogenesis in the simvastatin-treated groups correlated with the limitation of IS (in % of risk area) by 66 % and 62 % in C and D-H groups, respectively. However, simvastatin treatment decreased plasma cholesterol levels neither in the D-H animals nor in C., a2_The results indicate that other effects of statins (independent of cholesterol lowering) are involved in the improvement of contractile recovery and attenuation of lethal I/R injury in both, healthy and diseased individuals., A. Adameová, A. Harčárová, J. Matejíková, D. Pancza, M. Kuželová, S. Čarnická, P. Švec, M. Barteková, J. Styk, T. Ravingerová., and Obsahuje bibliografii
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