a1_Reduced tolerance to ischemia/reperfusion (IR) injury has been shown in elder human and animal hearts, however, the onset of this unfavorable phenotype and cellular mechanisms behind remain unknown. Moreover, aging may interfere with the mechanisms of innate cardioprotection (preconditioning, PC) and cause defects in protective cell signaling. We studied the changes in myocardial function and response to ischemia, as well as selected proteins involved in “pro-survival” pathways in the hearts from juvenile (1.5 months), younger adult (3 months) and mature adult (6 months) male Wistar rats. In Langendorffperfused hearts exposed to 30-min ischemia/2-h reperfusion with or without prior PC (one cycle of 5-min ischemia/5-min reperfusion), we measured occurrence of reperfusion-induced arrhythmias, recovery of contractile function (left ventricular developed pressure, LVDP, in % of pre-ischemic values), and size of infarction (IS, in % of area at risk size, TTC staining and computerized planimetry). In parallel groups, LV tissue was sampled for the detection of protein levels (WB) of Akt kinase (an effector of PI3-kinase), phosphorylated (activated) Akt (p-Akt), its target endothelial NO synthase (eNOS) and protein kinase Cε (PKCε) as components of “pro-survival” cascades. Maturation did not affect heart function, however, it impaired cardiac response to lethal IR injury (increased IS) and promoted arrhythmogenesis. PC reduced the occurrence of malignant arrhythmias, IS and improved LVDP recovery in the younger animals, while its efficacy was attenuated in the mature adults. Loss of PC protection was associated with age-dependent reduced Akt phosphorylation and levels of eNOS and PKCε in the hearts of mature animals compared with the younger ones, as well as with a failure of PC to upregulate these proteins., a2_Agingrelated alterations in myocardial response to ischemia may be caused by dysfunction of proteins involved in protective cell signaling that may occur already during the process of maturation., L. Griecsová, V. Farkašová, I. Gáblovský, V. K. M. Khandelwal, I. Bernátová, Z. Tatarková, P. Kaplan, T. Ravingerová., and Obsahuje bibliografii
Several pre-clinical and clinical studies have demonstrated zoledronic acid (Zol), which regulates the mevalonate pathway, has efficient anti-cancer effects. Zol can also induce autophagy. The aim of this study is to add new understanding to the mechanism of autophagy induction by Zol. LC3B-II, the marker for autophagy was increased by Zol treatment in breast cancer cells. Autophagosomes induced by Zol were visualized and quantified in both transient (pDendra2-hLC3) and stable MCF-7- GFP-LC3 cell lines. Acidic vesicular organelles were quantified using acridine orange. Zol induced a dose and time dependent autophagy. Treatment of Zol increased oxidative stress in MCF-7 cells, which was reversed by GGOH or anti-oxidants. On the other hand, treatment with GGOH or anti-oxidants resulted in decreased levels of LC3B-II. Further, the induced autophagy was irreversible, as the washout of Zol after 2 h or 24 h resulted in similar levels of autophagy, as induced by continuous treatment after 72 h. Thus, it can be summarized that Zol can induce a dose dependent but irreversible autophagy, by its effect on the mevalonate pathway and oxidative stress. This study adds to the understanding of the mechanism of action of Zol, and that it can induce autophagy at clinically relevant shorter exposure times in cancer cells., V. K. M. Khandelwal, L. M. Mitrofan, J. M. T. Hyttinen, K. R. Chaudhari, R. Buccione, K. Kaarniranta, T. Ravingerová, J. Mönkkönen., 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