Iron is an essential mineral participating in numerous biological processes in the organism under physiological conditions. However, it may be also involved in the pathological mechanisms activated in various cardiovascular diseases including myocardial ischemia/reperfusion (I/R) injury, due to its involvement in reactive oxygen species (ROS) production. Furthermore, iron has been reported to participate in the mechanisms of iron-dependent cell death defined as "ferroptosis". On the other hand, iron may be also involved in the adaptive processes of ischemic preconditioning (IPC). This study aimed to elucidate whether small amounts of iron may modify the cardiac response to I/R in isolated perfused rat hearts and their protection by IPC. Pretreatment of the hearts with iron nanoparticles 15 min prior to sustained ischemia (iron preconditioning, Fe-PC) did not attenuate post-I/R contractile dysfunction. Recovery of left ventricular developed pressure (LVDP) was significantly improved only in the group with combined pretreatment with iron and IPC. Similarly, the rates of contraction and relaxation [+/-(dP/dt)max] were almost completely restored in the group preconditioned with a combination of iron and IPC but not with iron alone. In addition, the severity of reperfusion arrhythmias was reduced only in the iron+IPC group. No changes in protein levels of "survival" kinases of the RISK pathway (Reperfusion Injury Salvage Kinase) were found except for reduced caspase 3 levels in both preconditioned groups. The results indicate that a failure to precondition rat hearts with iron may be associated with the absent upregulation of RISK proteins and the pro-ferroptotic effect manifested by reduced glutathione peroxidase 4 (GPX4) levels. However, combination with IPC suppressed the negative effects of iron resulting in cardioprotection.
- MeSH
- ischemické přivykání * MeSH
- krysa rodu rattus MeSH
- myokard metabolismus MeSH
- potkani Wistar MeSH
- přivykání k ischémii * metody MeSH
- reperfuzní poškození myokardu * metabolismus MeSH
- srdce MeSH
- železo metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Remote ischemic preconditioning (RIPC) represents one of the forms of innate cardioprotection. While being effective in animal models, its application in humans has not been always beneficial, which might be attributed to the presence of various comorbidities, such as hypertension, or being related to the confounding factors, such as patients' sex and age. RIPC has been shown to mediate its cardioprotective effects through the activation of Reperfusion Injury Salvage Kinase (RISK) pathway in healthy animals, however, scarce evidence supports this effect of RIPC in the hearts of spontaneously hypertensive (SHR) rats, in particular, in relationship with aging. The study aimed to investigate the effectiveness of RIPC in male SHR rats of different age and to evaluate the role of RISK pathway in the effect of RIPC on cardiac ischemic tolerance. RIPC was performed using three cycles of inflation/deflation of the pressure cuff placed on the hind limb of anesthetized rats aged three, five and eight months. Subsequently, hearts were excised, Langendorff-perfused and exposed to 30-min global ischemia and 2-h reperfusion. Infarct-sparing and antiarrhythmic effects of RIPC were observed only in three and five months-old animals but not in eight months-old rats. Beneficial effects of RIPC were associated with increased activity of RISK and decreased apoptotic signaling only in three and five months-old animals. In conclusion, RIPC showed cardioprotective effects in SHR rats that were partially age-dependent and might be attributed to the differences in the activation of RISK pathway and various aspects of ischemia/reperfusion injury in aging animals.
- MeSH
- hypertenze * prevence a kontrola MeSH
- infarkt myokardu * metabolismus MeSH
- ischemie MeSH
- kojenec MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- potkani inbrední SHR MeSH
- reperfuzní poškození myokardu * metabolismus MeSH
- zvířata MeSH
- Check Tag
- kojenec MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Although physical exercise is known to reduce size of infarction, incidence of ventricular arrhythmias, and to improve heart function, molecular mechanisms of this protection are not fully elucidated. We explored the hypothesis that voluntary running, similar to adaptive interventions, such as ischemic or remote preconditioning, may activate components of pro-survival (RISK) pathway and potentially modify cell proliferation. Sprague-Dawley adult male rats freely exercised for 23 days in cages equipped with running wheels, while sedentary controls were housed in standard cages. After 23 days, left ventricular (LV) myocardial tissue samples were collected for the detection of expression and activation of RISK proteins (WB). The day before, a marker of cell proliferation 5-bromo-2'-deoxyuridine (BrdU) was given to all animals to detect its incorporation into DNA of the LV cells (ELISA). Running increased phosphorylation (activation) of Akt, as well as the levels of PKC? and phospho-ERK1/2, whereas BrdU incorporation into DNA was unchanged. In contrast, exercise promoted pro-apoptotic signaling - enhanced Bax/Bcl-2 ratio and activation of GSK-3ß kinase. Results suggest that in the rat myocardium adapted to physical load, natural cardioprotective processes associated with physiological hypertrophy are stimulated, while cell proliferation is not modified. Up-regulation of pro-apoptotic markers indicates potential induction of cell death mechanisms that might lead to maladaptation in the long-term.
- MeSH
- kondiční příprava zvířat fyziologie MeSH
- krysa rodu rattus MeSH
- mediátory zánětu metabolismus MeSH
- míra přežití trendy MeSH
- myokard metabolismus patologie MeSH
- náhodné rozdělení MeSH
- potkani Sprague-Dawley MeSH
- proliferace buněk fyziologie MeSH
- rizikové faktory MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Currently, there are no satisfactory interventions to protect the heart against the detrimental effects of ischemia-reperfusion injury. Although ischemic preconditioning (PC) is the most powerful form of intrinsic cardioprotection, its application in humans is limited to planned interventions, due to its short duration and technical requirements. However, many organs/tissues are capable of producing "remote" PC (RPC) when subjected to brief bouts of ischemia-reperfusion. RPC was first described in the heart where brief ischemia in one territory led to protection in other area. Later on, RPC started to be used in patients with acute myocardial infarction, albeit with ambiguous results. It is hypothesized that the connection between the signal triggered in remote organ and protection induced in the heart can be mediated by humoral and neural pathways, as well as via systemic response to short sublethal ischemia. However, although RPC has a potentially important clinical role, our understanding of the mechanistic pathways linking the local stimulus to the remote organ remains incomplete. Nevertheless, RPC appears as a cost-effective and easily performed intervention. Elucidation of protective mechanisms activated in the remote organ may have therapeutic and diagnostic implications in the management of myocardial ischemia and lead to development of pharmacological RPC mimetics.
- MeSH
- časové faktory MeSH
- infarkt myokardu metabolismus patologie patofyziologie prevence a kontrola MeSH
- ischemické přivykání metody MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myokard metabolismus patologie MeSH
- regionální krevní průtok MeSH
- reperfuzní poškození myokardu metabolismus patologie patofyziologie prevence a kontrola MeSH
- signální transdukce MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
