Všechny intracelulární a některé extracelulární proteiny jsou kontinuálně degradovány a nahrazovány syntézou nových proteinů. Oba tyto děje musejí zůstat ve vzájemné rovnováze, neboť její narušení by mohlo vést ke vzniku závažných onemocnění. Buňky obsahují mnoho proteolytických systémů, které zajišťují vysoce specifickou a kontrolovanou degradaci proteinů. Jedním z nich je proteazom, složitý molekulární stroj sloužící k degradaci proteinů konjugovaných s ubikvitinem. Od první izolace proteazomu v roce 1968 bylo objeveno mnoho detailů o fungování tohoto systému. V roce 2004 byla za tyto objevy dokonce udělena Nobelova cena za chemii. V naší přehledové práci jsme se zaměřili na shrnutí dosavadních poznatků o mechanizmech vysoce selektivní degradace proteinů ubikvitin‑proteazomovou dráhou. Jednotlivé kapitoly tohoto článku pojednávají o struktuře a funkci systému ubikvitin‑proteazom, mechanizmech regulace degradace proteinů a biologických účincích inhibitorů proteazomu.
All intracellular and some extracellular proteins are continually degraded and replaced by synthesis of new proteins. Both these processes need to stay in equilibrium since their balance may lead to emergence of diseases. Cells contain many proteolytic systems that ensure highly specific and controlled degradation of proteins. One of these systems is the proteasome, a very complex molecular engine allowing degradation of proteins conjugated to ubiquitin. Since the first isolation of proteasome in 1968, many details about its function have been uncovered. In 2004, Nobel Prize for chemistry was awarded for these discoveries. In our review article, we aimed to summarize information about the mechanism of highly selective degradation of proteins by the ubiquitin‑proteasome pathway. Individual parts of the paper summarize current knowledge about highly selective degradation of proteins by the ubiquitin‑proteasome system, mechanisms of protein degradation regulation and biological effects of proteasome inhibitors.
- Klíčová slova
- degradace proteinů, proteazomové inhibitory,
- MeSH
- NF-kappa B metabolismus MeSH
- polyubikvitin MeSH
- proteasomový endopeptidasový komplex * metabolismus MeSH
- proteiny * klasifikace metabolismus MeSH
- ubikvitin aktivující enzymy MeSH
- ubikvitin konjugující enzymy metabolismus MeSH
- ubikvitin * metabolismus MeSH
- ubikvitinace * fyziologie MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Ischemic preconditioning (I-PC) induced by brief episodes of ischemia and reperfusion (I/R) protects the heart against sustained I/R. Although activation of mitochondrial K(ATP) channels (mitoK(ATP)) interacting with reactive oxygen species (ROS) has been proposed as a key event in this process, their role in the antiarrhythmic effect is not clear. This study was designed: 1) to investigate the involvement of mito K(ATP) opening in the effect of I-PC (1 cycle of I/R, 5 min each) on ventricular arrhythmias during test ischemia (TI, 30-min LAD coronary artery occlusion) in Langendorff-perfused rat hearts and subsequent postischemic contractile dysfunction, and 2) to characterize potential mechanisms of protection conferred by I-PC and pharmacological PC induced by mito K(ATP) opener diazoxide (DZX), with particular regards to the modulation of ROS generation. Lipid peroxidation (an indicator of increased ROS production) was determined by measurement of myocardial concentration of conjugated dienes (CD) and thiobarbituric acid reactive substances (TBARS) in non-ischemic controls, non-preconditioned and preconditioned hearts exposed to TI, I-PC alone, as well as after pretreatment with DZX, mito K(ATP) blocker 5-hydroxydecanoate (5-HD) and antioxidant N-acetylcysteine (NAC). Total number of ventricular premature beats (VPB) that occurred in the control hearts (518+/-71) was significantly (P<0.05) reduced by I-PC (195+/-40), NAC (290+/-56) and DZX (168+/-22). I-PC and NAC suppressed an increase in CD and TBARS caused by ischemia indicating lower production of ROS. On the other hand, I-PC and DZX themselves moderately enhanced ROS generation, prior to TI. Bracketing of I-PC with 5-HD suppressed both, ROS production during PC and its cardioprotective effect. In conclusion, potential mechanisms of protection conferred by mito K(ATP) opening in the rat heart might involve a temporal increase in ROS production in the preconditioning phase triggering changes in the pro/antioxidant balance in the myocardium and attenuating ROS production during subsequent prolonged ischemia.
- MeSH
- acetylcystein farmakologie MeSH
- antiarytmika farmakologie MeSH
- antioxidancia farmakologie MeSH
- blokátory draslíkových kanálů farmakologie MeSH
- časové faktory MeSH
- diazoxid farmakologie MeSH
- draslíkové kanály metabolismus účinky léků MeSH
- financování organizované MeSH
- funkce levé komory srdeční účinky léků MeSH
- hydroxykyseliny farmakologie MeSH
- ischemické přivykání MeSH
- komorové extrasystoly metabolismus patofyziologie prevence a kontrola MeSH
- kontrakce myokardu účinky léků MeSH
- krysa rodu rattus MeSH
- kyseliny dekanové farmakologie MeSH
- látky reagující s kyselinou thiobarbiturovou metabolismus MeSH
- obnova funkce MeSH
- oxidační stres MeSH
- perfuze MeSH
- peroxidace lipidů MeSH
- potkani Wistar MeSH
- reaktivní formy kyslíku metabolismus MeSH
- reperfuzní poškození myokardu metabolismus patofyziologie prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
Contrary to clinical trials, experimental studies revealed that diabetes mellitus (DM) may initiate, besides increased myocardial vulnerability to ischemia-reperfusion injury (I/R) and pro/antioxidant dysbalance, development of adaptation leading to an enhanced tolerance to I/R. The aims were to characterize 1) susceptibility to ischemia-induced ventricular arrhythmias in the diabetic rat heart 2) its response to antioxidant N-acetylcysteine (NAC) and a NOS inhibitor L-NAME, and 3) the effect of DM on endogenous antioxidant systems. Seven days after streptozotocin injection (65 mg/kg, i.p.), Langendorff-perfused control (C) and DM hearts were subjected to 30-min occlusion of the LAD coronary artery with or without prior 15-min treatment with L-NAME (100 microM) or NAC (4 mM). Total number of ventricular premature beats (VPB), as well the total duration of ventricular tachycardia (VT) were reduced in the DM group (from 533+/-58 and 37.9+/-10.2 s to 224.3+/-52.6 and 19+/-13.5 s; P<0.05). In contrast to the antiarrhythmic effects of L-NAME and NAC in controls group (VPB 290+/-56 and 74+/-36, respectively; P<0.01 vs. control hearts), application of both drugs in the diabetics did not modify arrhythmogenesis (L-NAME: VPB 345+/-136, VT 25+/-13 s; NAC: VPB 207+/-50, VT 12+/-3.9 s; P>0.05 vs non-treated diabetic hearts). Diabetic state was associated with significantly elevated levels of CoQ10 and CoQ9 (19.6+/-0.8 and 217.3+/-9.5 vs. 17.4+/- 0.5 and 185.0+/-5.0 nmol/g, respectively, in controls; P<0.05), as well as alpha-tocopherol (38.6+/-0.7 vs. 31.5+/-2.1 nmol/g in controls; P<0.01) in the myocardial tissue. It is concluded that early period of DM is associated with enhanced resistance to ischemia-induced arrhythmias. Diabetes mellitus might induce adaptive processes in the myocardium leading to lower susceptibility to antioxidant and L-NAME treatment.
- MeSH
- acetylcystein farmakologie MeSH
- alfa-tokoferol metabolismus MeSH
- antioxidancia farmakologie MeSH
- experimentální diabetes mellitus komplikace farmakoterapie enzymologie patofyziologie MeSH
- funkce levé komory srdeční MeSH
- fyziologická adaptace MeSH
- inhibitory enzymů farmakologie MeSH
- ischemická choroba srdeční komplikace farmakoterapie enzymologie patofyziologie MeSH
- komorová tachykardie enzymologie etiologie patofyziologie prevence a kontrola MeSH
- krysa rodu rattus MeSH
- myokard enzymologie MeSH
- NG-nitroargininmethylester farmakologie MeSH
- potkani Wistar MeSH
- synthasa oxidu dusnatého antagonisté a inhibitory metabolismus MeSH
- ubichinon analogy a deriváty metabolismus MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
