Therapeutic strategies for ischemia reperfusion injury
Date
2019-08-27
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Abstract
Hüpoksilis-isheemiline kahjustus avaldub, kui peaaju või südame verevarustus on häiritud, mistõttu tekib hapniku- ja toitainevaegus. Ilma nendeta surevad rakud kiiresti. Antud töö aitabki paremini mõista, millised tegurid võiksid kaitsta kude hapnikupuuduse eest, mis kaasneb erinevate südameveresoonkonna haigustega. Tegu on molekulaarsel tasemel alusuuringutega rakkudel ja hiirtel, mille käigus uurisime kolme potentsiaalset terapeutilist mehhanismi isheemia reperfusiooni kahjustuse ravis - hüpotermia, vesiniksulfiid ja lümfangiogenees. Uued ravimeetodid aitavad laiendada arusaamist hüpoksilis-isheemilisest kahjustusest ja parandada patsientide taastumisvõimalusi.
Kliinilises praktikas on kehatemperatuuri langetamine kasutusel eelkõige sekundaarse ajukahjustuse vähendamiseks, samas näitavad mõningad uuringud, et hüpotermia on võimeline vähendama ka südamelihase kahjustust. Seni on hüpotermiat vaadeldud kui tegurit, mis vähendab metabolismi ja hapniku tarbimist. Meie tulemused näitavad, et lisaks sellele võimaldab hüpotermia suurendada vastupanu hapnikupuudusest tulenevale stressile läbi Nrf2 ja HIF1 signaaliradade.
Vesiniksulfiidi peeti pikka aega mürgiseks gaasiks, kuid sellel põhinevad ravimimeetodid võivad saada oluliseks mitmete südame-veresoonkonna haiguste puhul. Südamekahjustus vähendab rakus mitokondrite hulka, mis varustab aga rakku eluks vajaliku energiaga. Meie tulemused näitavad, et vesiniksulfiid reguleerib rakus mitokondrite hulka läbi AMPK-PGC1α signaaliraja. Südamekahjustuse puhul aitab eksogeenne vesiniksulfiid (SG-1002) taastada vesiniksulfiidi tasemed. Selle tulemusena suureneb südame mitokondrite hulk ja paraneb südame funktsioon.
Lümfangiogeneesile ehk lümfisoonte tekkele on isheemia reperfusiooni kahjustuse ravis oluliselt vähem tähepanu pööratud kui angiogeneesile ehk veresoonte tekkele, kuid isheemia reperfusiooni kahjustuse tulemusena muutub südame lümfisüsteem. Meie tulemused näitavad, et endogeense lümfangiogeneesi inhibeerimine südamekahjustuse olukorras tekitab põletikuvastust, südame talitushäiret ning ei toimunud iseloomulikku lümfisoonte tiheduse suurenemist. Selle leevendamiseks manustati hiirtele lokaalselt VEGFC-d, mis vähendas põletikku ja parandas südame talitushäiret. Seega on lümfangiogenees üks oluline uus terapeutiline lähenemine isheemia reperfusiooni kahjustuse ravis.
Ischemic-hypoxic injury is caused by diminished or absent blood flow and result of oxygen deprivation (e.g. stroke, heart attack). It encompasses a complex constellation of pathophysiological and molecular injuries, if left untreated can result in death. In this dissertation we studied therapeutic mechanisms that might be protective against ischemia reperfusion injury in order to enhance both our knowledge of ischemia reperfusion injury pathophysiology and mechanisms of protection. Clinical hypothermia is considered as one of the most effective intervention for a range of hypoxic ischemic pathologies of the central nervous system, however, the mechanisms that underlie its protective effects are uncertain. Currently, it is widely accepted that therapeutic effects of hypothermia are due to reduced metabolism and oxygen consumption. Our study demonstrates for the first time that mild hypothermia activates major transcription factors Nrf2 and HIF1A, which orchestrate adaptive responses to hypoxic stress. Hydrogen sulfide (H2S) is now recognized as a novel gaseous signaling molecule along with nitric oxide and carbon monoxide, although it was considered to be a toxic gas for hundreds of years. We show here that not only does H2S regulate mitochondrial biogenesis via AMPK-PGC1α signaling pathway but also that correcting H2S levels with SG-1002 (H2S-releasing prodrug) could protect against heart failure. The lymphatic system has been suggested to play an important role in cardiovascular disease. Our results show that inhibition of cardiac lymphangiogenesis exaggerates ischemia reperfusion injury even more. Furthermore, stimulation of cardiac lymphangiogenesis with VEGF-C improves cardiac function following ischemia reperfusion injury. This dissertation provides clues to additional opportunities that could be translated into more efficient therapeutic approaches towards ischemia reperfusion injury.
Ischemic-hypoxic injury is caused by diminished or absent blood flow and result of oxygen deprivation (e.g. stroke, heart attack). It encompasses a complex constellation of pathophysiological and molecular injuries, if left untreated can result in death. In this dissertation we studied therapeutic mechanisms that might be protective against ischemia reperfusion injury in order to enhance both our knowledge of ischemia reperfusion injury pathophysiology and mechanisms of protection. Clinical hypothermia is considered as one of the most effective intervention for a range of hypoxic ischemic pathologies of the central nervous system, however, the mechanisms that underlie its protective effects are uncertain. Currently, it is widely accepted that therapeutic effects of hypothermia are due to reduced metabolism and oxygen consumption. Our study demonstrates for the first time that mild hypothermia activates major transcription factors Nrf2 and HIF1A, which orchestrate adaptive responses to hypoxic stress. Hydrogen sulfide (H2S) is now recognized as a novel gaseous signaling molecule along with nitric oxide and carbon monoxide, although it was considered to be a toxic gas for hundreds of years. We show here that not only does H2S regulate mitochondrial biogenesis via AMPK-PGC1α signaling pathway but also that correcting H2S levels with SG-1002 (H2S-releasing prodrug) could protect against heart failure. The lymphatic system has been suggested to play an important role in cardiovascular disease. Our results show that inhibition of cardiac lymphangiogenesis exaggerates ischemia reperfusion injury even more. Furthermore, stimulation of cardiac lymphangiogenesis with VEGF-C improves cardiac function following ischemia reperfusion injury. This dissertation provides clues to additional opportunities that could be translated into more efficient therapeutic approaches towards ischemia reperfusion injury.
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Keywords
südame isheemiatõbi, isheemia-reperfusiooni kahjustus, molekulaarmehhanismid, hüpotermia, vesiniksulfiid, lümfisüsteem, adenosiinmonofosfaat, proteiinkinaasid