6月19日，自然出版集團子刊Cell Death and Disease在線發(fā)表了健康科學(xué)研究所楊黃恬研究組題為
“Concentration-dependent wrestling between detrimental and
protective effects of H2O2 during myocardial ischemia/reperfusion”
的最新研究成果，揭示了H2O2在心肌缺血復(fù)灌(ischemia/reperfusion,
I/R)過程中濃度依賴的損傷與保護的雙重作用和不同的作用機制。
心肌梗塞后及時恢復(fù)缺血區(qū)的血供(再灌注)是挽救缺血心肌的必需步驟，但該過程伴隨著嚴(yán)重再灌注損傷的發(fā)生。再灌注初期活性氧(reactive
oxygen species,
ROS)的大量釋放被認(rèn)為是造成這一損傷的主要因素之一。然而，ROS也作為啟動者介導(dǎo)了缺血預(yù)處理(ischemic
preconditioning, IPC)和后處理(ischemic postcondition,
IPoC)等措施對抗心肌I/R損傷的保護作用。為了解釋ROS 這種相互矛盾的雙重作用，研究者提出了一種假設(shè)，即低濃度ROS
作為第二信使參與了心肌保護作用，而高濃度ROS 則導(dǎo)致細(xì)胞損傷，但如何界定ROS
起損傷或保護作用濃度界限目前尚無明確的研究，而且該理論無法完美解釋眾多應(yīng)用抗氧化劑的臨床實驗沒有顯著心肌保護作用的事實。
博士研究生王志華、劉金龍等在楊黃恬研究員的指導(dǎo)下發(fā)現(xiàn)H2O2PC和PoC在10-100
mol/L濃度依賴地激活RISK信號通路、抑制其下游的糖原合成酶激酶(glycogen synthase kinase, GSK)3-
活性，進而改善I/R后心功能；而低濃度(1-3 mol/L)及高濃度(1 mmol/Lol/L)
H2O2他則通過不同的機制加重了I/R后心功能不全。低濃度H2O2PC和PoC (1-3 mol/L)
通過進一步上調(diào)心肌I/R導(dǎo)致的ER stress加重了I/R后心肌損傷，該效應(yīng)在3 mol/L
H2O2處理下達到平臺期；而高濃度H2O2 (≧100
mol/L)則通過促進氧化應(yīng)激反應(yīng)加重I/R后心肌損傷。研究發(fā)現(xiàn)證明了濃度是決定ROS不同作用的重要因素之一，揭示了ROS導(dǎo)致心肌I/R損傷和保護作用的濃度閾值和其內(nèi)在機制，其最終表現(xiàn)是不同濃度ROS啟動/激活的損傷與保護通路博弈的結(jié)果。研究發(fā)現(xiàn)還為解釋ROS矛盾作用的機理提供了新的視角，并為開發(fā)基于ROS的缺血性心臟病的治療措施提供了新的實驗證據(jù)。
此研究得到了國家自然科學(xué)基金委和國家科技部973項目的資助。
論文在線發(fā)表網(wǎng)址：http://www.nature.com/cddis/journal/v5/n6/full/cddis2014267a.html
Z-H Wang, J-L Liu, L Wu, Z Yu and H-T Yang, Concentration-dependent
wrestling between detrimental and protective effects of H2O2 during
myocardial ischemia/reperfusion. Cell Death and Disease (2014) 5,
e1297
Concentration-dependent wrestling between detrimental and
protective effects of H2O2 during myocardial ischemia/reperfusion
Reperfusion injury after acute myocardial ischemia is a complex
phenomenon that consists of mechanical dysfunction and cell death.
Reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress
are paradoxically implicated in myocardial ischemia/reperfusion
(I/R) injury and cardioprotection. However, the precise
interpretation for the dual role of ROS and its relationship with
the ER stress during I/R remain elusive.
To solve these issues, a team of researchers, led by Dr.
Huangtian Yang, at the Institute of Health Science, investigated
the concentration-dependent effects of hydrogen peroxide (H2O2)
preconditioning (PC) and postconditioning (PoC) on the ER stress
and pro-survival reperfusion injury salvage kinases (RISK)
activation using an ex vivo rat myocardial I/R model. They showed
three phases in the effects of H2O2PC and PoC in myocardial I/R
injury and protection. H2O2PC and PoC at the moderate level
(10-300 mol/L) concentration-dependently improved the
post-ischemic recovery of cardiac performance though the activation
of RISK pathway. In contrast, H2O2 exacerbated I/R-induced
contractile dysfunction via the enhancement of I/R-induced ER
stress at the low level (1 M), and promoted the oxidative
stress at the high level (≧100 mol/L). These findings
demonstrate that the differential effects of H2O2 are derived from
a quantity-dependent wrestling between its detrimental and
signaling roles. This study provides a new angle to interpret the
controversial roles of ROS in myocardial I/R and suggests a hint
for cardiologists to reconsider the clinical translation of
cardioprotective strategies.
This study entitled “Concentration-dependent wrestling between
detrimental and protective effects of H2O2 during myocardial
ischemia/reperfusion” was published online in Cell Death and
Disease on Jun 19, 2014, and was supported by the Major State Basic
Research Development Program of China, National Natural Sciences
Foundation of China, and National Science and Technology Major
Project of China.
