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Under physiological circumstances, there is an exquisite balance between reactive oxygen species (ROS) production and ROS degradation, resulting in low steady-state ROS levels. ROS participate in normal cellular function and in cellular homeostasis. Oxidative stress is the state of a transient or a persistent increase of steady-state ROS levels leading to disturbed signaling pathways and oxidative modification of cellular constituents. It is a key pathophysiological player in pathological hypertrophy, pathological remodeling, and the development and progression of heart failure. The heart is the metabolically most active organ and is characterized by the highest content of mitochondria of any tissue. Mitochondria are the main source of ROS in the myocardium. The causal role of oxidative stress in heart failure is highlighted by gene transfer studies of three primary antioxidant enzymes, thioredoxin, and heme oxygenase-1, and is further supported by gene therapy studies directed at correcting oxidative stress linked to metabolic risk factors. Moreover, gene transfer studies have demonstrated that redox-sensitive microRNAs constitute potential therapeutic targets for the treatment of heart failure. In conclusion, gene therapy studies have provided strong corroborative evidence for a key role of oxidative stress in pathological remodeling and in the development of heart failure.

40層細(xì)胞工廠

在生理環(huán)境下，活性氧 (ROS) 的產(chǎn)生和 ROS 降解之間存在微妙的平衡，導(dǎo)致穩(wěn)態(tài) ROS 水平較低。ROS 參與正常的細(xì)胞功能和細(xì)胞穩(wěn)態(tài)。氧化應(yīng)激是穩(wěn)態(tài) ROS 水平短暫或持續(xù)增加的狀態(tài)，導(dǎo)致信號通路紊亂和細(xì)胞成分的氧化修飾。它是病理性肥大、病理性重塑以及心力衰竭的發(fā)展和進(jìn)展的關(guān)鍵病理生理參與者。心臟是代謝最活躍的器官，其特征是所有組織中線粒體含量最高。線粒體是心肌中 ROS 的主要來源。三種主要抗氧化酶硫氧還蛋白和血紅素加氧酶-1 的基因轉(zhuǎn)移研究強(qiáng)調(diào)了氧化應(yīng)激在心力衰竭中的因果作用，并得到了旨在糾正與代謝風(fēng)險因素相關(guān)的氧化應(yīng)激的基因治療研究的進(jìn)一步支持。此外，基因轉(zhuǎn)移研究表明，氧化還原敏感的 microRNA 是治療心力衰竭的潛在治療靶點(diǎn)?？傊蛑委熝芯繛檠趸瘧?yīng)激在病理重塑和心力衰竭發(fā)展中的關(guān)鍵作用提供了強(qiáng)有力的佐證?；蜣D(zhuǎn)移研究表明，氧化還原敏感的 microRNA 是治療心力衰竭的潛在治療靶點(diǎn)?？傊蛑委熝芯繛檠趸瘧?yīng)激在病理重塑和心力衰竭發(fā)展中的關(guān)鍵作用提供了強(qiáng)有力的佐證?；蜣D(zhuǎn)移研究表明，氧化還原敏感的 microRNA 是治療心力衰竭的潛在治療靶點(diǎn)?？傊蛑委熝芯繛檠趸瘧?yīng)激在病理重塑和心力衰竭發(fā)展中的關(guān)鍵作用提供了強(qiáng)有力的佐證。

Gene transfer studies have provided strong corroborative evidence for a key role of oxidative stress in pathological cardiac hypertrophy and remodeling and in the development of heart failure. Since the heart is the metabolically most active organ and is characterized by the highest content of mitochondria of any tissue, this organ is very susceptible and vulnerable to oxidative stress. Oxidative stress not only causes protein oxidation, lipid peroxidation, and DNA damage but also oxidative changes of microRNAs [5,11]. The key pathogenetic role of oxidative changes of microRNAs has been unequivocally demonstrated [11].

Furthermore, the cellular levels of redox-sensitive microRNAs are altered in response to oxidative stress, and increasing evidence indicates that these redox-sensitive microRNAs constitute potential therapeutic targets for the treatment of heart failure [105,121,122,123]. The causal role of oxidative stress in heart failure is also supported by gene transfer studies of the three primary antioxidant enzymes (SODs, catalase, and glutathione peroxidase), of thioredoxin, and of heme oxygenase-1. Finally, multiple gene transfer prevention and intervention studies have demonstrated that gene therapy directed at the correction of metabolic risk factors resulted in a marked reduction of systemic oxidative stress and oxidative stress in the myocardium [63,64]. This correction of metabolic risk factors also resulted in improved cardiac function and prevention or reversal of pathological remodeling and heart failure [63,64]. The broad robustness of the strong link between reduction of oxidative stress and prevention and treatment of heart failure suggests that reduction of oxidative stress is an important mediator of the observed effects of metabolic gene therapy on cardiac structure and function.

Heart failure is the cardiovascular epidemic of this century and has a rather dismal prognosis [124]. The development of gene transfer strategies that result in an improved cellular redox state remains an important research area in the generation of new treatments for heart failure.

Author Contributions

B.D.G. conceived the present review. B.D.G. and M.M. did the research, wrote the manuscript, and drew the figures. The intellectual content of the final version of the manuscript was checked by both authors. All authors have read and agreed to the published version of the manuscript.

細(xì)胞轉(zhuǎn)瓶2L

基因轉(zhuǎn)移研究為氧化應(yīng)激在病理性心臟肥大和重塑以及心力衰竭發(fā)展中的關(guān)鍵作用提供了強(qiáng)有力的佐證。由于心臟是代謝最活躍的器官，其特征是任何組織中線粒體含量最高，因此該器官非常容易受到氧化應(yīng)激的影響。氧化應(yīng)激不僅會導(dǎo)致蛋白質(zhì)氧化、脂質(zhì)過氧化和 DNA 損傷，還會導(dǎo)致 microRNA 的氧化變化。microRNA 氧化變化的關(guān)鍵致病作用已得到明確證明。

此外，氧化還原敏感 microRNA 的細(xì)胞水平會因氧化應(yīng)激而發(fā)生改變，越來越多的證據(jù)表明這些氧化還原敏感 microRNA 是治療心力衰竭的潛在治療靶點(diǎn)。三種主要抗氧化酶（SOD、過氧化氫酶和谷胱甘肽過氧化物酶）、硫氧還蛋白和血紅素加氧酶-1 的基因轉(zhuǎn)移研究也支持氧化應(yīng)激在心力衰竭中的因果作用。最后，多項(xiàng)基因轉(zhuǎn)移預(yù)防和干預(yù)研究表明，針對代謝危險因素糾正的基因治療可顯著減少心肌中的全身氧化應(yīng)激和氧化應(yīng)激。這種代謝危險因素的糾正還導(dǎo)致心臟功能的改善以及病理重塑和心力衰竭的預(yù)防或逆轉(zhuǎn)。減少氧化應(yīng)激與預(yù)防和治療心力衰竭之間的密切聯(lián)系的廣泛穩(wěn)健性表明，減少氧化應(yīng)激是觀察到的代謝基因治療對心臟結(jié)構(gòu)和功能的影響的重要介質(zhì)。

心力衰竭是本世紀(jì)的心血管流行病，預(yù)后相當(dāng)差。導(dǎo)致細(xì)胞氧化還原狀態(tài)改善的基因轉(zhuǎn)移策略的開發(fā)仍然是產(chǎn)生心力衰竭新療法的重要研究領(lǐng)域。

來源: MDPI  https://www.mdpi.com/2227-9059/9/11/1645/htm

關(guān)鍵詞：gene therapy; gene transfer; heart failure; oxidative stress; reactive oxygen species; cardiac hypertrophy; cardiac remodeling; microRNA

             基因治療；基因轉(zhuǎn)移；心力衰竭；氧化應(yīng)激；活性氧；心臟肥大；心臟重塑；微小RNA