Nrf2 for cardiac protection: pharmacological options against oxidative stress

氧化应激 促炎细胞因子 转录因子 细胞生物学 活性氧 线粒体ROS 线粒体 生物 化学 氧化磷酸化 生物化学 炎症 免疫学 基因
作者
Qin M. Chen
出处
期刊:Trends in Pharmacological Sciences [Elsevier BV]
卷期号:42 (9): 729-744 被引量:79
标识
DOI:10.1016/j.tips.2021.06.005
摘要

Myocardial ischemic reperfusion leads to increased oxidative stress and cell death by necrosis, apoptosis, and necroptosis. During oxidative stress, the activity of Nrf2 as a transcription factor is regulated by protein stability, translation, nuclear localization, and protein–protein interactions. The Nrf2 transcription factor controls the expression of key components in eight antioxidant and redox systems for the removal of reactive oxygen species. The genes under the influence of Nrf2 status suggest its involvement in mitochondrial turnover, tissue recovery, repair, or remodeling, metabolic reprogramming, and the limitation of proinflammatory cytokines. Small-molecule Nrf2 inducers have shown promise in eliciting cardiac protection and inhibiting inflammation in experimental animals, suggesting a future direction for the development of nontoxic Nrf2 inducers using modern technologies. Myocardial ischemia or reperfusion increases the generation of reactive oxygen species (ROS) from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. ROS can be removed by eight endogenous antioxidant and redox systems, many components of which are expressed under the influence of the activated Nrf2 transcription factor. Transcriptomic profiling, sequencing of Nrf2-bound DNA, and Nrf2 gene knockout studies have revealed the power of Nrf2 beyond the antioxidant and detoxification response, from tissue recovery, repair, and remodeling, mitochondrial turnover, and metabolic reprogramming to the suppression of proinflammatory cytokines. Multifaceted regulatory mechanisms for Nrf2 protein levels or activity have been mapped to its functional domains, Nrf2-ECH homology (Neh)1–7. Oxidative stress activates Nrf2 via nuclear translocation, de novo protein translation, and increased protein stability due to removal of the Kelch-like ECH-associated protein 1 (Keap1) checkpoint, or the inactivation of β-transducin repeat-containing protein (β-TrCP), or Hmg-CoA reductase degradation protein 1 (Hrd1). The promise of small-molecule Nrf2 inducers from natural products or derivatives is discussed here. Experimental evidence is presented to support Nrf2 as a lead target for drug development to further improve the treatment outcome for myocardial infarction (MI). Myocardial ischemia or reperfusion increases the generation of reactive oxygen species (ROS) from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. ROS can be removed by eight endogenous antioxidant and redox systems, many components of which are expressed under the influence of the activated Nrf2 transcription factor. Transcriptomic profiling, sequencing of Nrf2-bound DNA, and Nrf2 gene knockout studies have revealed the power of Nrf2 beyond the antioxidant and detoxification response, from tissue recovery, repair, and remodeling, mitochondrial turnover, and metabolic reprogramming to the suppression of proinflammatory cytokines. Multifaceted regulatory mechanisms for Nrf2 protein levels or activity have been mapped to its functional domains, Nrf2-ECH homology (Neh)1–7. Oxidative stress activates Nrf2 via nuclear translocation, de novo protein translation, and increased protein stability due to removal of the Kelch-like ECH-associated protein 1 (Keap1) checkpoint, or the inactivation of β-transducin repeat-containing protein (β-TrCP), or Hmg-CoA reductase degradation protein 1 (Hrd1). The promise of small-molecule Nrf2 inducers from natural products or derivatives is discussed here. Experimental evidence is presented to support Nrf2 as a lead target for drug development to further improve the treatment outcome for myocardial infarction (MI). elevated in the blood of MI patients. Two isoforms, cTnI and cTnT, are commonly used for blood tests to determine whether chest-pain patients are undergoing a MI. Recently, high-sensitivity cTn tests have been implemented in hospitals across Europe, the USA, and many other countries, providing a useful tool for the early diagnosis of MI. CDDO-Me is 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, also known as bardoxolone methyl or RTA402, a synthetic triterpenoid modified from oleanolic acid. CDDO-Im is its imidazolide form, 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole, also known as RTA403. RTA408 (i.e., omaveloxolone) is a second-generation synthetic triterpenoid derivative of oleanolic acid. These compounds have been developed for clinical applications by Reata Pharmaceuticals and are therefore named after the abbreviation of the company. open heart surgery to restore or improve blood flow downstream of one or more obstructed coronary arteries. a biomarker for cardiac injury. The value of CK-MB can vary and assay sensitivity is low with potential nonspecificity. Muscle injury or kidney injury also causes elevation of CK-MB in the blood. This biomarker is viewed as a reference instead of a diagnostic tool for cardiac injury in patients. Blood levels of CK-MB are often measured in animal experiments with induced myocardial injury. interventricular artery; supplies blood to the muscle of the left ventricle and interventricular septum. Surgical occlusion of the LAD in a beating heart is a routine method to induce myocardial ischemia in experimental animals for studies of MI and its long-term effects such as heart failure. commonly known as a heart attack. Blockage of a coronary artery causes ischemia of the downstream tissue and is the prevalent cause of MI. Often, blood clots obstruct the coronary artery as a result of the erosion or rupture of an atherosclerotic plaque. Among the typical symptoms are chest pain, upper-body discomfort, abnormal heartbeat, shortness of breath, and nausea. MI has a high mortality rate if not treated immediately. Patients who have survived MI are at a high risk of developing heart failure over time. also known as angioplasty; a non-surgical procedure for opening of the coronary artery to resume blood flow using a catheter to implant a stent. a well-established Nrf2 inducer, known to alkylate Keap1 protein at cysteine residues. Cruciferous vegetables (e.g., broccoli, arugula, brussels sprouts, cabbage) are rich in glucosinolates. Hydrolysis of glucosinolates in plant cells or by microflora of the human gastrointestinal track produces isothiocyanates. Young broccoli plants contain glucoraphanin, which can be converted to SFN, an isothiocyanate organosulfur compound.
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