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Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion.

ABSTRACT: Ferroptosis is a recently identified form of regulated cell death defined by the iron-dependent accumulation of lipid reactive oxygen species. Ferroptosis has been studied in various diseases such as cancer, Parkinson's disease, and stroke. However, the exact function and mechanism of ferroptosis in ischemia/reperfusion (I/R) injury, especially in the intestine, remains unknown. Considering the unique conditions required for ferroptosis, we hypothesize that ischemia promotes ferroptosis immediately after intestinal reperfusion. In contrast to conventional strategies employed in I/R studies, we focused on the ischemic phase. Here we verified ferroptosis by assessing proferroptotic changes after ischemia along with protein and lipid peroxidation levels during reperfusion. The inhibition of ferroptosis by liproxstatin-1 ameliorated I/R-induced intestinal injury. Acyl-CoA synthetase long-chain family member 4 (ACSL4), which is a key enzyme that regulates lipid composition, has been shown to contribute to the execution of ferroptosis, but its role in I/R needs clarification. In the present study, we used rosiglitazone (ROSI) and siRNA to inhibit ischemia/hypoxia-induced ACSL4 in vivo and in vitro. The results demonstrated that ACSL4 inhibition before reperfusion protected against ferroptosis and cell death. Further investigation revealed that special protein 1 (Sp1) was a crucial transcription factor that increased ACSL4 transcription by binding to the ACSL4 promoter region. Collectively, this study demonstrates that ferroptosis is closely associated with intestinal I/R injury, and that ACSL4 has a critical role in this lethal process. Sp1 is an important factor in promoting ACSL4 expression. These results suggest a unique and effective mechanistic approach for intestinal I/R injury prevention and treatment.

SUBMITTER: Li Y

PROVIDER: S-EPMC6889315 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion.

Li Yang Y Feng Dongcheng D Wang Zhanyu Z Zhao Yan Y Sun Ruimin R Tian Donghai D Liu Deshun D Zhang Feng F Ning Shili S Yao Jihong J Tian Xiaofeng X

Cell death and differentiation 20190208 11

Ferroptosis is a recently identified form of regulated cell death defined by the iron-dependent accumulation of lipid reactive oxygen species. Ferroptosis has been studied in various diseases such as cancer, Parkinson's disease, and stroke. However, the exact function and mechanism of ferroptosis in ischemia/reperfusion (I/R) injury, especially in the intestine, remains unknown. Considering the unique conditions required for ferroptosis, we hypothesize that ischemia promotes ferroptosis immediat ...[more]

PMID: 30737476

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Project description:HJ11 is a novel traditional Chinese medicine developed from the appropriate addition and reduction of Si-Miao-Yong-An decoction, which has been commonly used to treat ischemia-reperfusion (I/R) injury in the clinical setting. However, the mechanism of action of HJ11 components remains unclear. Ferroptosis is a critical factor that promotes myocardial I/R injury, and the pathophysiological ferroptosis-mediated lipid peroxidation causes I/R injury. Therefore, this study explored whether HJ11 decoction ameliorates myocardial I/R injury by attenuating ACSL4-mediated ferroptosis. This study also explored the effect of ACSL4 expression on iron-dependent programmed cell death by preparing a rat model of myocardial I/R injury and oxygen glucose deprivation/reperfusion (OGD/R)-induced H9c2 cells. The results showed that HJ11 decoction improved cardiac function; attenuated I/R injury, apoptosis, oxidative stress, mitochondrial damage, and iron accumulation; and reduced infarct size in the myocardial I/R injury rat model. Additionally, HJ11 decoction suppressed the expression of ferroptosis-promoting proteins [Acyl-CoA synthetase long-chain family member 4 (ACSL4) and cyclooxygenase-2 (COX2)] but promoted the expression of ferroptosis-inhibiting proteins [ferritin heavy chain 1 (FTH1) and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4)] in the myocardial tissues of the I/R injury rat model. Similar results were found with the OGD/R-induced H9c2 cells. Interestingly, ACSL4 knockdown attenuated iron accumulation, oxidative stress, and ferroptosis in the OGD/R-treated H9c2 cells. However, ACSL4 overexpression counteracted the inhibitory effect of the HJ11 decoction on OGD/R-triggered oxidative stress and ferroptosis in H9c2 cells. These findings suggest that HJ11 decoction restrained the development of myocardial I/R injury by regulating ACSL4-mediated ferroptosis. Thus, HJ11 decoction may be an effective medication to treat myocardial I/R injury.

Project description:Myocardial ischemia-reperfusion (I/R) results in the generation of free radicals, accumulation of lipid peroxidation-derived unsaturated aldehydes, variable angina (pain), and infarction. The transient receptor potential ankyrin 1 (TRPA1) mediates pain signaling and is activated by unsaturated aldehydes, including acrolein and 4-hydroxynonenal. The contribution of TRPA1 (a Ca2+-permeable channel) to I/R-induced myocardial injury is unknown. We tested the hypothesis that cardiac TRPA1 confers myocyte sensitivity to aldehyde accumulation and promotes I/R injury. Although basal cardiovascular function in TRPA1-null mice was similar to that in wild-type (WT) mice, infarct size was significantly smaller in TRPA1-null mice than in WT mice (34.1?±?9.3 vs. 14.3?±?9.9% of the risk region, n = 8 and 7, respectively, P < 0.05), despite a similar I/R-induced area at risk (40.3?±8.4% and 42.2?±?11.3% for WT and TRPA1-null mice, respectively) after myocardial I/R (30 min of ischemia followed by 24 h of reperfusion) in situ. Positive TRPA1 immunofluorescence was present in murine and human hearts and was colocalized with connexin43 at intercalated disks in isolated murine cardiomyocytes. Cardiomyocyte TRPA1 was confirmed by quantitative RT-PCR, DNA sequencing, Western blot analysis, and electrophysiology. A role of TRPA1 in cardiomyocyte toxicity was demonstrated in isolated cardiomyocytes exposed to acrolein, an I/R-associated toxin that induces Ca2+ accumulation and hypercontraction, effects significantly blunted by HC-030031, a TRPA1 antagonist. Protection induced by HC-030031 was quantitatively equivalent to that induced by SN-6, a Na+/Ca2+ exchange inhibitor, further supporting a role of Ca2+ overload in acrolein-induced cardiomyocyte toxicity. These data indicate that cardiac TRPA1 activation likely contributes to I/R injury and, thus, that TRPA1 may be a novel therapeutic target for decreasing myocardial I/R injury. NEW & NOTEWORTHY Transient receptor potential ankyrin 1 (TRPA1) activation mediates increased blood flow, edema, and pain reception, yet its role in myocardial ischemia-reperfusion (I/R) injury is unknown. Genetic ablation of TRPA1 significantly decreased myocardial infarction after I/R in mice. Functional TRPA1 in cardiomyocytes was enriched in intercalated disks and contributed to acrolein-induced Ca2+ overload and hypercontraction. These data indicate that I/R activation of TRPA1 worsens myocardial infarction; TRPA1 may be a potential target to mitigate I/R injury.

Dataset Information

Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion.

Publications

Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion.

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