- Email: [email protected]
Control of protein cysteine oxidation in lung fibrosis via a coordinated network of protein disulfide oxidoreductases
S28
A. Newman / Free Radical Biology and Medicine 128 (2018) S21–S46
Results: PKM2 induction, -glutathionylation, and phosphorylation were all enhanced in metabolically stressed BMDMs but prevented in Grx1overexpressing BMDMs. The dimer/tetramer ratio was increased in response to metabolic stress as was HIF1a-dependent expression of GLUT1 and IL-1b. Compared to monocytes isolated from HFD-fed mice, monocyte from Grx1Mactg mice showed reduced priming, reduced expression of PKM2, GLUT1 and IL-1b and diminished PKM2 phosphorylation. Conclusion: Metabolic stress-induced PKM2 S-glutathionylation promotes PKM2 tetramer dissociation, phosphorylation and subsequent nuclear translocation, which, via HIF1a-dependent expression of glycolytic enzymes and inflammatory cytokines, reprograms monocyte-derived macrophages into a hyper-inflammatory phenotype. This mechanism may contribute to chronic inflammatory diseases associated with metabolic disorders.
https://doi.org/10.1016/j.freeradbiomed.2018.10.022
21
Reevaluation of hemodialysis effects on oxidative stress Aki Hirayama 1, n, Yumiko Nagano 1, Satomi Akazaki 2, Atsushi Ueda 3, Hirofumi Matsui 4, Kazumasa Aoyagi 1, Shigeru Oowada 5, Keizo Sato 2 1
Tsukuba University of Technology, Japan Kyushu University of Health and Welfare, Japan 3 University of Tsukuba Hospital Hitachi Medical Education and Research Center, Japan 4 University of Tsukuba, Japan 5 Asao Clinic, Japan 2
Patients with advanced-stage chronic renal failure (CKD) are exposed to strong oxidative stress, and hemodialysis (HD) is considered to improve this. Multiple reports have been published on this topic, including our previous reports (J Am Soc Nephrol1997). However, recent advances have revealed that the oxidative stress in CKD does not simply increase unidirectionally. By using the newly developed electron spin resonance (ESR)-based analytical methods, we reevaluated the effects of HD on the oxidative status of patients with CKD. Two methods, namely multiple free radical scavenging assay (MULTIS), which evaluates scavenging activities against multiple reactive oxygen species (ROS) using CYPMPO as a spin trap, and iStrap, which is a sensitive method to detect lipid-derived carbon-center radicals using a spin trapDPhPMPO, were used in this study. Thirty-three patients undergoing maintenance HDwere enrolled. Informed consent was obtained before the trial. Thirteen cases were complicated with type 2 diabetes. Confirming our previous result, serum hydroxyl radical scavenging activity was significantly improved after HD. By contrast, scavenging activities against alkoxyl and alkylperoxyl radicals were significantly reduced after HD, which suggests a deterioration of the radical scavenging system downstream of the radical chain reaction. These reductions in scavenging activities were more obvious in patients with diabetes. The changes in the signal intensity of DPhPMPO in the whole tested group varied, whereas that of the diabetic patients was increased after HD, consistent with the alkylperoxyl radical findings. The superoxide scavenging activity was higher in the CKD subjects than that in the non-CKD subjects before HD, which then decreased after HD. These results indicate that the HD process does not simply decrease oxidative stress. Although intensive improvements have been made on the materials used in the HD session, such as the dialyzer membranes, ROS downstream of radical chain reactions are still not adequately controlled.
https://doi.org/10.1016/j.freeradbiomed.2018.10.023
22
Lipid oxidation inactivates the anticoagulant function of protein Z-dependent protease inhibitor (ZPI) Xin Huangn, Steven Olson University of Illinois at Chicago, USA
Lipid oxidation due to oxidative stress plays an important role in the pathogenesis of inflammatory and thrombotic cardiovascular diseases. Several findings suggest that lipid peroxidation can alter the function of coagulation proteins and contribute to a hypercoagulable state, but the molecular mechanisms are unclear. Here, we report that oxidized phospholipids suppress the anticoagulant function of the serpin, protein Z-dependent protease inhibitor (ZPI), a specific inhibitor of membrane-associated factor Xa (FXa) that requires protein Z (PZ), phospholipid, and calcium as cofactors. We found that this suppression arises from a diminished ability of the oxidized membrane to function as a cofactor to promote ZPI inhibition of membranebound FXa, due fully or in part to the susceptibility of the bound ZPI-PZ complex to oxidative inactivation. Surprisingly, free ZPI was also susceptible to inactivation by oxidized membrane vesicles in the absence of calcium. Oxidized vesicles containing both Phosphatidylserine and polyunsaturated fatty acids were required to promoteinactivation of theZPIPZcomplexor free ZPI, indicating that binding of thePZ-complexedor freeZPIto peroxide-modified phospholipid vesicles mediates the inactivation. Heparin protected the ZPI-PZ complex and free ZPI from inactivation, suggesting that blocking the heparin-binding site on ZPI interferes with ZPI binding to lipid or to PZ. This was confirmed by direct lipid-binding experiments. Native PAGE indicated that oxidization induced dissociation of the ZPI-PZ complex and increased the negative charge of ZPI. We conclude that compromised ZPI anticoagulant function could contribute to thrombus initiation and growth in oxidative stress-induced cardiovascular diseases.
https://doi.org/10.1016/j.freeradbiomed.2018.10.024
23
Control of protein cysteine oxidation in lung fibrosis via a coordinated network of protein disulfide oxidoreductases Yvonne Janssen-Heiningern, Vikas Anathy, Evan Elko, Amit Kumar, Albert van der Vliet University of Vermont, USA
Pulmonary fibrosis (IPF) is a devastating progressive disease that is fatal within 3-5 years of diagnosis. We recently demonstrated increases in protein S-glutathionylation (PSSG) in lungs from patients with IPF which correlated with loss of lung function (Anathy, Nature Medicine 2018). We have also shown that PSSG in lung epithelial cells is controlled by glutaredoxin (GLRX) glutathione S-transferase P (GSTP), and protein disulfide isomerase A3 (PDIA3). Assessment of transcripts of these oxidoreductases in IPF lung tissues and controls revealed small but statistically significant increases in mRNA levels of PDIA3, whereas expression of GSTPand GLRXmRNAs was unchanged in IPF patients compared to controls. Despite the lack of GSTPmRNA expression changes in IPF, we have observed robust expression of GSTP in hyperplastic type II epithelial cells and in regions of
A. Newman / Free Radical Biology and Medicine 128 (2018) S21–S46
disease progression in IPF.Pharmacological inhibition of GSTP, using TLK117, a clinically applicable inhibitor of GSTP, protected against the progression of bleomycin-induced fibrosis in association with decreased S-glutathionylation (McMillan JCI Insight 2016). Despite slight changes in GLRXmRNA, GLRX enzymatic activity was strongly attenuated in lungs from patients with IPF. Administration of recombinant active Glrx to mice with pre-existing bleomycin or TGFB1-induced fibrosis reversed the existing increases in fibrosis in association with decreased S-glutathionylation. Similarly, epithelial specific ablation of Pdia3, or pharmacological inhibition of PDIs also attenuated bleomycin-induced lung epithelial apoptosis and fibrosis in mice. Collectively these findings suggest that multiple redox enzymes (PDIA3, GSTP, GLRX) act in concert to control the extent of S-glutathionylation, apoptosis and fibrogenesis. Coordinated targeting of this enzyme axis may provide a powerful strategy to restore redox homeostasis and reverse fibrosis. Our findings also indicate that global transcriptomics analyses in lung tissue homogenates may not identify relevant targets for pharmacological manipulation, given that PDIA3, GSTP, and GLRX activities, were found be a strong determinants of disease progression, instead of mRNA expression. Supported by NIH R35HL135828,R01HL085646,R01HL122383.
https://doi.org/10.1016/j.freeradbiomed.2018.10.025
24
4-HNE-mediated post-translational modulation of DICER in heart failure Ligia Kiyuna 1, n, Ian J MacRae 2, Che-Hong Chen 3, Daria Mochly-Rosen 3, Julio Cesar Ferreira 1 1
University of Sao Paulo, Brazil Scripps Research Institute, USA 3 Stanford University School of Medicine, USA 2
S29
25
Oxidative stress induced S-thiolation by glutathione and homocysteine Klaus Klarskovn, Grace Ahuie-Kouakou Université de Sherbrooke, Canada
Although Vitamin C (AA, ascorbic acid; ascorbate ion at physiological pH) has multiple functions in humans its primary role is most likely as antioxidant thereby protecting the organism against continuously produced oxidative stress. When ascorbate is oxidized it loses one electron to give an ascorbyl free radical (AR), which subsequently easily undergoes oxidation to dehydroascorbate (DHA). Both AR and DHA are rapidly reduced back to ascorbate by several enzymes including NADH-cytochrome b5 reductase, thioredoxin reductase, protein disulfide isomerase, glutaredoxin-1 (thioltransferase), some glutathione-S-transferases and small thiol containing molecules like glutathione (GSH) and homocysteine (HCY). Homocysteine is a non-protein amino acid, differing from cysteine by an additional –CH2- in the amino acid side-chain. There is a strong correlation between an elevated blood concentration of HCY and the risk of developing oxidative stress related pathologies including cardiovascular and neurological diseases. However, the mechanism(s) by which hyperhomocysteinemia induces endothelial and neurological dysfunction as well as the role of oxidative stress is still unknown. In this study, we demonstrate that DHA catalyses S-glutathionylation and S-homocysteinylation. Oxidative stress catalyzed heterodimer formation was investigated using DHA or hydrogen peroxide in the presence of both HCY and GSH. Interestingly, while hydrogen peroxide favors peptide S-glutathionylation the presence of DHA induces increased thiolation by homocysteine compared to by glutathione. Furthermore, both S-homocysteinylated peptide and Grx-1 can be glutathionylated by disulfide exchange with glutathione dimer. In contrast, preliminary results indicate that GSH reduces the S-homocysteinylated peptide without immediate peptide S-glutathionylation. Moreover, the sites of S-thiolation in recombinant Grx-1 was determined by LCMS/ MS analyses. The biological role and type of oxidative stress that direct posttranslational protein modifications remain to be further elucidated.
https://doi.org/10.1016/j.freeradbiomed.2018.10.027 4-hydroxy-2-nonenal (4-HNE) is a major by-product of lipid peroxidation, a process that is exacerbated under oxidative stress conditions. This aldehyde is a very reactive molecule associated with the establishment and progression of many diseases, including cardiovascular diseases. Using mass spectrometry analysis, our group has recently found that 4-HNE directly targets DICER— a critical enzyme for microRNA (miRNA) biology— in failing hearts. Considering that targeted deletion of DICER in the heart leads to dilated cardiomyopathy and heart failure (HF), we hypothesized that 4-HNE adducted DICER could compromise its function and drive cardiac dysfunction. In a post-myocardial infarction-induced HF animal model, we found that DICER activity dropped 46.5% (53,5% 73,9; n¼6) in failing hearts when compared to sham group, followed by a reduction in miRNA levels. Pharmacological activation of aldehyde dehydrogenase 2 (ALDH2), a key mitochondrial enzyme responsible for 4-HNE removal, prevented cardiac 4-HNE protein adduct accumulation and minimized DICER loss of activity (72,15% 714,6; n¼ 6) in heart failure. Consistent with our in vivo data, H9C2 myoblasts acutely exposed to 50mM 4-HNE showed an increase in 4-HNE-protein adducts followed by a 16,7% reduction (83,3% 71,2; n¼4) in DICER activity. Notably, in vitro experiments using recombinant protein revealed that 4-HNE directly interacts with DICER, and the formation of 4-HNE-DICER adduct causes loss of DICER enzymatic activity in a time- and concentration-dependent manner. Taken together, our findings using animal and cellular models suggest that DICER is impaired under acute and chronic (cardiac dysfunction) aldehyde load. Moreover, a better clearance of cardiac 4-HNE improves both DICER activity and heart failure outcome in rodents. Overall, a better understanding of post-translational DICER regulation and its impact on microRNA profiles will certainly contribute to the discovery/development of improved and novel therapeutic strategies to tackle heart failure.
https://doi.org/10.1016/j.freeradbiomed.2018.10.026
26
Trafficking of cholesterol hydroperoxides to macrophage mitochondria: implications for atherogenesis under oxidative stress Witold Korytowski 1, n, Pawel Pabisz 1, Katarzyna Wawak 1, Albert Girotti 2 1 2
Jagiellonian University, Poland Medical College of Wisconsin, USA
Under oxidative stress conditions associated with chronic inflammation and obesity, scavenger receptor-expressing macrophages in arterial subendothelial spaces can internalize oxidized low-density lipoprotein (oxLDL) in unregulated fashion, potentially giving rise to foam cell-containing atherosclerotic lesions (plaques). In addition to other oxidized lipids, oxLDL contains cholesterol oxides such as 7-hydroperoxide (7-OOH), 7-alcohol (7-OH), and 7-ketone (7¼O), all of which can be detected in atherosclerotic plaques. 7-OOH being highly reactive, generates 7-OH and 7¼ O via free radical redox turnover, so 7-OH/7¼ O levels typically far exceed those of 7-OOH. To limit adverse buildup of cholesterol and its oxides, macrophages export these lipids
A. Newman / Free Radical Biology and Medicine 128 (2018) S21–S46
Results: PKM2 induction, -glutathionylation, and phosphorylation were all enhanced in metabolically stressed BMDMs but prevented in Grx1overexpressing BMDMs. The dimer/tetramer ratio was increased in response to metabolic stress as was HIF1a-dependent expression of GLUT1 and IL-1b. Compared to monocytes isolated from HFD-fed mice, monocyte from Grx1Mactg mice showed reduced priming, reduced expression of PKM2, GLUT1 and IL-1b and diminished PKM2 phosphorylation. Conclusion: Metabolic stress-induced PKM2 S-glutathionylation promotes PKM2 tetramer dissociation, phosphorylation and subsequent nuclear translocation, which, via HIF1a-dependent expression of glycolytic enzymes and inflammatory cytokines, reprograms monocyte-derived macrophages into a hyper-inflammatory phenotype. This mechanism may contribute to chronic inflammatory diseases associated with metabolic disorders.
https://doi.org/10.1016/j.freeradbiomed.2018.10.022
21
Reevaluation of hemodialysis effects on oxidative stress Aki Hirayama 1, n, Yumiko Nagano 1, Satomi Akazaki 2, Atsushi Ueda 3, Hirofumi Matsui 4, Kazumasa Aoyagi 1, Shigeru Oowada 5, Keizo Sato 2 1
Tsukuba University of Technology, Japan Kyushu University of Health and Welfare, Japan 3 University of Tsukuba Hospital Hitachi Medical Education and Research Center, Japan 4 University of Tsukuba, Japan 5 Asao Clinic, Japan 2
Patients with advanced-stage chronic renal failure (CKD) are exposed to strong oxidative stress, and hemodialysis (HD) is considered to improve this. Multiple reports have been published on this topic, including our previous reports (J Am Soc Nephrol1997). However, recent advances have revealed that the oxidative stress in CKD does not simply increase unidirectionally. By using the newly developed electron spin resonance (ESR)-based analytical methods, we reevaluated the effects of HD on the oxidative status of patients with CKD. Two methods, namely multiple free radical scavenging assay (MULTIS), which evaluates scavenging activities against multiple reactive oxygen species (ROS) using CYPMPO as a spin trap, and iStrap, which is a sensitive method to detect lipid-derived carbon-center radicals using a spin trapDPhPMPO, were used in this study. Thirty-three patients undergoing maintenance HDwere enrolled. Informed consent was obtained before the trial. Thirteen cases were complicated with type 2 diabetes. Confirming our previous result, serum hydroxyl radical scavenging activity was significantly improved after HD. By contrast, scavenging activities against alkoxyl and alkylperoxyl radicals were significantly reduced after HD, which suggests a deterioration of the radical scavenging system downstream of the radical chain reaction. These reductions in scavenging activities were more obvious in patients with diabetes. The changes in the signal intensity of DPhPMPO in the whole tested group varied, whereas that of the diabetic patients was increased after HD, consistent with the alkylperoxyl radical findings. The superoxide scavenging activity was higher in the CKD subjects than that in the non-CKD subjects before HD, which then decreased after HD. These results indicate that the HD process does not simply decrease oxidative stress. Although intensive improvements have been made on the materials used in the HD session, such as the dialyzer membranes, ROS downstream of radical chain reactions are still not adequately controlled.
https://doi.org/10.1016/j.freeradbiomed.2018.10.023
22
Lipid oxidation inactivates the anticoagulant function of protein Z-dependent protease inhibitor (ZPI) Xin Huangn, Steven Olson University of Illinois at Chicago, USA
Lipid oxidation due to oxidative stress plays an important role in the pathogenesis of inflammatory and thrombotic cardiovascular diseases. Several findings suggest that lipid peroxidation can alter the function of coagulation proteins and contribute to a hypercoagulable state, but the molecular mechanisms are unclear. Here, we report that oxidized phospholipids suppress the anticoagulant function of the serpin, protein Z-dependent protease inhibitor (ZPI), a specific inhibitor of membrane-associated factor Xa (FXa) that requires protein Z (PZ), phospholipid, and calcium as cofactors. We found that this suppression arises from a diminished ability of the oxidized membrane to function as a cofactor to promote ZPI inhibition of membranebound FXa, due fully or in part to the susceptibility of the bound ZPI-PZ complex to oxidative inactivation. Surprisingly, free ZPI was also susceptible to inactivation by oxidized membrane vesicles in the absence of calcium. Oxidized vesicles containing both Phosphatidylserine and polyunsaturated fatty acids were required to promoteinactivation of theZPIPZcomplexor free ZPI, indicating that binding of thePZ-complexedor freeZPIto peroxide-modified phospholipid vesicles mediates the inactivation. Heparin protected the ZPI-PZ complex and free ZPI from inactivation, suggesting that blocking the heparin-binding site on ZPI interferes with ZPI binding to lipid or to PZ. This was confirmed by direct lipid-binding experiments. Native PAGE indicated that oxidization induced dissociation of the ZPI-PZ complex and increased the negative charge of ZPI. We conclude that compromised ZPI anticoagulant function could contribute to thrombus initiation and growth in oxidative stress-induced cardiovascular diseases.
https://doi.org/10.1016/j.freeradbiomed.2018.10.024
23
Control of protein cysteine oxidation in lung fibrosis via a coordinated network of protein disulfide oxidoreductases Yvonne Janssen-Heiningern, Vikas Anathy, Evan Elko, Amit Kumar, Albert van der Vliet University of Vermont, USA
Pulmonary fibrosis (IPF) is a devastating progressive disease that is fatal within 3-5 years of diagnosis. We recently demonstrated increases in protein S-glutathionylation (PSSG) in lungs from patients with IPF which correlated with loss of lung function (Anathy, Nature Medicine 2018). We have also shown that PSSG in lung epithelial cells is controlled by glutaredoxin (GLRX) glutathione S-transferase P (GSTP), and protein disulfide isomerase A3 (PDIA3). Assessment of transcripts of these oxidoreductases in IPF lung tissues and controls revealed small but statistically significant increases in mRNA levels of PDIA3, whereas expression of GSTPand GLRXmRNAs was unchanged in IPF patients compared to controls. Despite the lack of GSTPmRNA expression changes in IPF, we have observed robust expression of GSTP in hyperplastic type II epithelial cells and in regions of
A. Newman / Free Radical Biology and Medicine 128 (2018) S21–S46
disease progression in IPF.Pharmacological inhibition of GSTP, using TLK117, a clinically applicable inhibitor of GSTP, protected against the progression of bleomycin-induced fibrosis in association with decreased S-glutathionylation (McMillan JCI Insight 2016). Despite slight changes in GLRXmRNA, GLRX enzymatic activity was strongly attenuated in lungs from patients with IPF. Administration of recombinant active Glrx to mice with pre-existing bleomycin or TGFB1-induced fibrosis reversed the existing increases in fibrosis in association with decreased S-glutathionylation. Similarly, epithelial specific ablation of Pdia3, or pharmacological inhibition of PDIs also attenuated bleomycin-induced lung epithelial apoptosis and fibrosis in mice. Collectively these findings suggest that multiple redox enzymes (PDIA3, GSTP, GLRX) act in concert to control the extent of S-glutathionylation, apoptosis and fibrogenesis. Coordinated targeting of this enzyme axis may provide a powerful strategy to restore redox homeostasis and reverse fibrosis. Our findings also indicate that global transcriptomics analyses in lung tissue homogenates may not identify relevant targets for pharmacological manipulation, given that PDIA3, GSTP, and GLRX activities, were found be a strong determinants of disease progression, instead of mRNA expression. Supported by NIH R35HL135828,R01HL085646,R01HL122383.
https://doi.org/10.1016/j.freeradbiomed.2018.10.025
24
4-HNE-mediated post-translational modulation of DICER in heart failure Ligia Kiyuna 1, n, Ian J MacRae 2, Che-Hong Chen 3, Daria Mochly-Rosen 3, Julio Cesar Ferreira 1 1
University of Sao Paulo, Brazil Scripps Research Institute, USA 3 Stanford University School of Medicine, USA 2
S29
25
Oxidative stress induced S-thiolation by glutathione and homocysteine Klaus Klarskovn, Grace Ahuie-Kouakou Université de Sherbrooke, Canada
Although Vitamin C (AA, ascorbic acid; ascorbate ion at physiological pH) has multiple functions in humans its primary role is most likely as antioxidant thereby protecting the organism against continuously produced oxidative stress. When ascorbate is oxidized it loses one electron to give an ascorbyl free radical (AR), which subsequently easily undergoes oxidation to dehydroascorbate (DHA). Both AR and DHA are rapidly reduced back to ascorbate by several enzymes including NADH-cytochrome b5 reductase, thioredoxin reductase, protein disulfide isomerase, glutaredoxin-1 (thioltransferase), some glutathione-S-transferases and small thiol containing molecules like glutathione (GSH) and homocysteine (HCY). Homocysteine is a non-protein amino acid, differing from cysteine by an additional –CH2- in the amino acid side-chain. There is a strong correlation between an elevated blood concentration of HCY and the risk of developing oxidative stress related pathologies including cardiovascular and neurological diseases. However, the mechanism(s) by which hyperhomocysteinemia induces endothelial and neurological dysfunction as well as the role of oxidative stress is still unknown. In this study, we demonstrate that DHA catalyses S-glutathionylation and S-homocysteinylation. Oxidative stress catalyzed heterodimer formation was investigated using DHA or hydrogen peroxide in the presence of both HCY and GSH. Interestingly, while hydrogen peroxide favors peptide S-glutathionylation the presence of DHA induces increased thiolation by homocysteine compared to by glutathione. Furthermore, both S-homocysteinylated peptide and Grx-1 can be glutathionylated by disulfide exchange with glutathione dimer. In contrast, preliminary results indicate that GSH reduces the S-homocysteinylated peptide without immediate peptide S-glutathionylation. Moreover, the sites of S-thiolation in recombinant Grx-1 was determined by LCMS/ MS analyses. The biological role and type of oxidative stress that direct posttranslational protein modifications remain to be further elucidated.
https://doi.org/10.1016/j.freeradbiomed.2018.10.027 4-hydroxy-2-nonenal (4-HNE) is a major by-product of lipid peroxidation, a process that is exacerbated under oxidative stress conditions. This aldehyde is a very reactive molecule associated with the establishment and progression of many diseases, including cardiovascular diseases. Using mass spectrometry analysis, our group has recently found that 4-HNE directly targets DICER— a critical enzyme for microRNA (miRNA) biology— in failing hearts. Considering that targeted deletion of DICER in the heart leads to dilated cardiomyopathy and heart failure (HF), we hypothesized that 4-HNE adducted DICER could compromise its function and drive cardiac dysfunction. In a post-myocardial infarction-induced HF animal model, we found that DICER activity dropped 46.5% (53,5% 73,9; n¼6) in failing hearts when compared to sham group, followed by a reduction in miRNA levels. Pharmacological activation of aldehyde dehydrogenase 2 (ALDH2), a key mitochondrial enzyme responsible for 4-HNE removal, prevented cardiac 4-HNE protein adduct accumulation and minimized DICER loss of activity (72,15% 714,6; n¼ 6) in heart failure. Consistent with our in vivo data, H9C2 myoblasts acutely exposed to 50mM 4-HNE showed an increase in 4-HNE-protein adducts followed by a 16,7% reduction (83,3% 71,2; n¼4) in DICER activity. Notably, in vitro experiments using recombinant protein revealed that 4-HNE directly interacts with DICER, and the formation of 4-HNE-DICER adduct causes loss of DICER enzymatic activity in a time- and concentration-dependent manner. Taken together, our findings using animal and cellular models suggest that DICER is impaired under acute and chronic (cardiac dysfunction) aldehyde load. Moreover, a better clearance of cardiac 4-HNE improves both DICER activity and heart failure outcome in rodents. Overall, a better understanding of post-translational DICER regulation and its impact on microRNA profiles will certainly contribute to the discovery/development of improved and novel therapeutic strategies to tackle heart failure.
https://doi.org/10.1016/j.freeradbiomed.2018.10.026
26
Trafficking of cholesterol hydroperoxides to macrophage mitochondria: implications for atherogenesis under oxidative stress Witold Korytowski 1, n, Pawel Pabisz 1, Katarzyna Wawak 1, Albert Girotti 2 1 2
Jagiellonian University, Poland Medical College of Wisconsin, USA
Under oxidative stress conditions associated with chronic inflammation and obesity, scavenger receptor-expressing macrophages in arterial subendothelial spaces can internalize oxidized low-density lipoprotein (oxLDL) in unregulated fashion, potentially giving rise to foam cell-containing atherosclerotic lesions (plaques). In addition to other oxidized lipids, oxLDL contains cholesterol oxides such as 7-hydroperoxide (7-OOH), 7-alcohol (7-OH), and 7-ketone (7¼O), all of which can be detected in atherosclerotic plaques. 7-OOH being highly reactive, generates 7-OH and 7¼ O via free radical redox turnover, so 7-OH/7¼ O levels typically far exceed those of 7-OOH. To limit adverse buildup of cholesterol and its oxides, macrophages export these lipids