Liproxstatin-1 protects the mouse myocardium against ischemia/reperfusion injury by decreasing VDAC1 levels and restoring GPX4 levels

Feng, Yan; Madungwe, Ngonidzashe B; Aliagan, Abdulhafiz Imam; Tombo, Nathalie; Bopassa, Jean C.

doi:10.1016/j.bbrc.2019.10.006

Cited by 186 publications

(149 citation statements)

References 27 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…H9c2 cells were lysed in a buffer containing (150 mM NaCl, 50 mM Tris, 5 mM EDTA, 10 mM Hepes, 0.1% octylphenylpolyethylene glycol (IGEPAL CA-630), 0.25% sodium deoxycholate, pH 7.4, supplemented with Complete Protease Inhibitor Cocktail Tablets. Whole-cell lysates were centrifuged at 13,000 × g, for 10 min at 4 • C. Equal amounts (40 µg) of proteins were loaded in each well of 4-20% Tris-glycine gels (Bio-Rad) and subjected to electrophoresis for 90 min at 125 V of constant voltage as described previously (55). Gels were transferred onto a nitrocellulose membrane by electrophoretic transfer at 90 V of constant voltage for 90 min.…”

Section: Western Blot Analysismentioning

confidence: 99%

Chronic GPER1 Activation Protects Against Oxidative Stress-Induced Cardiomyoblast Death via Preservation of Mitochondrial Integrity and Deactivation of Mammalian Sterile-20-Like Kinase/Yes-Associated Protein Pathway

et al. 2020

Self Cite

View full text Add to dashboard Cite

Introduction: Estrogen (17β-estradiol, E2) is well-known to induce cardioprotective effects against ischemia/reperfusion (I/R) injury. We recently reported that acute application of E2 at the onset of reperfusion in vivo induces cardioprotective effects against I/R injury via activation of its non-steroidal receptor, G protein-coupled estrogen receptor 1 (GPER1). Here, we investigated the impact and mechanism underlying chronic GPER1 activation in cultured H9c2 rat cardiomyoblasts. Methods: H9c2 rat cardiomyoblasts were cultured and pretreated with the cytotoxic agent H 2 O 2 for 24 h and incubated in the presence of vehicle (control), GPER1 agonists E2 and G1, or GPER1 agonists supplemented with G15 (GPER1 antagonist) for 48 or 96 h. After treatment, cells were collected to measure the rate of cell death and viability using flow cytometry and Calcein AM assay or MTT assay, respectively. The resistance to opening of the mitochondrial permeability transition pore (mPTP), the mitochondrial membrane potential, and ATP production was assessed using fluorescence microscopy, and the mitochondrial structural integrity was observed with electron microscopy. The levels of the phosphorylation of mammalian sterile-20-like kinase (MST1) and yes-associated protein (YAP) were assessed by Western blot analysis in whole-cell lysate, while the expression levels of mitochondrial biogenesis genes, YAP target genes, and proapoptotic genes were measured by qRT-PCR. Results: We found that after H 2 O 2 treatment, chronic E2/G1 treatment decreased cell death effect was associated with the prevention of the S phase of the cell cycle arrest compared to control. In the mitochondria, chronic E2/G1 activation treatment preserved the cristae morphology, and increased resistance to opening of mPTP, but Imam Aliagan et al. Chronic GPER1 Actions and Cell Death with little change to mitochondrial fusion/fission. Additionally, chronic E2/G1 treatment predominantly reduced phosphorylation of MST1 and YAP, as well as increased MST1 and YAP protein levels. E2 treatment also upregulated the expression levels of TGFβ and PGC-1α mRNAs and downregulated PUMA and Bim mRNAs. Except for ATP production, all the E2 or G1 effects were prevented by the cotreatment with the GPER1 antagonist, G15. Conclusion: Together, these results indicate that chronic GPER1 activation with its agonists E2 or G1 treatment protects H9c2 cardiomyoblasts against oxidative stressinduced cell death and increases cell viability by preserving mitochondrial structure and function as well as delaying the opening of mPTP. These chronic GPER1 effects are associated with the deactivation of the non-canonical MST1/YAP mechanism that leads to genetic upregulation of cell growth genes (CTGF, CYR61, PGC-1α, and ANKRD1), and downregulation of proapoptotic genes (PUMA and Bim).

show abstract

Section: Western Blot Analysismentioning

confidence: 99%

Chronic GPER1 Activation Protects Against Oxidative Stress-Induced Cardiomyoblast Death via Preservation of Mitochondrial Integrity and Deactivation of Mammalian Sterile-20-Like Kinase/Yes-Associated Protein Pathway

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Ferroptosis, known as simultaneously occurring and mutually amplifying accumulation of redox-active iron, glutathione depletion, and lipid peroxidation [ 127 ], was identified in 2012 [ 128 ] and since that time it has been documented in several cardiac pathologies, including doxorubicin-induced cardiomyopathy [ 77 ] and acute I/R injury under conditions without metabolic disorders [ 77 , 129 ] as well as with diabetes [ 130 , 131 ], post-myocardial infarction heart failure in the early and middle stages [ 132 ], and in septic heart injury [ 133 ]. At a cellular level, ferroptosis has been found in various models of cardiomyocytes, such as H9c2 cells subjected to hypoxia/reoxygenation with normal and high glucose levels [ 130 , 131 ] and rat ventricular myocytes [ 132 ].…”

Section: Iron and Ferroptosis: A Less-known Form Of Cell Death Andmentioning

confidence: 99%

“…As mentioned above, ferroptosis has been found to underlie lethal injury of the heart due to both acute and chronic I/R and in various types of cardiomyopathies [ 77 , 102 , 129 , 130 , 131 , 132 ]. In contrast, targeting ferroptosis has been suggested as a feasible approach for managing these cardiac pathologies.…”

Section: Iron and Ferroptosis: A Less-known Form Of Cell Death Andmentioning

confidence: 99%

“…Other interventions with anti-ferroptotic effects include activation of mTOR [ 149 ] and inhibition of HO-1, causing heme degradation with resultant release of free iron (inhibitor zinc protoporphyrin IX) [ 77 , 151 , 154 ], as well as other lipid peroxidation inhibitors (liproxstatin-1) [ 129 ]. In summary, these findings concerning ferroptosis confirm a paradigm of an important role of nonapoptotic cell death in the heart [ 130 , 155 , 156 , 157 ] and indicate that pharmacological interventions targeting one of these necrotic-like cell death modes or multi-target approaches can affect cardiovascular mortality at a greater extent than it is in the case of caspase modulation.…”

Section: Iron and Ferroptosis: A Less-known Form Of Cell Death Andmentioning

confidence: 99%

See 1 more Smart Citation

The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection

Ravingerová

Kindernay

Barteková

et al. 2020

IJMS

106

105

View full text Add to dashboard Cite

Iron is an essential mineral participating in different functions of the organism under physiological conditions. Numerous biological processes, such as oxygen and lipid metabolism, protein production, cellular respiration, and DNA synthesis, require the presence of iron, and mitochondria play an important role in the processes of iron metabolism. In addition to its physiological role, iron may be also involved in the adaptive processes of myocardial “conditioning”. On the other hand, disorders of iron metabolism are involved in the pathological mechanisms of the most common human diseases and include a wide range of them, such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease, and accelerate the development of atherosclerosis. Furthermore, iron also exerts potentially deleterious effects that may be manifested under conditions of ischemia/reperfusion (I/R) injury, myocardial infarction, heart failure, coronary artery angioplasty, or heart transplantation, due to its involvement in reactive oxygen species (ROS) production. Moreover, iron has been recently described to participate in the mechanisms of iron-dependent cell death defined as “ferroptosis”. Ferroptosis is a form of regulated cell death that is distinct from apoptosis, necroptosis, and other types of cell death. Ferroptosis has been shown to be associated with I/R injury and several other cardiac diseases as a significant form of cell death in cardiomyocytes. In this review, we will discuss the role of iron in cardiovascular diseases, especially in myocardial I/R injury, and protective mechanisms stimulated by different forms of “conditioning” with a special emphasis on the novel targets for cardioprotection.

show abstract

“…Ferroptosis is a non-apoptotic cell death initiated by increased ROS production and mitochondrial deformities [61]. Liproxstatin-1 is a ferroptosis inhibitor, which was shown to protect the mouse myocardium against ischemia/reperfusion injury [62]. It was suggested that Liproxstatin-1 displays cytoprotective activity as a radical-trapping antioxidant (RTA) [63].…”

Section: Is It Possible To Identify Common Factors Playing a Role In mentioning

confidence: 99%

Cardiotoxicity and Heart Failure: Lessons from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Anticancer Drugs

Sachinidis

2020

Cells

View full text Add to dashboard Cite

Human-induced pluripotent stem cells (hiPSCs) are discussed as disease modeling for optimization and adaptation of therapy to each individual. However, the fundamental question is still under debate whether stem-cell-based disease modeling and drug discovery are applicable for recapitulating pathological processes under in vivo conditions. Drug treatment and exposure to different chemicals and environmental factors can initiate diseases due to toxicity effects in humans. It is well documented that drug-induced cardiotoxicity accelerates the development of heart failure (HF). Until now, investigations on the understanding of mechanisms involved in HF by anticancer drugs are hindered by limitations of the available cellular models which are relevant for human physiology and by the fact that the clinical manifestation of HF often occurs several years after its initiation. Recently, we identified similar genomic biomarkers as observed by HF after short treatment of hiPSCs-derived cardiomyocytes (hiPSC-CMs) with different antitumor drugs such as anthracyclines and etoposide (ETP). Moreover, we identified common cardiotoxic biological processes and signal transduction pathways which are discussed as being crucial for the survival and function of cardiomyocytes and, therefore, for the development of HF. In the present review, I discuss the applicability of the in vitro cardiotoxicity test systems as modeling for discovering preventive mechanisms/targets against cardiotoxicity and, therefore, for novel HF therapeutic concepts.

show abstract

Liproxstatin-1 protects the mouse myocardium against ischemia/reperfusion injury by decreasing VDAC1 levels and restoring GPX4 levels

Cited by 186 publications

References 27 publications

Chronic GPER1 Activation Protects Against Oxidative Stress-Induced Cardiomyoblast Death via Preservation of Mitochondrial Integrity and Deactivation of Mammalian Sterile-20-Like Kinase/Yes-Associated Protein Pathway

Chronic GPER1 Activation Protects Against Oxidative Stress-Induced Cardiomyoblast Death via Preservation of Mitochondrial Integrity and Deactivation of Mammalian Sterile-20-Like Kinase/Yes-Associated Protein Pathway

The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection

Cardiotoxicity and Heart Failure: Lessons from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Anticancer Drugs

Contact Info

Product

Resources

About