Competition through Dimerization between Antiapoptotic and Proapoptotic HS-1-associated Protein X-1 (Hax-1)

Koontz, Jason; Kontrogianni‐Konstantopoulos, Aikaterini

doi:10.1074/jbc.m113.536151

Cited by 21 publications

(21 citation statements)

References 46 publications

(61 reference statements)

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“…All these results supported our conclusion that the mitochondrial Omi/HtrA2 promotes cardiomyocytes apoptosis again. However, the exact mechanism by which HAX-1 is degraded by Omi/HtrA2 during ischemia/reperfusion injury is the subject of ongoing investigation, although recent evidence suggests that HAX-1 can either function as an anti- or pro-apoptotic regulator, and in turn influence cell survival or death, through homo- or heterodimerization39. Future studies are therefore needed to determine whether Omi/HtrA2 helps balance the formation of HAX-1 homo- or heterodimers in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction

Wang

Yuan

Liu

et al. 2016

Sci Rep

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Myocardial apoptosis is a significant problem underlying ischemic heart disease. We previously reported significantly elevated expression of cytoplasmic Omi/HtrA2, triggers cardiomyocytes apoptosis. However, whether increased Omi/HtrA2 within mitochondria itself influences myocardial survival in vivo is unknown. We aim to observe the effects of mitochondria-specific, not cytoplasmic, Omi/HtrA2 on myocardial apoptosis and cardiac function. Transgenic mice overexpressing cardiac-specific mitochondrial Omi/HtrA2 were generated and they had increased myocardial apoptosis, decreased systolic and diastolic function, and decreased left ventricular remodeling. Transiently or stably overexpression of mitochondria Omi/HtrA2 in H9C2 cells enhance apoptosis as evidenced by elevated caspase-3, -9 activity and TUNEL staining, which was completely blocked by Ucf-101, a specific Omi/HtrA2 inhibitor. Mechanistic studies revealed mitochondrial Omi/HtrA2 overexpression degraded the mitochondrial anti-apoptotic protein HAX-1, an effect attenuated by Ucf-101. Additionally, transfected cells overexpressing mitochondrial Omi/HtrA2 were more sensitive to hypoxia and reoxygenation (H/R) induced apoptosis. Cyclosporine A (CsA), a mitochondrial permeability transition inhibitor, blocked translocation of Omi/HtrA2 from mitochondrial to cytoplasm, and protected transfected cells incompletely against H/R-induced caspase-3 activation. We report in vitro and in vivo overexpression of mitochondrial Omi/HtrA2 induces cardiac apoptosis and dysfunction. Thus, strategies to directly inhibit Omi/HtrA2 or its cytosolic translocation from mitochondria may protect against heart injury.

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Section: Discussionmentioning

confidence: 99%

Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction

Wang

Yuan

Liu

et al. 2016

Sci Rep

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“…Furthermore, Hax1 gene mutations in humans lead to severe neutropenia and symptoms of immunodeficiency, neurological disease and neurodevelopment abnormalities [27–29]. In addition, Hax1 has multifunctional roles in other key cellular processes like calcium homeostasis and cell migration [27, 30]. Despite the reported prosurvival role of Hax1 various models [27], its function in cardiac cell apoptosis needs further elucidation.…”

Section: Introductionmentioning

confidence: 99%

“…Unlike mouse Hax1, the human and rat genes have been shown to be heavily spliced, giving rise to variants that display differences in the NH2 terminus [32]. Interestingly, Koontz and Kontrogianni-Konstantopoulos have reported that Hax1 is a family of anti- and proapoptotic proteins that may regulate cell fate via homo- or heterodimerization [30]. …”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells

Abdelwahid

et al. 2016

Apoptosis

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Cardiomyocyte apoptosis is a major process in pathogenesis of a number of heart diseases, including ischemic heart diseases and cardiac failure. Ensuring survival of cardiac cells by blocking apoptotic events is an important strategy to improve cardiac function. Although the role of ER disruption in inducing apoptosis has been demonstrated, we do not yet fully understand how it influences the mitochondrial apoptotic machinery in cardiac cell models. Recent investigations have provided evidences that the prosurvival protein HCLS1-associated protein X-1 (Hax1) protein is intimately associated with the pathogenesis of heart disease, mitochondrial biology, and protection from apoptotic cell death. To study the role of Hax1 upon ER stress induction, Hax1 was overexpressed in cardiac cells subjected to ER stress, and cell death parameters as well as mitochondrial alterations were examined. Our results demonstrated that the Hax1 is significantly downregulated in cardiac cells upon ER stress induction. Moreover, overexpression of Hax1 protected from apoptotic events triggered by Tunicamycin-induced ER stress. Upon treatment with Tunicamycin, Hax1 protected from mitochondrial fission, downregulation of mitofusins 1 and 2 (MFN1 and MFN2), loss of mitochondrial membrane potential (ΔΨm), production of reactive oxygen species (ROS) and apoptotic cell death. Taken together, our results suggest that Hax1 inhibits ER stress-induced apoptosis at both the pre- and post-mitochondrial levels. These findings may offer an opportunity to develop new agents that inhibit cell death in the diseased heart.

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“…The fluorescence intensity in each well is directly proportional to the ROS level within the cell cytosol. 58 In a separate experiment, the cells grown on the scaffolds for 48 h were stained with cell-permeant calcein AM dye (Life Technologies) to trace viability.…”

Section: Nanoscaffold/peptide Immune Toxicity Analysis Toward Mammalimentioning

confidence: 99%

Antifungal nanofibers made by controlled release of sea animal derived peptide

et al. 2015

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Candida albicans is a common human-pathogenic fungal species with the ability to cause several diseases including surface infections. Despite the clear difficulties of Candida control, antimicrobial peptides (AMPs) have emerged as an alternative strategy for fungal control. In this report, different concentrations of antifungal Cm-p1 (Cencritchis muricatus peptide 1) were electrospun into nanofibers for drug delivery. The nanofibers were characterized by mass spectrometry confirming the presence of the peptide on the scaffold. Atomic force microscopy and scanning electronic microscopy were used to measure the diameters, showing that Cm-p1 affects fiber morphology as well as the diameter and scaffold thickness. The Cm-p1 release behavior from the nanofibers demonstrated peptide release from 30 min to three days, leading to effective yeast control in the first 24 hours. Moreover, the biocompatibility of the fibers were evaluated through a MTS assay as well as ROS production by using a HUVEC model, showing that the fibers do not affect cell viability and only nanofibers containing 10% Cm-p1-PVA improved ROS generation. In addition, the secretion of pro-inflammatory cytokines IL-6 and TNF-α by the HUVECs was also slightly modified by the 10% Cm-p1-PVA nanofibers. In conclusion, the electrospinning technique applied here allowed for the manufacture of biodegradable biomimetic nanofibrous extracellular membranes with the ability to control fungal infection.

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Competition through Dimerization between Antiapoptotic and Proapoptotic HS-1-associated Protein X-1 (Hax-1)

Cited by 21 publications

References 46 publications

Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction

Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction

Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells

Antifungal nanofibers made by controlled release of sea animal derived peptide

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