scholarly journals Aorta-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease

2021 ◽  
Author(s):  
Abudupataer Mieradilijiang ◽  
Shichao Zhu ◽  
Shiqiang Yan ◽  
Kehua Xu ◽  
Jingjing Zhang ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Bicuspid Aortic Valve ◽  
Therapeutic Target ◽  
Mitochondrial Dynamics ◽  
Science And Technology ◽  
Mitochondrial Fission ◽  
Underlying Mechanism ◽  
Mitochondrial Fusion ◽  
Contractile Phenotype

Background: Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified. <br />Methods: A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs). <br />Results: Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients. <br />Conclusions: The aorta-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA. <br /><br />Funding: National Key R&D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.

scholarly journals Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Abudupataer Mieradilijiang ◽  
Shichao Zhu ◽  
Shiqiang Yan ◽  
Kehua Xu ◽  
Jingjing Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Bicuspid Aortic Valve ◽  
Therapeutic Target ◽  
Mitochondrial Dynamics ◽  
Science And Technology ◽  
Underlying Mechanism ◽  
Mitochondrial Fusion ◽  
Contractile Phenotype

Background: Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified. Methods: A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta smooth muscle-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs). Results: Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients. Conclusions: The aorta smooth muscle-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta smooth muscle-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA.Funding: National Key R&D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.

scholarly journals Should all patients with aortic aneurysm and bicuspid aortic valve also undergo hemiarch?

JTCVS Open ◽  
2021 ◽  
Vol 5 ◽  
pp. 39-43
Author(s):  
Isao Anzai ◽  
Jacob Kriegel ◽  
Ilya Kim ◽  
Christian Pearsall ◽  
Matthew Lewis ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Bicuspid Aortic Valve

scholarly journals Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lixiang Wang ◽  
Xin Li ◽  
Yuki Hanada ◽  
Nao Hasuzawa ◽  
Yoshinori Moriyama ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Er Stress ◽  
Disease Progression ◽  
Acute Liver Injury ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Related Protein ◽  
Liver Disease Progression

AbstractMitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

scholarly journals T-2 Toxin-Induced Oxidative Stress Leads to Imbalance of Mitochondrial Fission and Fusion to Activate Cellular Apoptosis in the Human Liver 7702 Cell Line

Toxins ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 43 ◽  
Author(s):  
Junhua Yang ◽  
Wenbo Guo ◽  
Jianhua Wang ◽  
Xianli Yang ◽  
Zhiqi Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Apoptosis ◽  
Human Liver ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Mitochondrial Dynamic ◽  
Normal Human Liver ◽  
Induced Apoptosis

T-2 toxin, as a highly toxic mycotoxin to humans and animals, induces oxidative stress and apoptosis in various cells and tissues. Apoptosis and mitochondrial fusion/fission are two tightly interconnected processes that are crucial for maintaining physiological homeostasis. However, the role of mitochondrial fusion/fission in apoptosis of T-2 toxin remains unknown. Hence, we aimed to explore the putative role of mitochondrial fusion/fission on T-2 toxin induced apoptosis in normal human liver (HL-7702) cells. T-2 toxin treatment (0, 0.1, 1.0, or 10 μg/L) for 24 h caused decreased cell viability and ATP concentration and increased production of (ROS), as seen by a loss of mitochondrial membrane potential (∆Ψm) and increase in mitochondrial fragmentation. Subsequently, the mitochondrial dynamic imbalance was activated, evidenced by a dose-dependent decrease and increase in the protein expression of mitochondrial fusion (OPA1, Mfn1, and Mfn2) and fission (Drp1 and Fis1), respectively. Furthermore, the T-2 toxin promoted the release of cytochrome c from mitochondria to cytoplasm and induced cell apoptosis triggered by upregulation of Bax and Bax/Bcl-2 ratios, and further activated the caspase pathways. Taken together, these results indicate that altered mitochondrial dynamics induced by oxidative stress with T-2 toxin exposure likely contribute to mitochondrial injury and HL-7702 cell apoptosis.

scholarly journals CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 833 ◽  
Author(s):  
Kim ◽  
Park ◽  
Choi ◽  
Kong ◽  
Kang
Keyword(s):  
Status Epilepticus ◽  
Neuronal Death ◽  
Granule Cells ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Acid Methyl Ester ◽  
Underlying Mechanism ◽  
Ca1 Neurons ◽  
Prolonged Seizure ◽  
Mitochondrial Elongation

2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid that exhibits promising anti-cancer, anti-inflammatory, antioxidant and neuroprotective activities. In addition, CDDO-Me affects cellular differentiation and cell cycle arrest, and irreversibly inhibits Lon protease-1 (LONP1). In the present study, we evaluate the effects of CDDO-Me on mitochondrial dynamics and its downstream effectors in order to understand the underlying mechanism of the neuronal death following status epilepticus (SE, a prolonged seizure activity). CDDO-Me increased dynamin-related proteins 1 (DRP1)-serine 616 phosphorylation via activating extracellular-signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK), but not protein kinase A (PKA) or protein phosphatases (PPs). In addition, CDDO-Me facilitated DRP1-mediated mitochondrial fissions, which selectively attenuated SE-induced CA1 neuronal death. Unlike CDDO-Me, LONP1 knockdown led to SE-induced massive degeneration of dentate granule cells, CA1 neurons and hilus interneurons without altering the expression and phosphorylation of DRP1, ERK1/2, JNK and PP2B. LONP1 knockdown could not inhibit SE-induced mitochondrial elongation in CA1 neurons. Co-treatment of CDDO-Me with LONP1 siRNA ameliorated only CA1 neuronal death, concomitant with abrogation of mitochondrial elongation induced by SE. Thus, our findings suggest that CDDO-Me may selectively attenuate SE-induced CA1 neuronal death by rescuing the abnormal mitochondrial machinery, independent of LONP1 activity.

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