Biomechanical and biochemical regulation of cathepsin K expression in endothelial cells converge at AP-1 and NF-κB
Abstract
Cathepsins K and V are powerful elastases elevated in endothelial cells by tumor necrosis factor-α (TNFα) stimulation and disturbed blood flow both of which contribute to inflammation-mediated arterial remodeling. However, mechanisms behind endothelial cell integration of biochemical and biomechanical cues to regulate cathepsin production are not known. To distinguish these mechanisms, human aortic endothelial cells (HAECs) were stimulated with TNFα and exposed to pro-remodeling or vasoprotective shear stress profiles. TNFα upregulated cathepsin K via JNK/c-jun activation, but vasoprotective shear stress inhibited TNFα-stimulated cathepsin K expression. JNK/c-jun were still phosphorylated, but cathepsin K mRNA levels were significantly reduced to almost null indicating separate biomechanical regulation of cathepsin K by shear stress separate from biochemical stimulation. Treatment with Bay 11-7082, an inhibitor of IκBα phosphorylation, was sufficient to block induction of cathepsin K by both pro-remodeling shear stress and TNFα, implicating NF-κB as the biomechanical regulator, and its protein levels were reduced in HAECs by vasoprotective shear stress. In conclusion, NF-κB and AP-1 activation were necessary to activate cathepsin K expression in endothelial cells, highlighting integration of biochemical and biomechanical stimuli to control cathepsins K and V, powerful elastases implicated for arterial remodeling due to chronic inflammation and disturbed blood flow.
Funding source: National Institutes of Health
Award Identifier / Grant number: 1DP2OD007433-01
Funding statement: This work was supported by the National Institutes of Health [1DP2OD007433-01 to M.O.P] and also by a National Science Foundation Graduate Research Fellowship to P.M.K.
Acknowledgments:
This work was supported by the National Institutes of Health [1DP2OD007433-01 to M.O.P] and also by a National Science Foundation Graduate Research Fellowship to P.M.K.
Conflict of Interest statement: None declared.
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©2016 by De Gruyter
Artikel in diesem Heft
- Frontmatter
- Review
- Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function
- Research Articles/Short Communications
- Protein Structure and Function
- Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations
- Two new isoforms of the human hepatoma-derived growth factor interact with components of the cytoskeleton
- Cell Biology and Signaling
- Activation of corticotropin releasing factor receptors up regulates collagen production by hepatic stellate cells via promoting p300 expression
- On the regulative role of the glutamate receptor in mitochondria
- Proteolysis
- Biomechanical and biochemical regulation of cathepsin K expression in endothelial cells converge at AP-1 and NF-κB
- New insights into the substrate specificity of macrophage elastase MMP-12
Artikel in diesem Heft
- Frontmatter
- Review
- Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function
- Research Articles/Short Communications
- Protein Structure and Function
- Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations
- Two new isoforms of the human hepatoma-derived growth factor interact with components of the cytoskeleton
- Cell Biology and Signaling
- Activation of corticotropin releasing factor receptors up regulates collagen production by hepatic stellate cells via promoting p300 expression
- On the regulative role of the glutamate receptor in mitochondria
- Proteolysis
- Biomechanical and biochemical regulation of cathepsin K expression in endothelial cells converge at AP-1 and NF-κB
- New insights into the substrate specificity of macrophage elastase MMP-12