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ADAMTS-7 Increase Contributes to Worsened Neurological Outcome in Mice on High Fat Diet
1Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA.
Background:
Obesity and associated metabolic disturbance are associated with worse outcomes after brain ischemia. Cerebrovascular remodeling mediated by matrix metalloproteinase 9 (MMP-9) may contribute to this poor outcome. A disintegrin and metalloproteinase-7 (ADAMTS-7) has been shown to regulate vascular remodeling in peripheral vessels. This study was designed to determine the role of ADAMTS-7 in regulating MMP-9 activity, cerebrovascular remodeling and neurological outcomes in mice.
Methods:
Six-week-old CD-1 male mice were fed regular diet (RD) or high fat diet (HFD) for 10 weeks before they had left middle cerebral arterial occlusion (MCAO) for 1.5 h. Their brains were harvested for Western blotting, immunostaining or cerebral vascular casting. Lentiviral particles containing shRNA targeting ADAMTS-7 mRNA or scramble shRNA were injected intracerebroventricularly.
Results:
HFD feeding increased ADAMTS-7 and MMP-9 activity, reduced middle cerebral arterial root diameter, and worsened neurological outcomes after the MCAO. Silencing ADAMTS-7 attenuated these HFD-induced effects. ADAMTS-7 was expressed in the neurons, astrocytes, oligodendrocytes, and blood vessels in the brain.
Conclusions:
HFD increased ADAMTS-7 to lead to MMP-9 activation, which then induces cerebrovascular remodeling and poor neurological outcomes after brain ischemia. ADAMTS-7 is expressed in multiple cell types in the brain.
Insights
High-fat diets worsen brain ischemia outcomes by increasing ADAMTS-7, which activates MMP-9, leading to cerebrovascular remodeling. Silencing ADAMTS-7 improves outcomes in mice.
Area of Science:
- Neuroscience
- Metabolic research
- Vascular biology
Background:
- Obesity and metabolic disturbances are linked to poor outcomes following brain ischemia.
- Matrix metalloproteinase 9 (MMP-9) mediated cerebrovascular remodeling contributes to poor outcomes.
- A disintegrin and metalloproteinase-7 (ADAMTS-7) influences peripheral vascular remodeling.
Purpose of the Study:
- To investigate the role of ADAMTS-7 in regulating MMP-9 activity.
- To determine ADAMTS-7's impact on cerebrovascular remodeling.
- To assess ADAMTS-7's effect on neurological outcomes after brain ischemia in mice.
Main Methods:
- Mice were fed a regular diet (RD) or high-fat diet (HFD) for 10 weeks.
- Middle cerebral arterial occlusion (MCAO) was induced for 1.5 hours.
- Intracerebroventricular injection of lentiviral particles with shRNA targeting ADAMTS-7 or scramble shRNA was performed.
Main Results:
- HFD feeding elevated ADAMTS-7 and MMP-9 activity.
- HFD reduced middle cerebral arterial root diameter and worsened neurological outcomes post-MCAO.
- Silencing ADAMTS-7 mitigated HFD-induced effects, with ADAMTS-7 expressed in various brain cell types.
Conclusions:
- High-fat diet increases ADAMTS-7, activating MMP-9.
- This activation leads to cerebrovascular remodeling and adverse neurological outcomes post-brain ischemia.
- ADAMTS-7 is expressed across multiple brain cell types, highlighting its potential role.
