ADAMTS-7 Increase Contributes to Worsened Neurological Outcome in Mice on High Fat Diet.

Abstract

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.