Journal
JOURNAL OF THE AMERICAN HEART ASSOCIATION
Volume 10, Issue 18, Pages -Publisher
WILEY
DOI: 10.1161/JAHA.121.021511
Keywords
autotaxin; blood-brain barrier; ischemic stroke; lysophosphatidic acid; permeability; superoxide radicals
Categories
Funding
- Louisiana State University Health Sciences-Shreveport Intramural Grant [110101074A]
- National Institutes of Health [HL141998, HL141998-01S1, AA025744, AA026708, AA025744-02S1, HL122354, HL145753, P20GM121307]
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The autotaxin/LPA axis plays a crucial role in regulating blood-brain barrier integrity and mitochondrial function after ischemic stroke. Inhibitors of autotaxin or autotaxin/LPA receptor can effectively protect the blood-brain barrier and mitochondrial function.
Background The loss of endothelial integrity increases the risk of intracerebral hemorrhage during ischemic stroke. Adjunct therapeutic targets for reperfusion in ischemic stroke are in need to prevent blood-brain barrier disruption. Recently, we have shown that endothelial permeability is mediated by lysophosphatidic acid (LPA), but the role of autotaxin, which produces LPA, remains unclear in stroke. We investigate whether autotaxin/LPA axis regulates blood-brain barrier integrity after cerebral ischemia. Methods and Results Ischemic stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by 24-hour reperfusion. The therapeutic efficacy of autotaxin/LPA receptor blockade was evaluated using triphenyl tetrazolium chloride staining, Evans blue permeability, infrared imaging, mass spectrometry, and XF24 analyzer to evaluate blood-brain barrier integrity, autotaxin activity, and mitochondrial bioenergetics. In our mouse model of ischemic stroke, the mRNA levels of autotaxin were elevated 1.7-fold following the cerebral ischemia and reperfusion (I/R) group compared with the sham. The enzymatic activity of autotaxin was augmented by 4-fold in the I/R group compared with the sham. Plasma and brain tissues in I/R group showed elevated LPA levels. The I/R group also demonstrated mitochondrial dysfunction, as evidenced by decreased (P<0.01) basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity. Treatment with autotaxin inhibitors (HA130 or PF8380) or autotaxin/LPA receptor inhibitor (BrP-LPA) rescued endothelial permeability and mitochondrial dysfunction in I/R group. Conclusions Autotaxin-LPA signaling blockade attenuates blood-brain barrier disruption and mitochondrial function following I/R, suggesting targeting this axis could be a new therapeutic approach toward treating ischemic stroke.
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