Background—
Stroke is one of the most common causes of death and long term disability worldwide primarily affecting the elderly population. Lectin-like oxidized LDL receptor 1 (LOX-1) is the receptor for oxidized LDL identified in endothelial cells. Binding of OxLDL to LOX-1 induces several cellular events in endothelial cells, such as activation of transcription factor NF-kB, upregulation of MCP-1, and reduction in intracellular NO. Accumulating evidence suggests that LOX-1 is involved in endothelial dysfunction, inflammation, atherogenesis, myocardial infarction, and intimal thickening after balloon catheter injury. Interestingly, a recent study demonstrated that acetylsalicylic acid (aspirin), which could prevent ischemic stroke, inhibited Ox-LDL-mediated LOX-1 expression in human coronary endothelial cells. The expression of LOX-1 was increased at a transient ischemic core site in the rat middle cerebral artery occlusion model. These data suggest that LOX-1 expression induces atherosclerosis in the brain and is the precipitating cause of ischemic stroke. Therefore, the goal of the present study was to investigate the role of endothelial LOX-1 in stroke using experimental mouse model.
Methods and Results—
12-week-old male
LOX-1TG
generated recently in our group and wild-type (WT) mice were applied for a transient middle cerebral artery occlusion (MCAO) model to induce ischemia/reperfusion (I/R) brain injury.
LOX-1TG
mice developed 24h post-MCAO significantly larger infarcts in the brain compared to WT (81.51±8.84 vs. 46.41±10.13, n=7,
p
< 0.05) as assessed morphologically using Triphenyltetrazolium chloride (TTC) staining. Moreover,
LOX-1TG
showed higher neurological deficit in RotaRod (35.57±8.92 vs. 66.14±10.63, n=7,
p
< 0.05) and Bederson tests (2.22±0.14 vs. 1.25±0.30, n=9-12,
p
< 0.05) - two experimental physiological tests for neurological function.
Conclusions—
Thus, our data suggest that LOX-1 plays a critical role in the ischemic stroke when expressed at unphysiological levels. Such
LOX-1
-associated phenotype could be due to the endothelial dysfunction. Therefore, LOX-1 may represent novel therapeutic targets for preventing ischemic stroke.
NNC 55-0396, a T-type calcium channel blocker, protects against the brain injury induced by middle cerebral artery occlusion and reperfusion in mice
