Role of oxidized LDL and lectin-like oxidized LDL receptor-1 in cerebral vasospasm after subarachnoid hemorrhage

Abstract

T he consequences of subarachnoid hemorrhage (SAH) after cerebral aneurysm rupture are devastating, with mortality rates as high as 50% and the majority of survivors left with moderate to severe disability. 15 Cerebral vasospasm causes cerebral ischemia and is a major contributor to the high morbidity and mortality rates associated with SAH. The pathogenesis of cerebral vasospasm, however, has not been fully clarified, and potential preventative therapies for this phenomenon have not been established. 7,8,17 Oxyhemoglobin derived from a subarachnoid clot and the free radicals subsequently generated have been considered important causes of cerebral vasospasm. 22,24,33,43 These radicals, by means of a scavenging effect, may be related to cerebral vasospasm by suppressing nitric ox- Object. Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a serious complication. Free radicals derived from subarachnoid clotting are recognized to play an important role. Oxidized low-density lipoprotein (ox-LDL) and lectin-like oxidized LDL receptor-1 (LOX-1) have been shown to be related to the pathogenesis of atherosclerosis and may increase in cerebral arteries after SAH, due to the action of free radicals derived from a subarachnoid clot. These molecules may also affect the pathogenesis of vasospasm, generating intracellular reactive oxygen species and downregulating the expression of endothelial NO synthase (eNOS). If so, apple polyphenol might be effective in the prevention of vasospasm due to an abundant content of procyanidins, which exhibit strong radical scavenging effects, and the ability to suppress ox-LDL and LOX-1. The purposes of this study were to investigate changes in levels of ox-LDL and LOX-1 after SAH and whether administering apple polyphenol can modify cerebral vasospasm.Methods. Forty Japanese white rabbits were assigned randomly to 4 groups: an SAH group (n = 10); a shamoperation group (n = 10), which underwent intracisternal saline injection; a low-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 10 mg/kg per day from Day 0 to Day 3; and a high-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 50 mg/kg per day. At Day 4, the basilar artery and brain was excised from each rabbit. The degree of cerebral vasospasm was evaluated by measuring the cross-sectional area of each basilar artery, and the expression of ox-LDL, LOX-1, and eNOS was examined for each basilar artery by immunohistochemical staining and reverse transcriptase polymerase chain reaction. In addition, neuronal apoptosis in the cerebral cortex was evaluated by TUNEL.Results. Compared with the sham group, the expression of ox-LDL and LOX-1 in the basilar arterial wall was significantly increased in the SAH group, the expression of eNOS was significantly decreased, and the cross-sectional area of basilar artery was significantly decreased. Compared with the SAH group, the cross-sectional area of basilar artery was increased in the polyphenol groups, together with the ...

Serum soluble lectin‐like oxidized low‐density lipoprotein receptor‐1 as a biomarker of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

“…LOX‐1 can combine with ox‐LDL in endothelial cells and play a key role in vascular dysfunction, including apoptosis and inhibition of vasodilatation (Ma et al, (); Sakurai & Sawamura, ). LOX‐1 is also expressed in the intracerebral artery and its expression can be up‐regulated significantly in rabbits with SAH (Matsuda et al, ). In a previous case report, remarkable expressions of LOX‐1 was found in hypertrophic media outside the intima in ruptured dissection using immunohistochemical examination (Saito, Fujimura, Inoue, Shimizu, & Tominaga, ).…”

“…Ox‐LDL, via binding to LOX‐1, increases intracellular reactive oxygen species, leads to a reduction in nitric oxide availability and down‐regulates endothelial nitric oxide synthase and initiates the inhibition of vasodilatation (Ma et al, (); Sakurai & Sawamura, ). Ox‐LDL and LOX‐1 were increased in the basilar arterial wall of rabbits with SAH (Matsuda et al, ). So, it is assumed that LOX‐1 might be implicated the pathogenesis of DCI.…”

Intracerebral Hemorrhage, Oxidative Stress, and Antioxidant Therapy

“…Oxidized low-density lipoprotein (oxLDL) and lectin-like oxidized LDL receptor-1 (LOX-1) can damage endothelial function, enhancing platelet aggregation and promoting thrombosis, thus playing an important role in the pathogenesis of cerebral vasospasm after SAH [ 96 , 97 ]. Although plasma oxLDL level is considered reflective of the oxidation state of the body [ 98 ], it is uncertain whether it can be used following ICH as a peripheral marker directly related to oxidative stress injury.…”

“…Sesamin, a lignan of sesame seed oil, is a promising natural product as a novel therapeutic strategy based on the regulation of microglial activities via inhibition of inducible NO synthase (iNOS) protein expression and accompanied by the activated p44/42 MAPK pathway in ICH [ 133 ]. Other natural plant extracts can be used as natural antioxidants, including resveratrol [ 134 ], astaxanthin [ 135 ], baicalein [ 136 ], astragaloside [ 137 ], proanthocyanidin [ 138 ], (−)-epigallocatechin-3-gallate [ 139 ], and apple polyphenol [ 97 ]. Studies in ICH animal models have shown that treatment using these extracts can exhibit neuroprotective effects by inhibiting oxidative stress, upregulating antioxidant levels, and reducing SBI after ICH.…”

Lectin-like oxidized low-density lipoprotein receptor (LOX-1) in sickle cell disease vasculopathy

“…It is noteworthy that in our experiments using HBMVECs, expression of LOX-1 peaked after 1 h of incubation with SCD RBCs. A recent study reported increased expression of LOX-1 in cerebral vasculature after subarachnoid hemorrhage, which may play a role in the pathogenesis of vasospasm [24]. Given that primary hemorrhagic stroke is one of the most devastating neurologic complications of sickle cell disease [25], LOX-1 mediated vasospasm may also be a contributing factor in sickle cell disease vasculopathy leading to stroke.…”