Abstract
Blood-brain barrier (BBB) disruption is a common and critical pathology following subarachnoid hemorrhage (SAH). We investigated the BBB disruption property of secreted protein acidic and rich in cysteine (SPARC) after SAH. A total of 197 rats underwent endovascular perforation to induce SAH or sham operation. Small interfering ribonucleic acid (siRNA) for SPARC or scrambled siRNA was administered intracerebroventricularly to rats 48 h before SAH. Anti-SPARC monoclonal antibody (mAb) 236 for functional blocking or normal mouse immunoglobulin G (IgG) was administered intracerebroventricularly 1 h after SAH. Selective integrin αVβ3 inhibitor cyclo(-RGDfK) or phosphate-buffered saline was administered intranasally 1 h before SAH, along with recombinant SPARC treatment. Neurobehavior, SAH severity, brain edema, immunohistochemical staining, and Western blot were evaluated. The expression of SPARC and integrin αVβ3 was upregulated after SAH in the endothelial cells. SPARC siRNA and anti-SPARC mAb 236 prevented neuroimpairments and brain edema through protection of BBB as measured by IgG extravasation 24 and 72 h after SAH. Recombinant SPARC aggravated neuroimpairments and cyclo(-RGDfK) suppressed the harmful neurological effects via inhibition of activated c-Jun N-terminal kinase, p38, and matrix metalloproteinase-9 followed by retention of endothelial junction proteins. SPARC may induce post-SAH BBB disruption via integrin αVβ3 signaling pathway.
Highlights
Aneurysmal subarachnoid hemorrhage (SAH) is a serious life-threatening cerebrovascular disease arising from a ruptured intracranial aneurysm [1,2,3]
The novel findings in the present study are as follows: (1) the expression of secreted protein acidic and rich in cysteine (SPARC) and integrin αVβ3 is upregulated in endovascular perforation SAH rats; (2) knockdown of SPARC and functional blocking against endogenous SPARC prevented neurological impairments through protection of the Blood-brain barrier (BBB) as measured by immunoglobulin G (IgG) extravasation after SAH; (3) exogenous SPARC aggravated neurobehavioral impairments after SAH, and integrin αVβ3 inhibitor suppressed the harmful neurological effects of SPARC via inhibition of two mitogenactivated protein kinases (MAPKs) JNK and p38 and matrix metalloproteinase (MMP)-9 followed by retention of zonula occludens (ZO)-1 and vascular endothelial- (VE-)cadherin
The present study demonstrated that the expression of both SPARC and integrin αVβ3 was upregulated within 12 h, and, SPARC and integrin αVβ3 signaling pathways are possibly involved in acute phase brain injury after SAH
Summary
Aneurysmal subarachnoid hemorrhage (SAH) is a serious life-threatening cerebrovascular disease arising from a ruptured intracranial aneurysm [1,2,3]. Arterial blood spreads into the subarachnoid space leading to devastating brain injury. This brain injury is caused by blood components, their secondary products, which are induced by tissue damage, and mechanical stress caused by the rapid elevation of intracranial pressure [4,5,6,7]. Many secondary products induced by tissue damage have been reported to cause the breakdown of the endothelial junctions forming the blood-brain barrier (BBB), leading to vasogenic edema (which is a major cause of brain injury and an independent risk factor for mortality and poor outcome after SAH [4, 8]). The molecular mechanisms of post-SAH BBB disruption remain unclear
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