Proteomic Expression Changes in Large Cerebral Arteries After Experimental Subarachnoid Hemorrhage in Rat Are Regulated by the MEK-ERK1/2 Pathway

Anne H Müller,Janne Nielsen,Alistair V.G Edwards,Lars Edvinsson,Gro K Povlsen,Karin Warfvinge,Martin R Larsen

doi:10.1007/s12031-017-0944-7

Abstract

Subarachnoid hemorrhage (SAH) is a serious clinical condition where leakage of blood into the subarachnoid space causes an acute rise in intracranial pressure and reduces cerebral blood flow, which may lead to delayed cerebral ischemia and poor outcome. In experimental SAH, we have previously shown that the outcome can be significantly improved by early inhibition of the MAPK/ERK kinase/extracellular signal-regulated kinase (MEK/ERK1/2) pathway. The aim of this study was to apply mass spectrometry to investigate the overall late effects of experimental SAH on cerebrovascular protein expression. SAH was induced in rats that were treated with the MEK1/2 inhibitor U0126 or vehicle. Neurological outcome was assessed using a battery of behavioral tests. Specific protein expression of large cerebral arteries was analyzed quantitatively with high-throughput tandem mass spectrometry. SAH resulted in a marked reduction of neurological scores, which was counteracted by U0126 treatment. Mass spectrometry analysis demonstrated regulation of 184 proteins after SAH, regulations that were in part prevented by U0126 treatment. Network analysis identified several protein networks including a strong structural network centered around 14-3-3. Additionally, protein networks with functions in mRNA metabolism and protein folding were identified. Treatment with U0126 inhibited cerebral vessel wall pERK1/2 expression and significantly improved outcome of the rats. In conclusion, we show that SAH induces a broad array of specific changes in the overall protein networks in cerebral artery smooth muscle cells and suggest that this is essential for understanding the vascular pathophysiology after SAH.

Highlights

Subarachnoid hemorrhage (SAH) is a condition caused by leakage of blood from a ruptured aneurysm into the subarachnoid space which causes an acute rise in intracranial pressure (ICP) and a diminished cerebral blood flow (CBF)
Measurements of the physiological parameters during SAH surgery showed that ICP reached values of 10–20 mmHg above Mean arterial blood pressure (MABP) (80–100 mmHg) and cortical CBF was lowered to 75% compared to flow before insult, and did not return to baseline for a minimum of 10 min
It is worth noting that much of previous work to find novel ways of therapy in order to reduce cerebral vasospasm and the development of late cerebral ischemia after SAH have centered on single molecular approaches

Summary

Introduction

Subarachnoid hemorrhage (SAH) is a condition caused by leakage of blood from a ruptured aneurysm into the subarachnoid space which causes an acute rise in intracranial pressure (ICP) and a diminished cerebral blood flow (CBF). There is a mortality rate of about 15%. The DCI phase is progressive and can result in infarction, neuronal loss, and poor outcome (Edvinsson and Povlsen 2011). Experimental studies have indicated plasticity of contractile cerebrovascular endothelin, 5hydroxytryptamine 1B (5-HT1B), angiotensin AT1, and thromboxane A2 receptors in the ischemic process (Ansar and Edvinsson 2008; Ansar et al 2010; Hansen-Schwartz et al 2003). These receptor alterations are associated with reduced regional CBF and poor outcome (Ansari 2007)

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