Abstract 2673: C-reactive Protein Increases The Severity Of Stroke Outcome In Mice
C-reactive protein (CRP) is an acute-phase reactant that is elevated in a variety of chronic inflammatory conditions including obesity and autoimmune disorders. Elevated CRP is associated with greater incidence and severity of stroke. However, it is unknown whether CRP directly impacts the severity of stroke outcome. We previously demonstrated that CRP antagonizes endothelial NO synthase (eNOS) by attenuating eNOS serine 1176 phosphorylation via the activation of SHIP-1 in endothelium, which blunts signaling downstream of PI3 kinase. Furthermore, we have shown that modulation of the eNOS serine 1176 phosphorylation site affects vascular reactivity and determines stroke size in vivo. We therefore hypothesize that CRP increases stroke vulnerability in vivo by altering the phosphorylation state of eNOS. To test our hypothesis, we subjected wild-type (WT) and CRP transgenic mice (TG-CRP), which have modest elevations in CRP, to a stroke model of temporal focal ischemia with subsequent reperfusion. Mean blood pressure measured acutely from the common carotid artery under aerrane anesthesia (30 % oxygen, 70% nitrous oxide and 1.5% aerrane) was similar in TG-CRP mice (96 ± 8 mmHg, Mean ± SD, n=6) and WT mice (93 ± 9 mmHg, n=14). Using Laser Doppler flowmetry, we monitored cerebral blood flow (CBF) above the middle cerebral artery (MCA) during 30 minutes of MCA occlusion (MCAO) provoked by a filament and during the first 30 minutes of subsequent reperfusion. Although there was a directional trend, in TG-CRP mice CBF reperfusion after 30 minutes (55 ± 34 %, n=5) was not different from WT mice (80 ± 16 %, n=5, P=0.28). However, the TG-CRP mice demonstrated markedly larger infarct volumes as compared with WT mice after 30 minutes of MCAO and 48 hours of reperfusion (100 ± 26 mm3 in TG-CRP vs. 51 ± 21 mm3 in WT, n=5/group, p< 0.03). Neurological deficit after 48 hours of reperfusion was also worse in TG-CRP mice (3.0 points) as compared with WT mice (1.8 point). These findings indicate that CRP increases the severity of stroke outcome in a mouse model of cerebral reperfusion. As such, future therapies aimed at CRP or its mechanism of action in stroke may potentially prevent or improve the stroke outcomes in patients with chronic inflammatory conditions such as obesity.
- © 2012 by American Heart Association, Inc.