ApoE−/− mice exhibited markedly reduced lesion sizes throughout atherosclerotic aortas and significantly less advanced lesions. The proportion of Mac3-positive macrophages was higher in plaques from HDAC9 −/− ApoE −/− mice, but this was largely because of a lower proportion of advanced lesions. Analysis of human atherosclerotic plaques revealed no association between rs2107595 and specific plaque characteristics. Conclusions-Our results suggest that HDAC9 represents the disease-relevant gene at the stroke and coronary artery disease risk locus on 7p21.1, and that risk alleles in this region mediate their effects through increased HDAC9 expression. Targeted inhibition of HDAC9 might be a viable strategy to prevent atherosclerosis.
Atherosclerosis leads to vascular lesions that involve major rearrangements of the vascular proteome, especially of the extracellular matrix (ECM). Using single aortas from ApoE knock out mice, we quantified formation of plaques by single-run, high-resolution mass spectrometry (MS)-based proteomics. To probe localization on a proteome-wide scale we employed quantitative detergent solubility profiling. This compartment- and time-resolved resource of atherogenesis comprised 5117 proteins, 182 of which changed their expression status in response to vessel maturation and atherosclerotic plaque development. In the insoluble ECM proteome, 65 proteins significantly changed, including relevant collagens, matrix metalloproteinases and macrophage derived proteins. Among novel factors in atherosclerosis, we identified matrilin-2, the collagen IV crosslinking enzyme peroxidasin as well as the poorly characterized MAM-domain containing 2 (Mamdc2) protein as being up-regulated in the ECM during atherogenesis. Intriguingly, three subunits of the osteoclast specific V-ATPase complex were strongly increased in mature plaques with an enrichment in macrophages thus implying an active de-mineralization function.
Subarachnoid hemorrhage (SAH) is a stroke subtype associated with high mortality and morbidity as a result of early and delayed ischemic processes. Nearly one quarter of all patients with SAH die shortly after hemorrhage because of elevated intracranial pressure (ICP) and the resulting global cerebral ischemia.1,2 Hospitalized patients further experience severe complications, including rebleeding, early brain injury, and delayed cerebral ischemia, which together contribute to a devastatingly high 1-month mortality rate of 50%. 1,2 Early brain injury is the predominant cause of death after SAH and is characterized by elevated ICP, decreased cerebral blood flow (CBF), and global cerebral ischemia resulting in secondary injuries, including disruption of the blood-brain barrier, inflammation, and oxidative stress, which all cause neuronal cell death. [3][4][5] In both animal and clinical studies, the severity of bleeding and the extent of decreased CBF correlated with neurological outcome [6][7][8] ; however, how and to what extent the initial global ischemia or subsequent elevated ICP contribute to early brain injury remains poorly understood. [3][4][5] A feasible way to reduce elevated ICP is decompressive craniectomy (DC), a technique that dates back more than a century. 9 In recent years, both animal and clinical studies reported beneficial effects of DC for treating conditions, such as traumatic brain injury 10,11 and malignant middle cerebral artery (MCA) infarction. 12,13 With respect to SAH, however, relatively few studies have been published regarding the application of DC and its effect on outcome; moreover, the results published to date are contradictory and controversial. [14][15][16][17][18] To address these questions, we performed DC to evaluate the role of SAH-induced elevated ICP and subsequent global ischemia and to investigate whether DC may serve as a therapeutic option for SAH using a standardized animal model. MethodsIn total, 41 male C57BL/6 mice (22-25 g; Charles River Laboratories, Sulzfeld, Germany) were used. All experiments were approved by the Government of Upper Bavaria (protocol number 55.2.1.54-2532-90-13) and were performed in accordance with standard ethical guidelines. Experimental DesignInitially, 40 animals were assigned randomly to the following 4 experimental groups: sham surgery, SAH, DC after SAH, and DC before SAH (Figure 1). All assessments were performed by an Background and Purpose-Elevated intracranial pressure (ICP) is a key feature of subarachnoid hemorrhage (SAH). Here, we examined the role of elevated ICP in the pathophysiology of SAH, and we investigated whether decreasing ICP by performing decompressive craniectomy (DC) can improve outcome. Methods-SAH was induced in male C57BL/6 mice via endovascular Circle of Willis perforation in the following 4 groups:sham surgery, SAH, DC after SAH, and DC before SAH. DC was performed either 15 minutes before or after SAH induction. ICP, cerebral blood flow, heart rate, oxygen saturation, and end-tidal PCO 2 were monitored for ...
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