Aortic aneurysms and dissection (AAD) are a major source of disease in the adult aorta. Despite advances in diagnosis and endovascular and surgical repair, these lesions are associated with significant morbidity and mortality. A number of risk factors for aortic aneurysms are present within patients harboring cerebral aneurysms including atherosclerosis and cigarette smoking. Prior studies have also found common links between genetic loci predisposing patients to both aortic and cerebral aneurysms, but definitive putative genes have not been completely identified. Additionally, similar molecular alterations have been found in both aortic and cerebral aneurysms, but the differential mechanisms behind formation of aortic versus cerebral aneurysms remain unclear. Limitations in both diagnosis and treatment of both AAD and cerebral aneurysms are in part due to an incomplete understanding of the pathogenesis behind these vascular diseases. Currently, there are not effective medical therapies for any of these conditions.
In both aortic aneurysms and cerebral aneurysms, there is progressive degeneration of the media with progressive loss of smooth muscle cells (SMC).1,4,12 This leads to aneurysm growth and, ultimately, rupture. Activation of remodeling genes such as matrix metalloproteinases (MMP) and their balancing genes, for example, tissue inhibitor of metalloproteinase (TIMP), are known to be critical behind vascular remodeling in both aortic and cerebral aneurysms. Although many other genes have been implicated in tissue destruction in both aortic and cerebral aneurysms, common protective pathways are less clear.
The AKT signaling pathway plays a critical role in the regulation of numerous metabolic functions. It can be activated by numerous factors including insulin, cytokines, and growth factors and functions in many, including cellular processes including metabolism, proliferation, migration, and survival.5 The AKT pathways also have a significant regulatory role specifically in vascular processes. In the heart, AKT helps regulate cardiomyocyte survival, remodeling, and hypertrophy.3,7 Within blood vessel walls, AKT helps control endothelial nitric oxide synthase and vascular tone (9,10).6,8 AKT also regulates SMC proliferation (14-16)2,11 and migration (15,17).2,14 Additionally, inflammation9 and metabolic insult13 can downregulate AKT signaling, resulting in endothelial dysfunction. Although many of these characteristics may be critical elements of aneurysm and dissection pathogenesis, alterations in the AKT pathway have not previously been assessed.
In a recent publication in Circulation Research, Shen et al. found that Akt2-deficient mice showed decreased elastic fibers and medial thickness in the aorta.10 Angiotensin II exposure in mice resulted in aortic aneurysm, dissection, and rupture. Akt2-deficient mice displayed profound tissue destruction, apoptotic cell death, and inflammatory cell infiltration. Angiotensin II-infused Akt2-deficient mice also had upregulation of matrix metalloproteinase-9 and reduced expression of tissue inhibitor of metalloproteinase-1.
To further assess mechanisms behind AKT-dependent regulation, the authors assessed whether the transcription factor forkhead box protein O1 (FOXO1), a downstream target of AKT, regulates MMP-9 and TIMP expression.10 Using either viral vector or small interfering mRNA inhibition, the authors found that FOXO1 activation downregulated MMP-9 expression and upregulated TIMP expression. Using chromatic immunoprecipitation analysis, the authors also found that FOXO1 binds to both the MMP-9 and TIMP promoters. Further experiments demonstrated that these effects were at least in part due to AKT-dependent regulation of MMP-9 and TIMP through FOXO1.
The authors also found that AKT levels were significantly diminished in human AAD.10 Additionally, the phospo-AKT levels and phospo-AKT/total AKT ratios were significantly lower in AAD versus controls, indicating that AKT activation is likely reduced in AAD. AKT levels were higher in hyperplastic intitma and adventitia, particularly in inflammatory and proliferating cells. AKT levels were significantly decreased in degenerative layers of the intima, and less likely to be expressed in preserved areas. Taken together, this provides further evidence that AKT expression is reduced in human ADD tissues and is particularly decreased in the medial layers where AKT signaling may be decreased.
This study provides evidence that alteration in the AKT2 pathway may contribute to AAD development and provide a promising pharmacological target. Although further elements of the pathway need to be defined, this may also be a beneficial target for cerebrovascular disease whereby there is significant dysfunction of smooth muscle cells such as ischemic stroke, intracerebral hemorrhage, dissections, and cerebral aneurysm formation and/or rupture.
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4. Lopez-Candales A, Holmes DR, Liao S, Scott MJ, Wickline SA, Thompson RW. Decreased vascular smooth muscle cell density in medial degeneration of human abdominal aortic aneurysms. Am J Pathol. 1997;150(3):993–1007.
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9. Shen YH, Zhang L, Gan Y, et al.. Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells. J Biol Chem. 2006;281:7727–7736.
10. Shen YH, Zhang L, Ren P, et al.. AKT2 confers protection against aortic aneurysms and dissections. Circ Res. 2013;112(4):618–632.
11. Stabile E, Zhou YF, Saji M, et al.. Akt controls vascular smooth muscle cell proliferation in vitro and in vivo by delaying G1/S exit. Circ Res. 2003;93(11):1059–1065.
12. Starke RM, Ali MS, Jabbour PM, et al.. Cigarette smoke modulates vascular smooth muscle phenotype: implications for carotid and cerebrovascular disease. PLoS One. 2013;8(8):e71954.
13. Wang XL, Zhang L, Youker K, et al.. Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. Diabetes. 2006;55(8):2301–2310.
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