Hypertension Accelerated Experimental Abdominal Aortic Aneurysm Through Upregulation of Nuclear Factor κB and Ets

Abstract

Abstract-In this study, we focused on the effect of hypertension on the transcription factors nuclear factor B (NFB) and ets in the mechanisms of abdominal aortic aneurysm (AAA), and we investigated how hypertension affects the progression of AAA. AAA was produced by elastase perfusion in hypertensive rats and normotensive rats. The size of AAA rapidly increased in hypertensive rats as compared with normotensive rats. Western blot analysis demonstrated that the expression of matrix metalloproteinase (MMP)-2, -3 , -9, and -12, as well as intercellular adhesion molecule, was increased in hypertensive AAA rats, accompanied by upregulation of NFB and ets. Moreover, in situ zymography showed that the activity of MMPs was increased in the aorta of a hypertensive AAA model as compared with that in a normotensive AAA model. Interestingly, transfection of chimeric decoy oligodeoxynucleotide (ODN) resulted in significant inhibition of aortic dilatation both in normotensive and hypertensive rats at 4 weeks after transfection. Destruction of elastic fibers was also significantly inhibited by transfection of chimeric decoy ODN in both hypertensive rats and normotensive rats. The expression of MMP-2, -3, -9, and -12, as well as intercellular adhesion molecule, was significantly attenuated by the chimeric decoy ODN, accompanied by inhibition of the migration of macrophages. Also, the effect of chimeric decoy ODN was confirmed in an organ culture. The present study demonstrated that hypertension accelerated the progression of experimental AAA through upregulation of NFB and ets. Inhibition of NFB and ets could be a novel therapeutic strategy to treat AAA in hypertensive patients. bdominal aortic aneurysm (AAA) is a common degenerative condition associated with aging and atherosclerosis. 1 Because the main pathogenesis of AAA is considered to be based on atherosclerosis, patients with aneurysms and atherosclerotic disease share similar risk factors, including male sex, 2 older age, 3 and a lipid profile that includes lower high-density lipoprotein and higher triglyceride and lowdensity lipoprotein concentrations. 4 However, the risk factors for atherosclerosis and AAA are not completely the same, because there are certain pathogenetic, epidemiological, and genetic differences between these 2 diseases. 5,6 Indeed, although hypertension induces sheer stress, oxidative stress, and vascular inflammation followed by atherosclerosis, a consistent relation between blood pressure and the prevalence of AAA has not been demonstrated. 7,8 Hypertension has been reported to be both independently associated with AAA and not associated with AAA. 8,9 Basic phenomena in the pathogenesis of AAA are degradation of extracellular matrix components and loss of structural integrity of the aortic wall. 10 AAA disease typically involves tissue inflammation as seen by the presence of inflammatory cells, which are considered to participate in the immunopathogenesis of AAA leading to destruction of the aortic matrix. 11,12 Recent investigations have emph...

Hypertension overrides the protective effect of female hormones on the development of aortic aneurysm secondary to Alk5 deficiency via ERK activation

“…Hypertension imposes hemodynamic stress that activates NF-B pathway, elaborating expression of proinflammatory mediators such as VCAM-1 and ICAM-1 in the aortic wall (16). Shiraya et al (37) have previously shown that hypertension-induced upregulation of NF-B is associated with worsening pathology of aortic aneurysm induced by elastase perfusion (37). However, in our model, development of aortic phenotype by NE-induced hypertension is not associated with changes of NF-B activity, indicating that the deleterious effect of hypertension in Alk5 iko females is not maneuvered via regulating NF-B signaling pathway.…”

Molecular mechanism of cerebral aneurysm formation focusing on NF-κB as a key mediator of inflammation

“…For example, in a previous report, iNOS, which is actively involved in the pathogenesis of CA formation through the production of reactive oxygen species and induction of apoptosis in the media [28], was also up-regulated by shear stress through NF-jB activation in endothelial cells [57]. Hypertension itself induced NF-jB activation in the rat model of aortic aneurysm [58] in vivo. These reports support our proposal.…”

Cardiac surgery and hypertension: a dangerous association that must be well known

“…Western blotting analysis demonstrated that the expression of matrix metalloproteinases (MMPs)-2, -3 , -9, and -12, as well as intercellular adhesion molecule, were increased in hypertensive abdominal aortic aneurysm rats, accompanied by upregulation of NF-κB and Ets, suggesting that hypertension accelerated the progression of experimental abdominal aortic aneurysm through upregulation of NF-κB and Ets. Destruction of elastic fibers was also significantly inhibited by transfection of chimeric decoy oligodeoxynucleotide in both hypertensive and normotensive rats [32]. Sangiorgi et al [33] also observed increased MMP-9 in patients with type A or B aortic dissection.…”

“…In some patients, an ACEI and a calcium channel blocker may be given together [66]. Inhibition of NF-κB and Ets could be a potential therapeutic strategy to treat abdominal aortic aneurysm in hypertensive patients [32]. Interventions on NO bioavailability may be very helpful in designing more effective prevention, diagnostic and therapeutic strategies to deal with coronary vascular dysfunction in hypertension and cardiovascular disease [67].…”