Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression

Abstract

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease.

Effects of Iliac Stenosis on Abdominal Aortic Aneurysm Formation in Mice and Humans

“…Additionally, ultrasound imaging showed a reduction in arterial velocity and a 61% increase in volume/length from days 0 to 56, as well as a rapid reduction in circumferential cyclic strain, providing quantitative evidence of decreased pulsatility due to changes in arterial material properties. These results are consistent with previous works that show that a low concentration of PPE results in elastin degradation and collagen turnover, both of which result in hemodynamic and morphological changes in the vessel [16,26]. Lastly, a decrease in iliac circumferential cyclic strain distal to the suture placement provided evidence that the partial iliac artery ligation increased peripheral vessel stiffness.…”

Four Surgical Modifications to the Classic Elastase Perfusion Aneurysm Model Enable Haemodynamic Alterations and Extended Elastase Perfusion

“…1). 11,15 Therefore, specific research aims have to be defined, and a crucial understanding of the pathophysiology and advanced microsurgical skills are necessary for translational investigations.…”

Simvastatin Treatment Upregulates HO-1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2

“…The possible physiological importance of HO-1 upregulation after simvastatin treatment may be associated with HO-1 modulation of the vascular tone (via CO production) and the increasing antioxidative capacity of the tissue, for example, through elevated GSH synthesis [ 40 , 42 ]. Moreover, it was presented that other statins like rosuvastatin may induce HO-1 in aortic tissue and suppress AAA progression [ 3 ]. In addition, rosuvastatin also acts protectively against atrial fibrillation via the activation of Akt/Nrf2/HO-1 signaling [ 24 ].…”

“…Recent studies of Ho et al [ 2 ] presented that mice lacking HO-1 are more prone to angiotensin II-induced AAA with more severe elastin degradation, medial degeneration, increased macrophage recruitment, and matrix metalloproteinase- (MMP-) 9 level. Also, Azuma et al [ 3 ] showed that HO-1 heterozygote mice have higher concentration of proinflammatory cytokines in blood such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor- α (TNF- α ), interleukin- (IL-) 1 β , and IL-6, which emphasizes the anti-inflammatory role of HO-1. Those authors also reported that HO-1 induction by heme slows down AAA progression.…”