Abstract
Heme oxygenase-1 (HO-1), encoded by HMOX1 gene and regulated by Nrf2 transcription factor, is a cytoprotective enzyme. Its deficiency may exacerbate abdominal aortic aneurysm (AAA) development, which is also often associated with hyperlipidemia. Beneficial effects of statins, the broadly used antilipidemic drugs, were attributed to modulation of Nrf2/HO-1 axis. However, the effect of statins on Nrf2/HO-1 pathway in patients with AAA has not been studied yet. We analyzed AAA tissue from patients treated with simvastatin (N = 28) or without statins (N = 14). Simvastatin treatment increased HO-1 protein level in AAA, both in endothelial cells (ECs) and in smooth muscle cells (SMCs), but increased Nrf2 localization was restricted only to vasa vasorum. Nrf2 target genes HMOX1, NQO1, and GCLM expression remained unchanged in AAA. In vitro studies showed that simvastatin raises HO-1 protein level slightly in ECs and to much higher extent in SMCs, which is not related to Nrf2/ARE activation, although HMOX1 expression is upregulated by simvastatin in both cell types. In conclusion, simvastatin-induced modulation of HO-1 level in ECs and SMCs in vitro is not related to Nrf2/ARE activity. Likewise, divergent HO-1 and Nrf2 localization together with stable expression of Nrf2 target genes, including HMOX1, in AAA tissue denotes Nrf2 independency.
Highlights
Abdominal aortic aneurysm (AAA) is characterized by overproduction of free radicals and depletion of antioxidative enzymes which localization may vary depending on the aortic layer and the stage of aneurysm development
Azuma et al [3] showed that Heme oxygenase-1 (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-) 1β, and IL-6, which emphasizes the anti-inflammatory role of HO-1
The results indicated that simvastatin might have an effect on HO-1 as upregulation of heme oxygenase-1 (HMOX1) mRNA (Figure 3(b)) and a strong increase in HO-1 at the protein level (Figures 3(c)-3(d)) with an increase in Bach1, a signaling molecule that dissociates from ARE when Nrf2 binds to DNA, was observed (Figures 3(b)-3(c))
Summary
Abdominal aortic aneurysm (AAA) is characterized by overproduction of free radicals and depletion of antioxidative enzymes which localization may vary depending on the aortic layer and the stage of aneurysm development. Yajima et al [1] indicated that during AAA development in rodents, over 200 genes involved in oxidative stress are upregulated including heme oxygenase-1 (HMOX1), inducible nitric oxide synthase (NOS2), or 12-lipoxygenase (ALOX12). 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-) 1β, and IL-6, which emphasizes the anti-inflammatory role of HO-1. Those authors reported that HO-1 induction by heme slows down AAA progression. Other protective effects of HO-1 may include reduction of vascular smooth muscle cell (VSMC) proliferation, inhibition of platelet aggregation, and attenuation of vasoconstriction [4, 5]
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