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.
Highlights
Abdominal aortic aneurysm (AAA) disease is a potentially lethal condition that is characterized by the destructive remodeling of the infrarenal (IR) aorta [1]
We found that the size of aortic diameters significantly increased in heme oxygenase-1 (HO-1) Het mice compared to WT mice beginning day 7, and progressively significantly increasing from days 14, 21, and 28 (45.0±7.6%, 64.8±15.3% (p = 0.010), 67.7±13.4% (p
In the porcine pancreatic elastase (PPE) murine AAA model, it is this inflammatory process, and not the infusion of PPE itself, that leads to aneurysmal dilatation [32]
Summary
Abdominal aortic aneurysm (AAA) disease is a potentially lethal condition that is characterized by the destructive remodeling of the infrarenal (IR) aorta [1]. It is a complex disease process involving the infiltration of inflammatory cells, the production of reactive oxygen species (ROS), upregulation and activation of degradative proteases, inactivation of nascent protease inhibitors, stimulation of apoptosis, degradation of elastin, transmural inflammation, and resistive hemodynamic conditions [2]. Other potential protective effects of HO-1 include a reduction of vascular smooth muscle cell (VSMC) proliferation, attenuation of vasoconstriction [6], scavenging of free radicals, inhibition of platelet aggregation [7], and up-regulation of transferrin expression with subsequent sequestration of oxidative free iron [8]. An increase in HO-1 gene expression has been observed under high-flow conditions and associated with experimental AAA attenuation [12]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have