Induction of Heme Oxygenase‐1 Is Linked to the Severity of Disease in Human Abdominal Aortic Aneurysm

Abstract

Background Rupture of abdominal aortic aneurysm (rAAA) is associated with high case fatality rates, and risk of rupture increases with the AAA diameter. Heme oxygenase‐1 (gene HMOX1 , protein HO‐1) is a stress‐induced protein and induction has protective effects in the vessel wall. HMOX1 −/− mice are more susceptible to angiotensin II‐induced AAA formation, but the regulation in human nonruptured and ruptured AAA is only poorly understood. Our hypothesis proposed that HO‐1 is reduced in AAA and lowering is inversely associated with the AAA diameter. Methods and Results AAA walls from patients undergoing elective open repair (eAAA) or surgery because of rupture (rAAA) were analyzed for aortic HMOX1 /HO‐1 expression by quantitative real‐time polymerase chain reaction and Western blot. Aortas from patients with aortic occlusive disease served as controls. HMOX1 /HO‐1 expression was 1.1‐ to 7.6‐fold upregulated in eAAA and rAAA. HO‐1 expression was 3‐fold higher in eAAA specimen with a diameter >84.4 mm, whereas HO‐1 was not different in rAAA. Other variables that are known for associations with AAA and HO‐1 induction were tested. In eAAA, HO‐1 expression was negatively correlated with aortic collagen content and oxidative stress parameters H 2 O 2 release, oxidized proteins, and thiobarbituric acid reactive substances. Serum HO‐1 concentrations were analyzed in patients with eAAA, and maximum values were found in an aortic diameter of 55 to 70 mm with no further increase >70 mm, compared with <55 mm. Conclusions Aortic HO‐1 expression was increased in eAAA and rAAA. HO‐1 increased with the severity of disease but was additionally connected to less oxidative stress and vasoprotective mechanisms.

Edaravone Attenuated Angiotensin II-Induced Atherosclerosis and Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice

“…Emerging evidence has suggested that the development of AAAs in humans is related to vascular oxidative stress and inflammation [ 23 , 40 , 41 , 42 , 43 ]. Therefore, reducing oxidative stress and inflammation can be an efficient strategy for limiting AAA development [ 44 ].…”

Pharmacotherapies and Aortic Heme Oxygenase-1 Expression in Patients with Abdominal Aortic Aneurysm

“…In the present study, aortic HO-1 mRNA and protein expressions in response to prescription of lipid-lowering and antihypertensive therapies as well as therapeutic anticoagulation were analyzed in aortic tissues of patients with late-stage AAA. These therapies were tested for their potential to induce HO-1 expression because an induction of HO-1 is considered to be protective in many cardiovascular diseases, including AAA [ 10 , 11 , 12 , 13 ].…”

“…Reverse transcription of mRNA into cDNA was performed with MultiScribe reverse transcriptase (Thermo Fisher Scientific, Darmstadt, Germany) using random hexamer primers according to the manufacturer’s instructions. Quantification of mRNA expression was performed by real-time PCR with GoTaq qPCR master mix (Promega, Walldorf, Germany) and the Step One Plus Real-Time PCR system (Thermo Fisher Scientific, Darmstadt, Germany) [ 13 ]. A geometric mean of three reference genes, namely, ribosomal protein L32 ( RPL32 ), TATA-box binding protein ( TBP ), and beta-2-microglobulin ( B2M ), was used for cDNA content normalization [ 15 ].…”

“…Ultrasonication (15 s) was applied to remove remaining DNA, and protein concentration was determined by BCA protein assay reagent (Thermo Fisher Scientific, Darmstadt, Germany). Proteins (15–30 µg) were separated by 4–12% Bis-Tris protein gels (Thermo Fisher Scientific, Darmstadt, Germany) and transferred to nitrocellulose membranes [ 13 ]. Membranes were incubated with a primary antibody against HO-1 using a dilution of 1:500–1:1000 (#610713, BD Biosciences, Heidelberg, Germany).…”

“…The genetic deletion of HO-1 exacerbated the development of AAA in mouse models [ 11 , 12 ]. We have recently shown that HO-1 expression was increased in human late-stage AAA and that the increase was inversely linked to oxidative stress [ 13 ]. Mice lacking HO-1 had increased thrombus formation in response to vessel injury [ 14 ].…”