Associations Between Plasma Heme Oxygenase-1 Levels and Coronary and Peripheral Artery Disease

Introduction: Peripheral artery disease affects 12-20% Americans over the age of 60. Thioredoxin-1 (Trx-1) is a class of small redox proteins. We have demonstrated earlier that Trx-1 reduces oxidative stress resulting in less inflammation and increased angiogenesis in cardiac muscle via heme oxygenase-1 (HO-1) and VEGF after myocardial infarction. In the current study, we evaluate the effect of Trx-1 on post-ischemic hindlimb recovery. Methods: Peripheral artery disease was mimicked using a hindlimb ischemia (HLI) model. Wild type (WT) and Trx-1 transgenic (Trx-1Tg/+) mice (8-12 weeks old) were subjected to femoral artery ligation. Following surgery, mice were observed for 5 weeks. Serial laser doppler images were obtained, and perfusion ratios between the ischemic and non-ischemic limbs were calculated at set time intervals. The perfusion ratios were compared between WT and Trx-1Tg/+ groups. Immunohistochemical analysis of the skeletal muscle was performed to quantify the extent of fibrosis, capillary and arteriolar density 35 days after surgery. In addition, another set of experiments was designed with Ad.Trx-1 gene therapy after femoral artery ligation to study the molecular mechanism of neovascularization with Trx-1. Results: The recovery of hind limb perfusion was significantly increased in Trx-1Tg/+ mice at day 7 (0.19 ± 0.03 vs. 0.36 ± 0.07 (n=12-9), day-21 (0.37 ± 0.05 vs. 0.62 ± 0.03 (n=12-9), and day 28 (0.40 ± 0.04 vs. 0.79 ± 0.04 (n=10-9); p<0.05). Capillary density [1265 ± 87.8 vs. 762.4 ± 86.6 counts/mm2 ; (n=5); p<0.05] and arteriolar density [36.2 ± 2.96 vs. 22± 1.33 counts/mm2 ; (n=5); p<0.05] staining showed significant increase in Trx-1Tg/+ mice as compared to WT mice. Picrosirrus Red and immunofluorescence staining showed decreased fibrosis [8.3 ± 0.46 vs. 22.2 ± 1.04 (n=5); p<0.0001] and increased HO-1 expression respectively in Trx-1Tg/+ mice group as compared to WT mice, respectively. Trx-1 gene therapy study also revealed by Western blot analysis, increased Trx-1 (4.2 fold) and HO-1 (8.2 fold) expression in Ad.Trx-1-HLI as compared to Ad.LacZ-HLI. Conclusions: Our results suggest that Trx-1 is a potential therapeutic agent to increase blood perfusion and angiogenesis for the treatment of critical limb ischemia patients.

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Plasma Heme Oxygenase-1 Levels in Patients with Coronary and Peripheral Artery Diseases

Disease Markers ◽

10.1155/2018/6138124 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Yoshimi Kishimoto ◽

Susumu Ibe ◽

Emi Saita ◽

Kenji Sasaki ◽

Hanako Niki ◽

...

Keyword(s):

Heme Oxygenase ◽

Ankle Brachial Index ◽

Protective Role ◽

Heme Oxygenase 1 ◽

Peripheral Artery ◽

Intracellular Enzyme ◽

Vessel Disease ◽

Artery Disease ◽

Peripheral Artery Diseases ◽

Progression Of Atherosclerosis

Aims. Heme oxygenase-1 (HO-1) is an intracellular enzyme that catalyzes the oxidation of heme to generate CO, biliverdin, and iron. Since these products have antiatherogenic properties, HO-1 may play a protective role against the progression of atherosclerosis. However, plasma HO-1 levels in patients with atherosclerotic diseases, such as coronary artery disease (CAD) and peripheral artery disease (PAD), have not been clarified yet. Methods. We investigated plasma HO-1 levels by ELISA in 410 consecutive patients undergoing elective coronary angiography who also had an ankle-brachial index (ABI) test for PAD screening. Results. Of the 410 study patients, CAD was present in 225 patients (55%) (1-vessel (1-VD), n=91; 2-vessel (2-VD), n=66; 3-vessel disease (3-VD), n=68). PAD (ABI < 0.9) was found in 36 (9%) patients. Plasma HO-1 levels did not differ between 225 patients with CAD and 185 without CAD (median 0.44 versus 0.35 ng/mL), but they were significantly lower in 36 patients with PAD than in 374 without PAD (0.27 versus 0.41 ng/mL, P<0.02). After excluding the 36 patients with PAD, HO-1 levels were significantly higher in 192 patients with CAD than in 182 without CAD (0.45 versus 0.35 ng/mL, P<0.05). HO-1 levels in 4 groups of CAD(−), 1-VD, 2-VD, and 3-VD were 0.35, 0.49, 0.44, and 0.44 ng/mL, respectively, and were highest in 1-VD (P<0.05). In the multivariate analysis, HO-1 levels were inversely associated with PAD, whereas they were also associated with CAD. The odds ratios for PAD and CAD were 2.12 (95% CI = 1.03–4.37) and 0.65 (95% CI = 0.42–0.99) for the HO-1 level of <0.35 ng/mL, respectively. Conclusions. Plasma HO-1 levels were found to be low in patients with PAD, in contrast to high levels in patients with CAD.

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Associations of coronary and peripheral artery disease with presence, expansion, and rupture of abdominal aortic aneurysm – a grin without a cat!

VASA ◽

10.1024/0301-1526/a000606 ◽

2017 ◽

Vol 46 (3) ◽

pp. 151-158 ◽

Cited By ~ 4

Author(s):

Hisato Takagi ◽

Takuya Umemoto

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Peripheral Artery Disease ◽

Literature Search ◽

Systematic Literature Search ◽

Peripheral Artery ◽

Epidemiological Evidence ◽

Abdominal Aortic ◽

Artery Disease ◽

Meta Analyses

Abstract. Both coronary and peripheral artery disease are representative atherosclerotic diseases, which are also known to be positively associated with presence of abdominal aortic aneurysm. It is still controversial, however, whether coronary and peripheral artery disease are positively associated with expansion and rupture as well as presence of abdominal aortic aneurysm. In the present article, we overviewed epidemiological evidence, i. e. meta-analyses, regarding the associations of coronary and peripheral artery disease with presence, expansion, and rupture of abdominal aortic aneurysm through a systematic literature search. Our exhaustive search identified seven meta-analyses, which suggest that both coronary and peripheral artery disease are positively associated with presence of abdominal aortic aneurysm, may be negatively associated with expansion of abdominal aortic aneurysm, and might be unassociated with rupture of abdominal aortic aneurysm.

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