Advertisement

A promoter variant of the heme oxygenase-1 gene may reduce the incidence of ischemic heart disease in Japanese

      Abstract

      Heme oxygenase-1 (HO-1) has been suggested to have antiatherogenic properties. This study was designed to examine the relationship between the HO-1 gene (HMOX1) and ischemic heart disease. The study population consisted of 1972 control subjects and 597 subjects with ischemic heart disease (myocardial infarction (MI) n=393, HMOX1 n=204). The control subjects were consecutively selected from the Suita study, an epidemiological cohort representing the general population in Japan. Patients with ischemic heart disease were recruited from the outpatient clinic of the National Cardiovascular Center (NCVC). We sequenced HMOX1 and found a T(−413)A polymorphism in the promoter region. Multiple logistic analyses indicated that the T(−413)A (TA+TT/AA) polymorphism, sex, smoking habit, DM and BMI affected the occurrence of ischemic heart disease. The odds ratios of the TA+TT allele for MI and AP were 1.42 (P=0.0468, 95% confidence interval: 0.01–0.35) and 1.86 (P=0.0096, 95% confidence interval: 0.08–0.55), respectively. Luciferase reporter assay indicated that the A allele promoter had significantly higher activity than the T allele promoter. The AA genotype of HMOX1 reduced the incidence of ischemic heart disease, possibly due to the high expression level of HMOX1.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Halliwell B
        • Gutteridge J.M
        Role of free radicals and catalytic metal ions in human disease: an overview.
        Meth. Enzymol. 1990; 186: 1-85
        • Ishikawa K
        • Maruyama Y
        Heme oxygenase as an intrinsic defense system in vascular wall: implication against atherogenesis.
        J. Atheroscler. Thromb. 2001; 8: 63-70
        • Ewing J.F
        • Maines M.D
        Rapid induction of heme oxygenase-1 mRNA and protein by hyperthermia in rat brain: heme oxygenase 2 is not a heat shock protein.
        Proc. Natl. Acad. Sci. U.S.A. 1991; 88: 5364-5368
        • Shibahara S
        • Yoshida T
        • Kikuchi G
        Induction of heme oxygenase by hemin in cultured pig alveolar macrophages.
        Arch. Biochem. Biophys. 1978; 188: 243-250
        • Siow R.C
        • Ishii T
        • Sato H
        • et al.
        Induction of the antioxidant stress proteins heme oxygenase-1 and MSP23 by stress agents and oxidised LDL in cultured vascular smooth muscle cells.
        FEBS Lett. 1995; 368: 239-242
        • Rizzardini M
        • Terao M
        • Falciani F
        • Cantoni L
        Cytokine induction of haem oxygenase mRNA in mouse liver. Interleukin 1 transcriptionally activates the haem oxygenase gene.
        Biochem. J. 1993; 290: 343-347
        • Murphy B.J
        • Laderoute K.R
        • Short S.M
        • Sutherland R.M
        The identification of heme oxygenase as a major hypoxic stress protein in Chinese hamster ovary cells.
        Br. J. Cancer. 1991; 64: 69-73
        • Wang L.J
        • Lee T.S
        • Lee F.Y
        • Pai R.C
        • Chau L.Y
        Expression of heme oxygenase-1 in atherosclerotic lesions.
        Am. J. Pathol. 1998; 152: 711-720
        • Ishikawa K
        • Sugawara D
        • Goto J
        • et al.
        Heme oxygenase-1 inhibits atherogenesis in Watanabe heritable hyperlipidemic rabbits.
        Circulation. 2001; 104: 1831-1836
        • Ishikawa K
        • Sugawara D
        • Wang Xp
        • et al.
        Heme oxygenase-1 inhibits atherosclerotic lesion formation in LDL-receptor knockout mice.
        Circ. Res. 2001; 88: 506-512
        • Iwai N
        • Katsuya T
        • Mannami T
        • et al.
        Association between SAH, an acyl-CoA synthetase gene, and hypertriglyceridemia, obesity, and hypertension.
        Circulation. 2002; 105: 41-47
        • Yamada N
        • Yamaya M
        • Okinaga S
        • et al.
        Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema.
        Am. J. Human Genet. 2000; 66: 187-195
        • Exner M
        • Schillinger M
        • Minar E
        • et al.
        Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with restenosis after percutaneous transluminal angioplasty.
        J. Endovasc. Ther. 2001; 8: 433-440
        • Kaneda H
        • Ohno M
        • Taguchi J
        • et al.
        Heme oxygenase-1 gene promoter polymorphism is associated with coronary artery disease in Japanese patients with coronary risk factors.
        Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1680-1685
        • Stocker R
        • Yamamoto Y
        • McDonagh A.F
        • Glazer A.N
        • Ames B.N
        Bilirubin is an antioxidant of possible physiological importance.
        Science. 1987; 235: 1043-1046
        • Ishikawa K
        • Navab M
        • Leitinger N
        • Fogelman A.M
        • Lusis A.J
        Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL.
        J. Clin. Invest. 1997; 100: 1209-1216
        • Duckers H.J
        • Boehm M
        • True A.L
        • et al.
        Heme oxygenase-1 protects against vascular constriction and proliferation.
        Nat. Med. 2001; 7: 693-698
        • Wagner C.T
        • Durante W
        • Christodoulides N
        • Hellums J.D
        • Schafer A.I
        Hemodynamic forces induce the expression of heme oxygenase in cultured vascular smooth muscle cells.
        J. Clin. Invest. 1997; 100: 589-596