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      Shorter GT repeat polymorphism in the heme oxygenase-1 gene promoter has protective effect on ischemic stroke in dyslipidemia patients

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          Abstract

          Background

          The microsatellite polymorphism of heme oxygenase (HO)-1 gene promoter has been shown to be associated with the susceptibility to ischemic event, including coronary artery disease (CAD), myocardial infarction, and peripheral vascular disease. We aimed to examine whether the length of (GT) n repeats in HO-1 gene promoter is associated with ischemic stroke in people with CAD risk factors, especially low level of HDL.

          Methods

          A total of 183 consecutive firstever ischemic stroke inpatients and 164 non-stroke patients were screened for the length of (GT) n repeats in HO-1 promoter. The long (L) and short (S) genotype are defined as the averaged repeat number >26 and ≦26, respectively.

          Results

          Stroke patients tended to have more proportions of hypertension, diabetics and genotype L, than those of genotype S. Patients with genotype L of HO-1 gene promoter have higher stroke risk in comparison with genotype S especially in dyslipidemia individuals. The significant differences on stroke risk in multivariate odds ratios were found especially in people with low HDL-C levels.

          Conclusions

          Subjects carrying longer (GT) n repeats in HO-1 gene promoter may have greater susceptibility to develop cerebral ischemic only in the presence of low HDL-C, suggesting the protective effects in HO-1 genotype S in the process of ischemic stroke, particularly in subjects with poor HDL-C status.

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          Most cited references30

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          Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications.

          In biological systems oxidation of heme is carried out by two isozymes of the microsomal heme oxygenase, HO-1 and HO-2. HO-1 is the commonly known heme oxygenase, the activity of which can be induced by up to 100-fold in response to a wide variety of stimuli (metals, heme, hormones, etc.). HO-2 was only recently discovered, and the isozyme appears to be uninducible. The two forms are products of two different genes and differ in their tissue expression. The primary structure of HO-1 and an HO-2 fragment of 91 amino acid residues show only 58% homology, but share a region with 100% secondary structure homology. This region is believed to be the catalytic site. Most likely, HO-1 gene is regulated in the same manner as metallothione in the gene. HO-1 has a heat shock regulatory element, and possibly many promoter elements, which bind to respective inducers and cause transcription of the gene. In vivo induction of HO-1 activity in the liver is accompanied by decreases in the total P-450 levels and, in a reconstituted system, cytochrome P-450b heme can be quantitatively converted to biliverdin by HO-1 and HO-2. The enzyme activity is inhibited in vivo for extended periods subsequent to binding of Zn- and Sn- protoporphyrins. This property appears useful for the suppression of bilirubin production. The metalloporphyrins, however, are not innocuous and cause major disruptions in cellular metabolism. In this review recent findings on heme oxygenase are highlighted.
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            Heme oxygenase: colors of defense against cellular stress.

            The discovery of the gaseous molecule nitric oxide in 1987 unraveled investigations on its functional role in the pathogenesis of a wide spectrum of biological and pathological processes. At that time, the novel concept that an endogenous production of a gaseous substance such as nitric oxide can impart such diverse and potent cellular effects proved to be very fruitful in enhancing our understanding of many disease processes including lung disorders. Interestingly, we have known for a longer period of time that there exists another gaseous molecule that is also generated endogenously; the heme oxygenase (HO) enzyme system generates the majority if not all of the endogenously produced carbon monoxide. This enzyme system also liberates two other by-products, bilirubin and ferritin, each possessing important biological functions and helping to define the uniqueness of the HO enzyme system. In recent years, interest in HO has emerged in numerous disciplines including the central nervous system, cardiovascular physiology, renal and hepatic systems, and transplantation. We review the functional role of HO in lung biology and its real potential application to lung diseases.
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              Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema.

              Cigarette smoke, containing reactive oxygen species, is the most important risk factor for chronic pulmonary emphysema (CPE). Heme oxygenase-1 (HO-1) plays a protective role as an antioxidant in the lung. A (GT)n dinucleotide repeat in the 5'-flanking region of human HO-1 gene shows length polymorphism and could modulate the level of gene transcription. To investigate the correlation between the length of the (GT)n repeat and susceptibility to the development of CPE, we screened the frequencies of alleles with varying numbers of (GT)n repeats in the HO-1 gene in 101 smokers with CPE and in 100 smokers without CPE. Polymorphisms of the (GT)n repeat were grouped into three classes: class S alleles ( /=30 repeats). The proportion of allele frequencies in class L, as well as the proportion of genotypic frequencies in the group with class L alleles (L/L, L/M, and L/S), was significantly higher in the smokers with CPE than in smokers without CPE. Moreover, we analyzed the promoter activities of the HO-1 gene carrying different (GT)n repeats (n=16, 20, 29, and 38), by transient-transfection assay in cultured cell lines. H2O2 exposure up-regulated the transcriptional activity of the HO-1 promoter/luciferase fusion genes with (GT)16 or (GT)20 but did not do so with (GT)29 or (GT)38. These findings suggest that the large size of a (GT)n repeat in the HO-1 gene promoter may reduce HO-1 inducibility by reactive oxygen species in cigarette smoke, thereby resulting in the development of CPE.
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                Author and article information

                Journal
                J Biomed Sci
                Journal of Biomedical Science
                BioMed Central
                1021-7770
                1423-0127
                2010
                23 February 2010
                : 17
                : 1
                : 12
                Affiliations
                [1 ]Central Laboratory, Shin Kong WHS Memorial Hospital, Taipei, Taiwan
                [2 ]School of Public Health, Taipei Medical University, Taipei, Taiwan
                [3 ]Changhua Christian Hospital Yunlin Branch, Yun-Lin County, Taiwan
                [4 ]Department of Neurology, Shin Kong WHS Memorial Hospital, Taipei, Taiwan
                [5 ]Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
                [6 ]Institutes of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
                Article
                1423-0127-17-12
                10.1186/1423-0127-17-12
                2841098
                20175935
                5eb7b82e-f460-40cc-bca8-70c0c9558e01
                Copyright ©2010 Bai et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 1 September 2009
                : 23 February 2010
                Categories
                Research

                Molecular medicine
                Molecular medicine

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