Paula Heinonen

University of Turku, Turku, Province of Western Finland, Finland

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Publications (3)23.52 Total impact

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    ABSTRACT: Screening of a foetal brain genomic DNA library allowed to isolate a 10-kb fragment of the gene encoding the human alpha2B-adrenergic receptor, that contained 5.5 kb of the 5'-flanking region, the open reading frame and 2.9 kb of the 3'-flanking region. The 1-kb fragment upstream from the start codon was rich in GC, lacked consensus TATA or CAAT box, but contained several Sp1-binding sites. Other potential cis-regulatory elements found in the 5'-flanking region included AP2, USF, Stat-6, NFkappaB and Olf-1. A single canonical polyadenylation signal (AATAAA) was found at position +3252/+3257 and the polyadenylation site was 3274 nucleotides downstream from ATG. Transfection experiments with chimeric luciferase constructs containing various truncated fragments of the 5'-region showed that the fragment -3160/+3 exhibited promoter activity in all tested cell lines and permitted the definition of a minimal 200-bp promoter (-603/-411) containing three putative Sp1-binding sites and two initiator elements. Transcriptional activity of this region was inhibited by the addition of mithramycin, a specific inhibitor of Sp1 binding to GC-rich sequences. The search for sequence variants within a fragment covering 1.7 kb of 5'-flanking region and the coding region allowed us to identify five novel single nucleotide polymorphisms. Interestingly, the G/C substitution at position -98 relative to the start codon was common and in complete linkage with a previously identified insertion/deletion polymorphism in the coding region which was showed to affect alpha2B-adrenergic receptor function. Based on transfection data and computer-assisted sequence analysis, the -98 G/C single nucleotide polymorphism was located within a portion of the 5'-UTR (-127/+3) affecting luciferase activity and it created additional putative binding site for Sp1. However, G/C substitution had no significant incidence on promoter activity in BHK-21 or HeLa cells.
    Biochemical Pharmacology 03/2004; 67(3):469-78. · 4.58 Impact Factor
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    ABSTRACT: A deletion variant of the alpha(2B)-adrenergic receptor (alpha(2B)-AR) has been associated with an increased risk of acute cardiac events in middle-aged men. Our aim was to determine the possible associations between the alpha(2B)-AR gene deletion variant and indicators of subclinical atherosclerosis in the brachial and carotid arteries. A total of 148 middle-aged men participating in an epidemiological twin study on risk factors for subclinical coronary heart disease were genotyped using PCR. Flow-mediated dilatation (FMD) of the brachial artery, carotid artery compliance and carotid intima-media thickness were measured using high-resolution ultrasound. FMD was 6.2+/-5.0% in subjects with the I/I (insertion/insertion) genotype, 5.5+/-4.1% in the I/D (insertion/deletion) group and 4.1+/-3.8% in the D/D (deletion/deletion) group ( P =0.03 for trend). In multivariate regression analysis controlling for age, presence of hypertension, smoking, use of angiotensin-converting enzyme inhibitors and plasma levels of low-density lipoprotein cholesterol and lipoprotein (a), the association between the alpha(2B)-AR genotype and FMD remained significant ( P =0.04 for trend). The alpha(2B)-AR genotype was not associated with intima-media thickness or carotid artery compliance. These findings indicate that subjects homozygous for the deletion allele of alpha(2B)-AR appear to have an increased risk of impaired endothelial function, which may provide an explanation for the previously observed increased risk of myocardial infarction in male subjects with this genotype. It is not known whether the association of the alpha(2B)-AR polymorphism with endothelial function is direct, or is mediated via altered sympathetic activation.
    Clinical Science 12/2002; 103(5):517-24. · 4.86 Impact Factor
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    ABSTRACT: Our aim was to study whether an insertion/deletion (I/D) polymorphism in the alpha2B-adrenoceptor gene is associated with the risk for cardiovascular diseases. alpha2-adrenoceptors mediate contraction of vascular smooth muscle and induce coronary vasoconstriction in humans. The alpha2-adrenoceptor subtype B mediates vasoconstriction in mice. A variant of the human alpha2B-adrenoceptor gene that encodes a D of three residues in an intracellular acidic motif has been shown to confer decreased receptor desensitization. This receptor variant could, therefore, be involved in diseases associated with enhanced vasoconstriction. This study was part of a prospective population-based study investigating risk factors for cardiovascular diseases in a cohort of middle-aged men from eastern Finland. Nine hundred twelve men aged 46 to 64 years were followed for an average time of 4.5 years. In this study population, 192 men (21%) had the D/D genotype; 256 (28%) had the I/I genotype, and 464 (51%) had a heterozygous genotype. In a Cox model adjusting for other coronary risk factors, men with the D/D genotype had 2.2 times (95% confidence interval: 1.1 to 4.4, p = 0.02) the risk to experience an acute coronary event (n = 15 for D/D, 10 for I/I and 12 for I/D) compared with men carrying either of the other two genotypes. The alpha2B-adrenoceptor genotype was not associated with hypertension in this study population. The D/D genotype of the alpha2B-adrenoceptor is a novel genetic risk factor for acute coronary events, but not for hypertension.
    Journal of the American College of Cardiology 06/2001; 37(6):1516-22. · 14.09 Impact Factor