title: Human aldosterone synthase gene polymorphism promotes miRNA binding and regulates gene expression.
abstract: Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure. Like other complex diseases, hypertension is caused by a combination of genetic and environmental factors. The renin-angiotensin-aldosterone system plays an important role in the regulation of blood pressure. The octapeptide angiotensin II (ANG II) is one of the most active vasopressor agents and is obtained from the precursor molecule, angiotensinogen, by the combined proteolytic action of renin and angiotensin-converting enzyme. ANG II increases the expression of aldosterone synthase (coded by Cyp11B2 gene), which is the rate-limiting enzyme in the biosynthesis of aldosterone. Previous studies have shown that increased expression of aldosterone synthase increases blood pressure and cardiac hypertrophy in transgenic mice. Human Cyp11B2 gene has a T/C polymorphism at -344 positions in its 5'-untranslated region (UTR), and the -344T allele is associated with hypertension. Human Cyp11B2 gene also has an A/G polymorphism at 735 position in its 3'-UTR (rs28491316) that is in linkage disequilibrium with single nucleotide polymorphism at -344. We show here that 1) microRNA (miR)-766 binds to the 735G-allele and not the 735A-allele of the hCyp11B2 gene and 2) transfection of miR-766 reduces the human aldosterone synthase mRNA and protein level in human adrenocortical cells H295R. These studies suggest that miR-766 may downregulate the expression of human aldosterone synthase gene and reduce blood pressure in human subjects containing -344T allele.
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo Health Science Campus, Toledo, Ohio.
authors.forename: Shreekrishna
authors.initials: S
authors.lastname: Maharjan
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo Health Science Campus, Toledo, Ohio.
authors.forename: Brahmaraju
authors.initials: B
authors.lastname: Mopidevi
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo Health Science Campus, Toledo, Ohio.
authors.forename: Meenakshi Kaul
authors.initials: MK
authors.lastname: Kaw
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo Health Science Campus, Toledo, Ohio.
authors.forename: Nitin
authors.initials: N
authors.lastname: Puri
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo Health Science Campus, Toledo, Ohio ashok.kumar2@utoledo.edu.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000483:Alleles; D000804:Angiotensin II / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D011110:Polymorphism, Genetic; D012084:Renin-Angiotensin System / Q000235:genetics
chemical_list: C575913:MIRN766 microRNA, human; D035683:MicroRNAs; D000804:Angiotensin II; D019405:Cytochrome P-450 CYP11B2
keywords: 3′-untranslated region; Cyp11b2; aldosterone synthase; blood pressure regulation; hypertension; miRNA; rs28491316; single nucleotide polymorphism