title: Induction of angiotensin-converting enzyme after miR-143/145 deletion is critical for impaired smooth muscle contractility.
abstract: MicroRNAs have emerged as regulators of smooth muscle cell phenotype with a role in smooth muscle-related disease. Studies have shown that miR-143 and miR-145 are the most highly expressed microRNAs in smooth muscle cells, controlling differentiation and function. The effect of miR-143/145 knockout has been established in the vasculature but not in smooth muscle from other organs. Using knockout mice we found that maximal contraction induced by either depolarization or phosphatase inhibition was reduced in vascular and airway smooth muscle but maintained in the urinary bladder. Furthermore, a reduction of media thickness and reduced expression of differentiation markers was seen in the aorta but not in the bladder. Supporting the view that phenotype switching depends on a tissue-specific target of miR-143/145, we found induction of angiotensin-converting enzyme in the aorta but not in the bladder where angiotensin-converting enzyme was expressed at a low level. Chronic treatment with angiotensin type-1 receptor antagonist restored contractility in miR-143/145-deficient aorta while leaving bladder contractility unaffected. This shows that tissue-specific targets are critical for the effects of miR-143/145 on smooth muscle differentiation and that angiotensin converting enzyme is one such target.
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden;
authors.forename: Diana
authors.initials: D
authors.lastname: Dahan
authors.affiliation: Department of Biology, Lund University, Lund, Sweden; and.
authors.forename: Mari
authors.initials: M
authors.lastname: Ekman
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden;
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Larsson-Callerfelt
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden;
authors.forename: Karolina
authors.initials: K
authors.lastname: Turczyńska
authors.affiliation: Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Boettger
authors.affiliation: Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden;
authors.forename: Karl
authors.initials: K
authors.lastname: Swärd
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden; sebastian.albinsson@med.lu.se.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Albinsson
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D017353:Gene Deletion; D005838:Genotype; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D009924:Organ Culture Techniques; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000235:genetics; D010641:Phenotype; D012137:Respiratory System / Q000201:enzymology / Q000503:physiopathology; D015398:Signal Transduction; D001743:Urinary Bladder / Q000201:enzymology / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; C532884:MIRN143 microRNA, mouse; D014662:Vasoconstrictor Agents; D007703:Peptidyl-Dipeptidase A
keywords: airway; angiotensin II; contractile protein; detrusor; miR-145; microRNA; myocardin; smooth muscle; urinary bladder; vascular biology