title: Cardiomyocyte and Vascular Smooth Muscle-Independent 11β-Hydroxysteroid Dehydrogenase 1 Amplifies Infarct Expansion, Hypertrophy, and the Development of Heart Failure After Myocardial Infarction in Male Mice.
abstract: Global deficiency of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme that regenerates glucocorticoids within cells, promotes angiogenesis, and reduces acute infarct expansion after myocardial infarction (MI), suggesting that 11β-HSD1 activity has an adverse influence on wound healing in the heart after MI. The present study investigated whether 11β-HSD1 deficiency could prevent the development of heart failure after MI and examined whether 11β-HSD1 deficiency in cardiomyocytes and vascular smooth muscle cells confers this protection. Male mice with global deficiency in 11β-HSD1, or with Hsd11b1 disruption in cardiac and vascular smooth muscle (via SM22α-Cre recombinase), underwent coronary artery ligation for induction of MI. Acute injury was equivalent in all groups. However, by 8 weeks after induction of MI, relative to C57Bl/6 wild type, globally 11β-HSD1-deficient mice had reduced infarct size (34.7 ± 2.1% left ventricle [LV] vs 44.0 ± 3.3% LV, P = .02), improved function (ejection fraction, 33.5 ± 2.5% vs 24.7 ± 2.5%, P = .03) and reduced ventricular dilation (LV end-diastolic volume, 0.17 ± 0.01 vs 0.21 ± 0.01 mL, P = .01). This was accompanied by a reduction in hypertrophy, pulmonary edema, and in the expression of genes encoding atrial natriuretic peptide and β-myosin heavy chain. None of these outcomes, nor promotion of periinfarct angiogenesis during infarct repair, were recapitulated when 11β-HSD1 deficiency was restricted to cardiac and vascular smooth muscle. 11β-HSD1 expressed in cells other than cardiomyocytes or vascular smooth muscle limits angiogenesis and promotes infarct expansion with adverse ventricular remodeling after MI. Early pharmacological inhibition of 11β-HSD1 may offer a new therapeutic approach to prevent heart failure associated with ischemic heart disease.
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science (C.I.W., M.A.J., K.M., K.J.M., R.V.R., C.M.M., J.R.S., B.R.W., K.E.C., G.A.G.), Queens Medical Research Institute, and Edinburgh Preclinical Imaging (M.A.J., A.T., C.M.M.), College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: White
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science (C.I.W., M.A.J., K.M., K.J.M., R.V.R., C.M.M., J.R.S., B.R.W., K.E.C., G.A.G.), Queens Medical Research Institute, and Edinburgh Preclinical Imaging (M.A.J., A.T., C.M.M.), College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Maurits A
authors.initials: MA
authors.lastname: Jansen
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science (C.I.W., M.A.J., K.M., K.J.M., R.V.R., C.M.M., J.R.S., B.R.W., K.E.C., G.A.G.), Queens Medical Research Institute, and Edinburgh Preclinical Imaging (M.A.J., A.T., C.M.M.), College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Kieran
authors.initials: K
authors.lastname: McGregor
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science (C.I.W., M.A.J., K.M., K.J.M., R.V.R., C.M.M., J.R.S., B.R.W., K.E.C., G.A.G.), Queens Medical Research Institute, and Edinburgh Preclinical Imaging (M.A.J., A.T., C.M.M.), College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Mylonas
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science (C.I.W., M.A.J., K.M., K.J.M., R.V.R., C.M.M., J.R.S., B.R.W., K.E.C., G.A.G.), Queens Medical Research Institute, and Edinburgh Preclinical Imaging (M.A.J., A.T., C.M.M.), College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Rachel V
authors.initials: RV
authors.lastname: Richardson
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science (C.I.W., M.A.J., K.M., K.J.M., R.V.R., C.M.M., J.R.S., B.R.W., K.E.C., G.A.G.), Queens Medical Research Institute, and Edinburgh Preclinical Imaging (M.A.J., A.T., C.M.M.), College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Adrian
authors.initials: A
authors.lastname: Thomson
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science (C.I.W., M.A.J., K.M., K.J.M., R.V.R., C.M.M., J.R.S., B.R.W., K.E.C., G.A.G.), Queens Medical Research Institute, and Edinburgh Preclinical Imaging (M.A.J., A.T., C.M.M.), College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Moran
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science (C.I.W., M.A.J., K.M., K.J.M., R.V.R., C.M.M., J.R.S., B.R.W., K.E.C., G.A.G.), Queens Medical Research Institute, and Edinburgh Preclinical Imaging (M.A.J., A.T., C.M.M.), College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science (C.I.W., M.A.J., K.M., K.J.M., R.V.R., C.M.M., J.R.S., B.R.W., K.E.C., G.A.G.), Queens Medical Research Institute, and Edinburgh Preclinical Imaging (M.A.J., A.T., C.M.M.), College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science (C.I.W., M.A.J., K.M., K.J.M., R.V.R., C.M.M., J.R.S., B.R.W., K.E.C., G.A.G.), Queens Medical Research Institute, and Edinburgh Preclinical Imaging (M.A.J., A.T., C.M.M.), College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science (C.I.W., M.A.J., K.M., K.J.M., R.V.R., C.M.M., J.R.S., B.R.W., K.E.C., G.A.G.), Queens Medical Research Institute, and Edinburgh Preclinical Imaging (M.A.J., A.T., C.M.M.), College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Gillian A
authors.initials: GA
authors.lastname: Gray
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000517:prevention & control*; D003326:Coronary Circulation; D003433:Crosses, Genetic; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control*; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D009929:Organ Size; D011654:Pulmonary Edema / Q000209:etiology / Q000517:prevention & control; D013318:Stroke Volume
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1