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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

Lookup NU author(s): Professor Brian Walker

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Abstract

Copyright © 2016 by the Endocrine Society. 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.


Publication metadata

Author(s): White CI, Jansen MA, McGregor K, Mylonas KJ, Richardson RV, Thomson A, Moran CM, Seckl JR, Walker BR, Chapman KE, Gray GA

Publication type: Article

Publication status: Published

Journal: Endocrinology

Year: 2016

Volume: 157

Issue: 1

Pages: 346-357

Print publication date: 01/01/2016

Online publication date: 01/01/2016

Acceptance date: 08/10/2015

ISSN (print): 0013-7227

ISSN (electronic): 1945-7170

Publisher: Endocrine Society

URL: https://doi.org/10.1210/en.2015-1630

DOI: 10.1210/en.2015-1630

PubMed id: 26465199


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