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: Christopher I White, Maurits A Jansen, Kieran McGregor, Katie J Mylonas, Rachel V Richardson, Adrian Thomson, Carmel M Moran, Jonathan R Seckl, Brian R Walker, Karen E Chapman, Gillian A Gray
• Journal: Endocrinology (Endocrinology) Vol. 157 Issue 1 Pg. 346-57 (Jan 2016) ISSN: 1945-7170 [Electronic] United States
• PMID: 26465199 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 11-beta-Hydroxysteroid Dehydrogenase Type 1

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (deficiency, genetics, metabolism)
• Animals
• Cardiomegaly (etiology, prevention & control)
• Coronary Circulation
• Crosses, Genetic
• Gene Expression Regulation
• Heart Failure (etiology, prevention & control)
• Heart Ventricles (metabolism, pathology, physiopathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Muscle, Smooth, Vascular (enzymology, metabolism, pathology)
• Myocardial Infarction (metabolism, pathology, physiopathology)
• Myocytes, Cardiac (enzymology, metabolism, pathology)
• Neovascularization, Physiologic
• Organ Size
• Pulmonary Edema (etiology, prevention & control)
• Stroke Volume