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

Endocrinology. 2016 Jan;157(1):346-57. doi: 10.1210/en.2015-1630. Epub 2015 Oct 14.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1