Cardiomyocyte and Vascular Smooth Muscle-Independent 11 beta-Hydroxysteroid Dehydrogenase 1 Amplifies Infarct Expansion, Hypertrophy, and the Development of Heart Failure After Myocardial Infarction in Male Mice

Global deficiency of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), an enzyme that regenerates glucocorticoids within cells, promotes angiogenesis, and reduces acute infarct expansion after myocardial infarction (MI), suggesting that 11 beta-HSD1 activity has an adverse influence on wound healing in the heart after MI. The present study investigated whether 11 beta-HSD1 deficiency could prevent the development of heart failure after MI and examined whether 11 beta-HSD1 deficiency in cardiomyocytes and vascular smooth muscle cells confers this protection. Male mice with global deficiency in 11 beta-HSD1, or with Hsd11b1 disruption in cardiac and vascular smooth muscle (via SM22 alpha-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 11 beta-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 beta-myosin heavy chain. None of these outcomes, nor promotion of periinfarct angiogenesis during infarct repair, were recapitulated when 11 beta-HSD1 deficiency was restricted to cardiac and vascular smooth muscle. 11 beta-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 11 beta-HSD1 may offer a new therapeutic approach to prevent heart failure associated with ischemic heart disease.