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 + or - 2.1% left ventricle [LV] vs 44.0 + or - 3.3% LV, P= .02), improved function (ejection fraction, 33.5 + or - 2.5% vs 24.7 + or - 2.5%, P= .03) and reduced ventricular dilation (LV end-diastolic volume, 0.17 + or - 0.01 vs 0.21 + or - 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.