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.
Highlights
Hsd11b1 mRNA and 11-HSD1 protein levels were both significantly reduced in the myocardium and aorta, but not in liver or skeletal muscle, of Hsd11b1CVCreϩ mice relative to their littermate controls (Hsd11b1CVCre-), consistent with selective disruption of gene expression in cardiomyocytes and vascular smooth muscle directed by SM22-␣-Cre (Figure 1) [21]
When injury was assessed at 8 weeks after myocardial infarction (MI) (Figure 2), either in vivo by magnetic resonance imaging (MRI) or in histological sections, infarct area was significantly less (P Ͻ .05) and average thickness was significantly greater (P Ͻ .005) in mice with global 11-HSD1 deficiency compared to their wild type (WT) controls
In this study we present three important findings: [1] that 11HSD1 amplifies infarct expansion and progression to press.endocrine.org/journal/endo 5 heart failure after MI, supporting the use of pharmacological inhibitors of 11HSD1 to prevent the development of heart failure in this setting; [2] that disruption of the Hsd11b1 gene in cardiac muscle does not prevent the expression of fetal genes or hypertrophic remodeling after MI suggesting that 11HSD1 in cardiomyocytes does not play a direct role in regulating this process; [3] that the promotion of peri-infarct angiogenesis associated with prevention of early infarct expansion in mice with global 11HSD1 deficiency [8] does not involve 11HSD1 in smooth muscle cells of the vessel wall
Summary
Cardiomyocyte and vascular smooth muscle independent 11-hydroxysteroid dehydrogenase 1 amplifies infarct expansion, hypertrophy and the development of heart failure following myocardial infarction in male mice. By 8 weeks after induction of MI, relative to C57Bl/6 wild type, globally 11-HSD1 deficient mice had reduced infarct size (34.7Ϯ2.1%LV vs 44.0Ϯ3.3%LV, Pϭ0.02), improved function (ejection fraction 33.5Ϯ2.5% vs 24.7Ϯ2.5%, Pϭ0.03) and reduced ventricular dilation (LVEDV 0.17Ϯ0.01ml vs 0.21Ϯ0.01ml, Pϭ0.01) This was accompanied by a reduction in hypertrophy, pulmonary edema and in the expression of genes encoding atrial natriuretic peptide and -myosin heavy chain. None of these outcomes, nor promotion of peri-infarct angiogenesis during infarct repair, were recapitulated when 11-HSD1 deficiency was restricted to cardiac and vascular smooth muscle. Pharmacological inhibition of 11-HSD1 may offer a new therapeutic approach to prevent heart failure associated with ischemic heart disease
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