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Abstract / Description of output
Global deficiency of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), an enzyme that regenerates glucocorticoids within cells, promotes angiogenesis and reduces acute infarct expansion following 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 following 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%LV vs 44.0±3.3%LV, P=0.02), improved function (ejection fraction 33.5±2.5% vs 24.7±2.5%, P=0.03) and reduced ventricular dilation (LVEDV 0.17±0.01ml vs 0.21±0.01ml, P=0.01). 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 peri-infarct 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.
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- 1 Article
Gray, G., White, C. I., Castellan, R. F. P., McSweeney, S. J. & Chapman, K., 1 Jan 2017, In: Journal of molecular endocrinology. 58, 1, p. R1-R13 13 p.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile