11β-HSD1 inhibition ameliorates diabetes-induced cardiomyocyte hypertrophy and cardiac fibrosis through modulation of EGFR activity.

11β-HSD1 has been recognized as a potential therapeutic target for type 2 diabetes. Recent studies have shown that hyperglycemia leads to activation of 11β-HSD1, increasing the intracellular glucocorticoid levels. Excess glucocorticoids may lead to the clinical manifestations of cardiac injury. Therefore, the aim of this study is to investigate whether 11β-HSD1 activation contributes to the development of diabetic cardiomyopathy. To investigate the role of 11β-HSD1, we administered a selective 11β-HSD1 inhibitor in type 1 and type 2 murine models of diabetes and in cultured cardiomyocytes. Our results show that diabetes increases cortisone levels in heart tissues. 11β-HSD1 inhibitor decreased cortisone levels and ameliorated all structural and functional features of diabetic cardiomyopathy including fibrosis and hypertrophy. We also show that high levels of glucose caused cardiomyocyte hypertrophy and increased matrix protein deposition in culture. Importantly, inhibition of 11β-HSD1 attenuated these changes. Moreover, we show that 11β-HSD1 activation mediates these changes through modulating EGFR phosphorylation and activity. Our findings demonstrate that 11β-HSD1 contributes to the development of diabetic cardiomyopathy through activation of glucocorticoid and EGFR signaling pathway. These results suggest that inhibition of 11β-HSD1 might be a therapeutic strategy for diabetic cardiomyopathy, which is independent of its effects on glucose homeostasis.