Cardiovascular side effects are frequent problems accompanying systemic glucocorticoid therapy, although the underlying mechanisms are not fully resolved. Reactive oxygen species (ROS) have been shown to promote various cardiovascular diseases although the link between glucocorticoid and ROS signaling has been controversial. As the family of NADPH oxidases has been identified as important source of ROS in the cardiovascular system we investigated the role of NADPH oxidases in response to the synthetic glucocorticoid dexamethasone in the cardiovascular system in vitro and in vivo in mice lacking functional NADPH oxidases due to a mutation in the gene coding for the essential NADPH oxidase subunit p22phox. We show that dexamethasone induced NADPH oxidase-dependent ROS generation, leading to vascular proliferation and angiogenesis due to activation of the transcription factor hypoxia-inducible factor-1 (HIF1). Chronic treatment of mice with low doses of dexamethasone resulted in the development of systemic hypertension, cardiac hypertrophy and left ventricular dysfunction, as well as in pulmonary hypertension and pulmonary vascular remodeling. In contrast, mice deficient in p22phox-dependent NADPH oxidases were protected against these cardiovascular side effects. Mechanistically, dexamethasone failed to upregulate HIF1α levels in these mice, while vascular HIF1α deficiency prevented pulmonary vascular remodeling. Thus, p22phox-dependent NADPH oxidases and activation of the HIF pathway are critical elements in dexamethasone-induced cardiovascular pathologies and might provide interesting targets to limit cardiovascular side effects in patients on chronic glucocorticoid therapy.

Department of Pediatric Cardiology and Congenital Heart Diseases German Heart Center Munich at the Technical University Munich Germany; DZHK Partner Site Munich Heart Alliance Munich Germany

Experimental and Molecular Pediatric Cardiology Department of Pediatric Cardiology and Congenital Heart Diseases German Heart Center Munich at the Technical University Munich Munich 80636 Germany

Experimental and Molecular Pediatric Cardiology Department of Pediatric Cardiology and Congenital Heart Diseases German Heart Center Munich at the Technical University Munich Munich 80636 Germany; DZHK Partner Site Munich Heart Alliance Munich Germany

Experimental and Molecular Pediatric Cardiology Department of Pediatric Cardiology and Congenital Heart Diseases German Heart Center Munich at the Technical University Munich Munich 80636 Germany; Laboratory of Transgenic Models of Diseases Institute of Molecular Genetics of the ASCR v v i Prague Czech Republic

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