Combined Statin and Glucocorticoid Therapy for the Safer Treatment of Preterm Birth

Abstract

Background: Prematurity is strongly associated with poor respiratory function in the neonate. Rescue therapies include treatment with glucocorticoids due to their anti-inflammatory and maturational effects on the developing lung. However, glucocorticoid treatment in the infant can increase the risk of long-term cardiovascular complications including hypertension, cardiac, and endothelial dysfunction. Accumulating evidence implicates a molecular link between glucocorticoid excess and depletion of nitric oxide (NO) bioavailability as a mechanism underlying the detrimental effects of postnatal steroids on the heart and circulation. Therefore, combined glucocorticoid and statin therapy, by increasing NO bioavailability, may protect the developing cardiovascular system while maintaining beneficial effects on the lung. Methods: We investigated combined glucocorticoid and statin therapy using an established rodent model of prematurity and combined experiments of cardiovascular function in vivo, with those in isolated organs as well as measurements at the cellular and molecular levels. Results: We show that neonatal glucocorticoid treatment increases the risk of later cardiovascular dysfunction in the offspring. Underlying mechanisms include decreased circulating NO bioavailability, sympathetic hyper-reactivity, and NO-dependent endothelial dysfunction. Combined neonatal glucocorticoid and statin therapy protects the developing cardiovascular system by normalizing NO and sympathetic signaling, without affecting pulmonary maturational or anti-inflammatory effects of glucocorticoids. Conclusions: Therefore, combined glucocorticoid and statin therapy may be safer than glucocorticoids alone for the treatment of preterm birth.

Molecular mechanisms underlying adverse effects of dexamethasone and betamethasone in the developing cardiovascular system

“…These results contribute important knowledge to consider in relation to balancing beneficial short‐term effects of antenatal glucocorticoid therapy versus potential long‐term adverse cardiovascular effects. They provide a platform from which further experiments in mammalian models can be designed with the aim of identifying antenatal glucocorticoid therapy regimes that maintain beneficial effects on the lung while minimizing adverse off‐target effects on the developing cardiovascular system, thereby making it safer for the treatment of preterm birth 5,29 …”

“…They provide a platform from which further experiments in mammalian models can be designed with the aim of identifying antenatal glucocorticoid therapy regimes that maintain beneficial effects on the lung while minimizing adverse off‐target effects on the developing cardiovascular system, thereby making it safer for the treatment of preterm birth. 5 , 29 …”

“…[21][22][23][24][25] Glucocorticoids are potent inducers of reactive oxygen species (ROS), and they can trigger hypertension and endothelial dysfunction, effects that can all be prevented by antioxidant treatment. 23,24,[26][27][28]29,30 Therefore, it is possible that mechanisms mediating off-target adverse effects of synthetic glucocorticoids relate to the induction of excess ROS production and associated intracellular signaling, including the activation of stress kinases, cell cycle changes, and the induction of cell senescence. 25,31 Since AGT in human practice is administered to the mother by intramuscular injection, possible differential UKRI | Medical Research Council (MRC), Grant/Award Number: MC_ UU_00014/4 model system to isolate effects of therapy on the developing heart and vasculature, independent of effects on the mother or placenta.…”

“… 21 , 22 , 23 , 24 , 25 Glucocorticoids are potent inducers of reactive oxygen species (ROS), and they can trigger hypertension and endothelial dysfunction, effects that can all be prevented by antioxidant treatment. 23 , 24 , 26 , 27 , 28 , 29 , 30 Therefore, it is possible that mechanisms mediating off‐target adverse effects of synthetic glucocorticoids relate to the induction of excess ROS production and associated intracellular signaling, including the activation of stress kinases, cell cycle changes, and the induction of cell senescence. 25 , 31 …”