Oral Presentation 46th Annual Meeting of the Fetal and Neonatal Physiological Society 2019

Neonatal therapy with hemin and melatonin reverts pulmonary vascular dysfunction in neonatal sheep with pulmonary hypertension born in chronic hypoxia. (#6)

Alejandro González-Candia 1 , Alejandro A Candia 1 , Cristopher González-Candia 1 , German Ebensperger 1 , Roberto V Reyes 1 , Anibal J Llanos 1 , Bernardo J. Krause 2 , Emilio A Herrera 1
  1. Faculty of Medicine, Universidad de Chile, Santiago, METROPOLITANA, Chile
  2. Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile

Introduction

Perinatal chronic hypoxia programs cardiopulmonary dysfunction and can lead to Neonatal Pulmonary Hypertension (NPH). This is a multifactorial syndrome with chronic hypoxia and oxidative stress, deriving in pulmonary vascular dysfunction and remodeling. We hypothesized that this pulmonary vascular dysfunction can be treated by using a combination of hemin as a vasodilator and anti-remodeling and melatonin as a vasodilator and antioxidant.

Methods and Results

Twenty lambs gestated and born at 3600 m were studied, 5 received vehicle, 5 received melatonin (1 mg*kg-1. oral during 21d), 5 received hemin (10 mg*Kg-1, SC, during 10d) and 5 received melatonin + hemin (combined treatments). We monitored the in vivo cardiopulmonary status every morning until 1 month old. At 1 month old, we evaluated pulmonary vascular reactivity by wire myography and protein expression by Western Blot. Finally, we determined histomorphometric analyses and vascular remodeling markers in pulmonary parenchyma. All procedures were approved by the Bioethics Committee (CBA # 0761 FMUCH).

Results

The combined treatment improved endothelium-dependent vasodilator function, enhancing pulmonary protein expression related to the nitrergic and prostanoid pathways, such as GCs-PKG and PGFIs-Ip. Hemin administration induced the hemoxygenase system expression (HO-1 and HO-2) in lung tissue. The media cellular density and KI67 positive cells showed no change between the analyzed groups, however, the remodeling marker α-actin decreased with the combined treatment relative to the control group (Figure 1).

Discussion and Conclusion

The combined treatment improved endothelial vasodilator function by increasing the nitric oxide, prostacyclin and hemoxygenase pathways in the pulmonary circulation. We conclude that the combined treatment was able to revert the endothelial dysfunction induced by perinatal chronic hypoxia. Future studies should focus on potential epigenetic mechanisms affected by this treatment, enhancing the vasodilators pathways expression and decreasing the risk of developing NPH and further cardiovascular diseases later in life.

Funding: Fondecyt 11511195d28fbd20d9a6-Figura+AGC+final.jpg