HEME OXYGENASE-1: A TALE OF INHIBITORY EFFECTS

PEREYRA ELBA N; MONZÓN CASANDRA; BESIO MORENO MARCOS; PIGNATARO OMAR P; RAICESTRINIDAD

Buenos Aires

Congreso; LXII Reunión Científica de la Sociedad Argentina de Investigación Clínica; 2017

SAIC

HEME OXYGENASE-1: A TALE OF INHIBITORY EFFECTS.Raices T, Monzón C, Besio Moreno M, Pignataro OP, Pereyra ENHeme oxygenase-1 is an inducible enzyme highly upregulated by oxidative stimuli. It catalyzes the degradation of heme to carbon monoxide (CO), free iron and biliverdin/bilirubin. Previously, we have demonstrated that HO-1 diminishes progesterone (P4) synthesis in MA-10 Leydig cells (LC). We have also shown that NO inhibits steroidogenesis in a similar fashion. Considering that both NO and CO are gasotransmitters capable of binding and inhibiting cytochromes P450 involved in steroidogenesis, we studied CO effects on P4 production using dichloromethane as a donor. Our results indicate that CO inhibits P4 production in basal and 0,5 mM dbAMPc- stimulated conditions and increases HO-1 protein levels. HO-1 antiproliferative effect has been described in a variety of tissues. To assess this, we incubated the cells with 1-25 µM hemin for 24hs and observed that LC proliferation decreased in a concentration-dependent manner. We studied cell cycle progression and found that a 24h incubation with 10 µM hemin resulted in G2/M arrest. Our group has also demonstrated that LC express histamine (HA) receptors type 1, 2 and 4 and that HA affects steroidogenesis and proliferation positively through HRH2 and negatively through HRH1 and HRH4 for steroidogenesis and only HRH4 for proliferation. With the aim of dissecting HO-1/HA interaction, we incubated the cells with 10 µM hemin and FMPH, amthamine or VUF 8430 (1 µM), agonists of HRH1, HRH2 and HRH4, respectively. Hemin reverts amthamine stimulation and potentiates FMPH and VUF steroidogenesis inhibition and VUF proliferation inhibition. In all experiments, if a P