Regulation Between Hypoxia-inducible Factor-α Subunits And Their Hydroxylases During The Development Of Hypoxic Pulmonary Hypertension

Background Hypoxia-inducible factor (HIF)-a subunits (HIF-1α, HIF-2α, andHIF-3α), which play a pivotal role during the development of hypoxia-induced pulmonary hypertension (HPH), are regulated through post-translational hydroxylation by their three prolyl hydroxylase domain-containing proteins (PHD1, PHD2 and PHD3) and one asparagine hydroxylase(also known as factor-inhibiting HIF, FIH). FIH can regulate the transactivity of HIF-a. Nitric oxide (NO) can inhibit the hypoxia induced expression of HIF-a (HIF-la, HIF-2a, HIF-3a) in cultured cell. We have investigated whether the effect of NO on the expression of HIF-α in hypoxic pulmonary hypertensionObjective To investigate differential and reciprocal regulation between HIF-a and PHDs. To study the dynamic levels and correlation relationship of HIFs (HEF-1α, HIF-2α, HIF-3α) and their hydroxylases(PHD1, PHD2, PHD3; FIH) during the development of HPH. To investigated the effect of NO on the expression of HIF-α in hypoxic pulmonary hypertension. To investigate the expression of PHDs, FIH and HIF-a in pulmonary artery of chronic obstructive pulmonary disease (COPD), clarify the roles of PHDs and FIH in HPH development and provide theoretical basis of mechanisms and remedies for COPD.Methods The study consisted of two parts. 1) Models of chronic HPH rats wereduplicated by anoxia (respired mixted gases containing 10% O₂, 8 hours per day for 21 days intermittently). After anoxia for 3d, 7d, 14d and 21d, or hypoxia 21d with administration of L-arginine(L-Arg group) or the NO synthase inhibitor, N(omega)-nitro- L-arginine methyl ester (L-NAME group) intraperitoneal injection every day; mean pulmonary artery pressure (mPAP), was measured by right-heart...