Hypoxia-induced Mitogenic Factor Mediated Hypoxic Pulmonary Hypertension Of Rat By Activated PI3K/Akt/mTOR Pathway

Objective : We demonstrated the expression of hypoxia-induced mitogenic factor(HIMF/FIZZ1/RELMα) within different time courses in chronic hypoxia induced pulmonary vascular remodeling. Moreover, by overexpressing and suppressing HIMF in pulmonary of the rats, we investigated the role of HIMF in hypoxic pulmonary hypertension. Methods:(1) We induced pulmonary vascular remodeling through chronic hypoxia exposure and detected the expression of HIMF for different time courses(0 day, 3 days, 7 days, 14 days and 21 days) in lung tissue, bronchia alveolus lavage fluid(BALF) and blood serum.(2) Rats in chronic-hypoxia exposure had been given lentivirus intratracheally to knockdown HIMF. Conversely, other rats had been given murine recombination HIMF protein for overex-pression before normoxia exposure.(3) We evaluated the expression of HIMF in lung tissue and pulmonary vascular remodeling throughout the pulmonary vascular bed of the rats.(4) We detected PI3K/Akt/m TOR expression in pulmonary artery walls.Results:(1) Chronic hypoxia induced pulmonary vessels significantly thickened and increased HIMF in lung tissue, BALF and blood serum.(2) Q-PCR and Western blot results reflected that hypoxia up-regulated HIMF m RNA and protein ex-pression in lung tissue peaked at the 3rd day and then decreased steadily but were still above the baseline till the 21 st day under hypoxia conditions.(3) The immunohistochemistry of lung sections demonstrated that hypoxia induced-HIMF expressed in bronchial fibrous, alveolar epithelium and pul-monary vasculature.(4) The HIMF protein was suppressed in rats with si RNA-lentivirus in hypoxia exposure, as well as pulmonary vascular remodeling.(5) Rats given murine recombination HIMF protein to normoxia increased vessels thickened and the recruitment of inflammatory cells compared to controls. Conclusions:1. HIMF was a secretory protein and could be secreted to lung tissue and blood. 2. HIMF was expressed in bronchial epithelial and alveolar epithelium, and pulmonary vasculature to hypoxia. HIMF up-regulated in a shot time and subsequently declined closing to the baseline. 3. Over-expression or suppression of HIMF could enhance or decrease pulmonary vascular remodeling throughout PI3K/Akt/m TOR pathway.