Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMalpha) induces the vascular and hemodynamic changes of pulmonary hypertension.
Pulmonary hypertension (PH) is a serious disease of multiple etiologies mediated by hypoxia, immune stimuli, and elevated pulmonary pressure that leads to vascular thickening and eventual right heart failure. In a chronic hypoxia model of PH, we previously reported the induction of a novel pleiotropic cytokine, hypoxia-induced mitogenic factor (HIMF), that exhibits mitogenic, vasculogenic, contractile, and chemokine properties during PH-associated vascular remodeling. To examine the role of HIMF in hypoxia-induced vascular remodeling, we performed in vivo knockdown of HIMF using short hairpin RNA directed at rat HIMF in the chronic hypoxia model of PH. Knockdown of HIMF partially blocked increases in mean pulmonary artery pressure, pulmonary vascular resistance, right heart hypertrophy, and vascular remodeling caused by chronic hypoxia. To demonstrate a direct role for HIMF in the mechanism of PH development, we performed HIMF-gene transfer into the lungs of rats using a HIMF-expressing adeno-associated virus (AAV). AAV-HIMF alone caused development of PH similar to that of chronic hypoxia with increased mean pulmonary artery pressure and pulmonary vascular resistance, right heart hypertrophy, and neomuscularization and thickening of small pulmonary arterioles. The findings suggest that HIMF represents a critical cytokine-like growth factor in the development of PH.
Angelini
Daniel J
DJ
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Su
Qingning
Q
Yamaji-Kegan
Kazuyo
K
Fan
Chunling
C
Skinner
John T
JT
Champion
Hunter C
HC
Crow
Michael T
MT
Johns
Roger A
RA
D000818:Animals; D001808:Blood Vessels / Q000503:physiopathology*; D002460:Cell Line; D002908:Chronic Disease; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D006439:Hemodynamics / Q000502:physiology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications*; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020932:Nerve Growth Factor / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
C486575:Retnla protein, rat; D020932:Nerve Growth Factor