Mice deficient in Mkp-1 develop more severe pulmonary hypertension and greater lung protein levels of arginase in response to chronic hypoxia.
The mitogen-activated protein (MAP) kinases are involved in cellular responses to many stimuli, including hypoxia. MAP kinase signaling is regulated by a family of phosphatases that include MAP kinase phosphatase-1 (MKP-1). We hypothesized that mice lacking the Mkp-1 gene would have exaggerated chronic hypoxia-induced pulmonary hypertension. Wild-type (WT) and Mkp-1(-/-) mice were exposed to either 4 wk of normoxia or hypobaric hypoxia. Following chronic hypoxia, both genotypes demonstrated elevated right ventricular pressures, right ventricular hypertrophy as demonstrated by the ratio of the right ventricle to the left ventricle plus septum weights [RV(LV + S)], and greater vascular remodeling. However, the right ventricular systolic pressures, the RV/(LV + S), and the medial wall thickness of 100- to 300-microm vessels was significantly greater in the Mkp-1(-/-) mice than in the WT mice following 4 wk of hypobaric hypoxia. Chronic hypoxic exposure caused no detectable change in eNOS protein levels in the lungs in either genotype; however, Mkp-1(-/-) mice had lower levels of eNOS protein and lower lung NO production than did WT mice. No iNOS protein was detected in the lungs by Western blotting in any condition in either genotype. Both arginase I and arginase II protein levels were greater in the lungs of hypoxic Mkp-1(-/-) mice than those in hypoxic WT mice. Lung levels of proliferating cell nuclear antigen were greater in hypoxic Mkp-1(-/-) than in hypoxic WT mice. These data are consistent with the concept that MKP-1 acts to restrain hypoxia-induced arginase expression and thereby reduces vascular remodeling and the severity of pulmonary hypertension.
Jin
Yi
Y
The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
Calvert
Thomas J
TJ
Chen
Bernadette
B
Chicoine
Louis G
LG
Joshi
Mandar
M
Bauer
John Anthony
JA
Liu
Yusen
Y
Nelin
Leif D
LD
D000818:Animals; D001119:Arginase / Q000378:metabolism*; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D002908:Chronic Disease; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000473:pathology*; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D009573:Nitrites / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D016278:Ventricular Function, Right / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D009566:Nitrates; D009573:Nitrites; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D001119:Arginase