Deficiency of MAP Kinase Phosphatase‐1 Induces Pulmonary Hypertension in Mice.

Abstract

MAP Kinase Phosphatase‐1 (MKP‐1), deactivator of MAP kinases, is a critical inflammatory regulator. We tested the hypothesis that MKP‐1 will control pulmonary hypertension development by dephosphorylating MAP kinases using MKP‐1 wild type (MKP‐1+/+), heterozygous (MKP‐1+/−), and null (MKP‐1−/−) mice. Animals were exposed to sea level (SL), Denver altitude (DA; 5280 feet) and severe altitude (HYP; 17,000 feet) for 6 weeks. Marked increase in right ventricular systolic pressure was found in MKP‐1+/− and MKP‐1−/− mice which were raised in SL and DA. Intensity of αSMA staining was increased in both MKP‐1+/− and MKP‐1−/−HYP lungs. Vessel to alveoli ratio was decreased in HYP lungs of MKP‐1+/− and MKP‐1−/−. Vessel (<50μm) wall thickness to diameter ratio was not affected by hypoxia in MKP‐1+/+ lungs (DA: 0.14 vs. HYP: 0.12), but increased in MKP‐1+/− (DA: 0.12 vs. HYP: 0.18) and MKP‐1−/− (DA: 0.12 vs. HYP: 0.2) lungs. Activation levels of ERK1/2 and JNK1/2 were similar in all groups. However, phosphop38 levels were greatest in the MKP‐1−/− lungs with positive reaction in vessels, respiratory epithelium, and interstitial cells. COX‐2, an inflammatory marker, also had strongest immunoreactivity in the MKP‐1+/− and MKP‐1−/− lungs. Therefore, lack of MKP‐1 induces sustained p38 activation and subsequent inflammation which might be a major contributor in the development of pulmonary hypertension. Funded by NHLBI HL 06491