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255 ROZIGLITAZONE ATTENUATES CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENTION.
  1. R. Nisbet1,
  2. D. Kleinhenz1,
  3. H. Thorson1,
  4. E. Walp1,
  5. J. Bland1,
  6. R. Sutliff1,
  7. C. M. Hart1
  1. 1Emory University and Atlanta VA Medical Centers, Atlanta, GA

Abstract

Chronic hypoxia (CH) causes pulmonary hypertension through complex mechanisms that continue to be defined. In human subjects, pulmonary hypertension was associated with reduced PPARγ expression. Because PPARγ activation stimulates vascular endothelial nitric oxide (NO) production and reduces superoxide production, we hypothesized that CH causes pulmonary hypertension by reducing PPARγ and NO bioavailability and increasing oxidative stress, thereby contributing to pulmonary vascular dysfunction. To test this hypothesis, male C57BL/6 mice (age 8-10 weeks) were exposed to CH (FiO2 10%) or room air for 3 weeks. During the last 10 days of exposure, each animal was treated with either the PPARγ ligand, roziglitazone (10 mg/kg/d) or with equal volume of vehicle (100 μL 0.5% methylcellulose) by gavage daily. At the end of the treatment period, measurements of right ventricular systolic pressure (RVSP) were obtained. After sacrifice, hearts were dissected for calculation of right ventricle (RV) to left ventricle (LV) + septum (S) weight ratio as an index of right ventricular hypertrophy. Serum was collected for measurement of nitrosyl-hemoglobin (NO-Hgb), an index of NO bioavailability, using electron spin resonance spectroscopy (ESR). Exposure to CH for 3 weeks reduced lung PPARγ expression and caused pulmonary hypertension as indicated by elevation of RVSP and RV:LV+S ratio. Treatment with roziglitazone during the final 10 days of CH exposure attenuated CH-induced pulmonary hypertension as well as CH-induced reductions in serum levels of NO-Hgb. These preliminary data suggest that PPARγ represents a novel and potentially effective therapeutic target in pulmonary hypertension that modulates nitroso-redox balance in the vasculature.

This abstract is funded by grants from the NIH and VA Research Service.

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