ABSTRACT
To determine whether atrial natriuretic peptide (ANP) plays a physiological role in modulating pulmonary hypertensive responses, we studied mice with gene-targeted disruption of the ANP gene under normoxic and chronically hypoxic conditions. Right ventricular peak pressure (RVPP), right ventricle weight- and left ventricle plus septum weight-to-body weight ratios [RV/BW and (LV+S)/BW, respectively], and muscularization of pulmonary vessels were measured in wild-type mice (+/+) and in mice heterozygous (+/-) and homozygous (-/-) for a disrupted proANP gene after 3 wk of normoxia or hypobaric hypoxia (0.5 atm). Under normoxic conditions, homozygous mutants had higher RVPP (22 +/- 2 vs. 15 +/- 1 mmHg; P < 0.05) than wild-type mice and greater RV/BW (1.22 +/- 0.08 vs. 0.94 +/- 0.07 and 0.76 +/- 0.04 mg/g; P < 0.05) and (LV+S)/BW (4.74 +/- 0. 42 vs. 3.53 +/- 0.14 and 3.18 +/- 0.18 mg/g; P < 0.05) than heterozygous or wild-type mice, respectively. Three weeks of hypoxia increased RVPP in heterozygous and wild-type mice and increased RV/BW and RV/(LV+S) in all genotypes compared with their normoxic control animals but had no effect on (LV+S)/BW. After 3 wk of hypoxia, homozygous mutants had higher RVPP (29 +/- 3 vs. 23 +/- 1 and 22 +/- 2 mmHg; P < 0.05), RV/BW (2.03 +/- 0.14 vs. 1.46 +/- 0.04 and 1.33 +/- 0.08 mg/g; P < 0.05), and (LV+S)/BW (4.76 +/- 0.23 vs. 3.82 +/- 0.09 and 3.44 +/- 0.14 mg/g; P < 0.05) than heterozygous or wild-type mice, respectively. The percent muscularization of peripheral pulmonary vessels was greater in homozygous mutants than that in heterozygous or wild-type mice under both normoxic and hypoxic conditions. We conclude that endogenous ANP plays a physiological role in modulating pulmonary arterial pressure, cardiac hypertrophy, and pulmonary vascular remodeling under normoxic and hypoxic conditions.
Subject(s)
Atrial Natriuretic Factor/genetics , Hypertension, Pulmonary/genetics , Hypoxia/complications , Animals , Atrial Natriuretic Factor/deficiency , Atrial Natriuretic Factor/physiology , Blood Pressure , Gene Deletion , Heart Atria/metabolism , Heart Atria/pathology , Hypertension, Pulmonary/pathology , Lung/blood supply , Mice , Mice, Inbred C57BL , Muscle, Smooth, Vascular/pathology , Mutagenesis , Organ Size , Pulmonary Artery/physiopathology , Pulmonary CirculationABSTRACT
In vitro, crocidolite asbestos toxicity to macrophages is mediated by the production of reactive oxygen metabolites. We examined whether exposure of macrophages to crocidolite asbestos induced lipid peroxidation as measured by the thiobarbituric acid assay. When elicited mouse peritoneal macrophages were exposed to crocidolite, a dose- and time-dependent increase in lipid peroxidation breakdown products accompanied cell death. Superoxide dismutase plus catalase or deferoxamine prevented both lipid peroxidation and loss of viability caused by crocidolite. We tested whether crocidolite-induced lipid peroxidation was causally responsible for cell death. Macrophages were not killed by crocidolite when incubated with 10 mM 3-aminobenzamide. The level of thiobarbituric acid-reactive material was the same, however, for cells incubated with crocidolite in the presence or absence of 3-aminobenzamide. When macrophagaes were pretreated for 24 h with 25 microM vitamin E and then incubated with crocidolite, no thiobarbituric acid-reactive products were detected. Vitamin E, however, did not prevent crocidolite cytotoxicity. These results suggest that exposure of macrophages to crocidolite asbestos produces lipid peroxidation as measured by thiobarbituric acid-reactive products. This reaction, however, is not directly responsible for irreversible injury in this model system.
