The diamine putrescine and the polyamines spermidine and spermine appear to be important regulators of cell growth and differentiation. We have found that polyamine biosynthesis increases following monocrotaline toxicity. Cell proliferation may be an important factor associated with monocrotaline-induced pulmonary hypertension. We will test the possibility that suppression of lung polyamine biosynthesis, which protects against the development of monocrotaline-induced pulmonary hypertension, is associated with a suppression of DNA synthesis in the lung. Diamine oxidase, an enzyme involved in putrescine catabolism, may contribute to monocrotaline-induced pulmonary hypertension. Antimetabolites of polyamine metabolism that can suppress DNA synthesis in some tissues are currently available. We plan to use monocrotaline toxicity and chronic hypoxia as models of pulmonary hypertension and to determine the influence of polyamine metabolism upon cell proliferation associated with the development of pulmonary hypertension in these models. In addition to autoradiography with 3H thymidine, we will use 3H difluoromethylornithine (DFMO). Because DFMO is a specific inhibitor of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine metabolism, it can be used to localize ODC in cells. We will determine metabolic and biochemical parameters. We will attempt to suppress DNA synthesis with DFMO to determine some of the possible roles of polyamines in the development of pulmonary hypertension.
| Hacker, A D (1993) Dietary restriction, polyamines and monocrotaline-induced pulmonary hypertension. Biochem Pharmacol 45:2475-81 |
| Hacker, A D (1992) Inhibition of deoxyribonucleic acid synthesis by difluoromethylornithine. Role of polyamine metabolism in monocrotaline-induced pulmonary hypertension. Biochem Pharmacol 44:965-71 |
