Polyamine Regulation in the Hypoxic Lung

Cell polyamine contents are governed by multiple interactive pathways (25). In de novo polyamine synthesis, PUT is synthesized from its precursor, ornithine, via ornithine decarboxylase (ODC), which is also one of the rate-limiting enzymes in polyamine synthesis. PUT is then converted sequentially to SPD and SPM via two other potentially rate-limiting enzymes, S-adenosyl-methionine decarboxylase (AdoMet-DC), and SPD- and SPM- synthases, respectively. De novo polyamine synthesis can be suppressed pharmacologically by a-difluoromethylornithine (DFMO), a specific inhibitor of ODC. ODC is unusual in terms of its regulation. The protein has one of the shortest half lives of known mammalian enzymes and is exquisitely sensitive to changes in the abundance of antizyme, a family of at least three 18-30 kDa proteins that inhibit ODC and promote its 26S proteasome-dependent degradation (19).

A second regulatory pathway is transmembrane transport (30). In some cells, polyamine uptake accompanies proliferation while it is down-regulated during quiescence. In polyamine-depleted cells, transport processes may restore polyamine levels and revitalize cell functions. Polyamine transport activity seems to require ongoing RNA and protein synthesis and, in some cells, may require an intact sodium gradient. There also appears to be considerable differences in terms of the number of polyamine transporters, with some cells expressing a single transporter with overlapping specificity for the three polyamines and others expressing uptake pathways that are relatively specific for each polyamine. It is unknown whether the multiple transporters are regulated differentially and if so, what biological significance such regulation might be. Like ODC, polyamine uptake is negatively regulated by antizyme.

A third pathway involves polyamine interconversion, catalyzed by the SPD and SPM aminopropyltransferases, another rate-limiting enzyme-SPD/SPMN1-acetyltransferase (SAT), and polyamine oxidase (5). These latter two enzymes are responsible for conversion of SPM back to SPD and SPD to PUT.

Finally, it has been speculated for many years that polyamine compartmentation was an important regulatory pathway. In support of this idea, the abundance of SPM in mitochondria and nuclei is known to change during the cell cycle (27). It has also been shown that mitochondria express a polyamine "uniporter" (34) which could govern mitochondrial polyamine contents independently of cytosolic changes. Subcellular polyamine distribution has not been explored in pathologic contexts.

De novo polyamine synthesis seems to be a dominant regulatory mechanism underlying most types of lung structural remodeling. Increased lung ODC activity is temporally-related to elevations in polyamine content that accompany postnatal lung growth (33), repair of hyperoxic lung injury (11), and monocrotaline-induced pulmonary hypertension (21, 23). ODC inhibition with DFMO prevents the entire spectrum of monocrotaline-induced lung pathology, including vascular hyperreactivity, edema, medial arterial thickening, pulmonary hypertension, and right ventricular hypertrophy (7, 22). These observations emphasize the importance of ODC and de novo polyamine synthesis in regulating lung polyamine contents and attendant changes in lung structure, including the monocrotaline model of chronic pulmonary hypertension.

Unlike the dominant role of increased de novo polyamine synthesis in other pulmonary diseases, hypoxic pulmonary vascular remodeling seems to have an unusual dependence on augmented polyamine transport and perhaps on polyamine interconversion. In support of this idea, we found that although polyamine contents were elevated by hypoxia (24), ODC activity was decreased in intact rat lungs (31). In contrast, PUT uptake was augmented and efflux was reduced in lungs from hypoxic rats. Activities of polyamine interconverting enzymes, AdoMet-DC, SAT, and polyamine oxidase, also were elevated.

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