Polyamine Transport as a Target for Intervention in Hypoxic Pulmonary Hypertension

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The hypoxia-induced increase in polyamine uptake by pulmonary vascular cells raises the question of whether lung cell polyamine regulatory pathways could serve as targets of pharmacologic intervention in hypoxic pulmonary hypertension. Based on the finding that hypoxia decreases ODC activity, ODC blockade would not seem to be a promising approach. Pharmacologic manipulation of polyamine import has not, until recently, been possible owing to the lack of suitable agents. Recently, however, Weeks et al. reported the development of a lysine-polyamine conjugate, ORI1202, which specifically inhibited polyamine import in a variety of transformed cells (37).

Polyamine Transport

Figure 4. Impact of the polyamine transport inhibitor, ORI1202, on hypoxic activation of p38 MAP kinase. A: Uptake of 0.3 (iM putrescine in normoxic control PASMCs (Con), PASMCs cultured in hypoxia for 6h (Hyp), control PASMCs incubated with 30 pM ORI1202 (ORI), and hypoxic PASMCs incubated with ORI1202 (Hyp + ORI). B: Western blot analyses of total and phospho-p38 in normoxic and hypoxic PASMCs with and without treatment with 30 pM ORI1202. Band intensities from 4 experiments were quantified by densitometry and expressed as a percentage of control. *P<0.05 vs. normoxic control (Modified from Ref. 28).

Figure 4. Impact of the polyamine transport inhibitor, ORI1202, on hypoxic activation of p38 MAP kinase. A: Uptake of 0.3 (iM putrescine in normoxic control PASMCs (Con), PASMCs cultured in hypoxia for 6h (Hyp), control PASMCs incubated with 30 pM ORI1202 (ORI), and hypoxic PASMCs incubated with ORI1202 (Hyp + ORI). B: Western blot analyses of total and phospho-p38 in normoxic and hypoxic PASMCs with and without treatment with 30 pM ORI1202. Band intensities from 4 experiments were quantified by densitometry and expressed as a percentage of control. *P<0.05 vs. normoxic control (Modified from Ref. 28).

We used ORI1202 to explore the importance of augmented putrescine transport in the adaptive response to hypoxia by PASMCs (28). As a molecular marker of the hypoxic effect, we assessed the amount of total and phosphorylated p38 MAP kinase, which is centrally involved in the response to hypoxia in a variety of cells (16, 38). The transport inhibitor profoundly reduced both the baseline import and the hypoxia-induced rise in PUT import (Fig. 4). While neither hypoxia nor ORI1202 altered the total p38, we found that hypoxia elevated the amount of phospho-p38 and, importantly, that the increase was suppressed by ORI1202. A conservative interpretation of these observations is that induction of PUT transport by hypoxia is necessary for activation of p38 MAP kinase and its downstream signaling pathways in PASMCs.

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Figure 5. Proposed model for lung cell-specific polyamine transport regulation in hypoxia. Hypoxia upregulates activity of a Na+-dependent polyamine transporter. In PAECs, all three polyamines are imported via this pathway, but in PASMCs, only PUT uptake is Na+-dependent. The biological roles of transported polyamines are speculative, but in PAECs may be required for elaboration of a serine protease which is permissive for hypoxia-mediated increases in SPD and SPM import in PASMCs, which occurs via a Na+-independent transport pathway. In contrast, the direct effect of hypoxia on Na+-dependent PUT uptake in PASMCs is required for p38 MAP Kinase activation and the ensuing adaptive response.

Figure 5. Proposed model for lung cell-specific polyamine transport regulation in hypoxia. Hypoxia upregulates activity of a Na+-dependent polyamine transporter. In PAECs, all three polyamines are imported via this pathway, but in PASMCs, only PUT uptake is Na+-dependent. The biological roles of transported polyamines are speculative, but in PAECs may be required for elaboration of a serine protease which is permissive for hypoxia-mediated increases in SPD and SPM import in PASMCs, which occurs via a Na+-independent transport pathway. In contrast, the direct effect of hypoxia on Na+-dependent PUT uptake in PASMCs is required for p38 MAP Kinase activation and the ensuing adaptive response.

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