Chronic Hypoxia Downregulates Kv Channel Expression in PASMC

Under resting conditions, K+ permeability is much greater than other ions (e.g., Na+, Ca2+, CI") permeabilities. Therefore, resting Em in PASMC is primarily determined by K+ permeability which is mainly related to the whole-cell K+ current (/K). K+ currents through Kv channels (/K(V)). in particular, have been demonstrated to be predominately responsible for the maintenance of the Em in PASMCs under resting conditions (61, 115). Whole-cell /K(V) at any given time is determined by the following equation:

4(V) = N * 'KV X ^open where N is the number of functional Kv channels expressed in the plasma membrane; /Kv is the current through a single Kv channel; and Popcn is the steady-state open probability of a Kv channel. When Kv channels close (i.e., iKv or.Popcn declines) and/or the number of Kv channels in the plasma membrane declines (i.e., N decreases) as expression of Kv channels is reduced, Em becomes more depolarized as a result of decreased /K(V)- In contrast, opening of Kv channels (i.e., a rise in z'Kv or Popen) and/or increasing expression of Kv channels (i.e., N

rises) cause membrane hyperpolarization (Em becomes closer to the £K~-85 mV) as a result of increased IK(y)- In other words, the mRNA and protein expression level of different Kv channel genes plays an important role in determining

whole-cell /K(V) and, ultimately, in regulating Em and [Ca ]cyt in PASMC.

whole-cell /K(V) and, ultimately, in regulating Em and [Ca ]cyt in PASMC.

Figure 5. Hypoxia downregulates Kv channel expression in rat PASMC, but not in MASMC. A: PCR-amplified products for Kv channel a and p subunits in normoxia (N) and hypoxia (H). B: Summarized data (means±SE) showing mRNA levels of Kv channel a and P subunits normalized to P-actin transcript levels. ** P<0.01 vs. normoxia. C and D: Western blot analyses of Kvl .5 and 2.1 in normoxia and hypoxia. ** J°<0.01 vs. normoxia (Reproduced from Ref. 80).

Figure 5. Hypoxia downregulates Kv channel expression in rat PASMC, but not in MASMC. A: PCR-amplified products for Kv channel a and p subunits in normoxia (N) and hypoxia (H). B: Summarized data (means±SE) showing mRNA levels of Kv channel a and P subunits normalized to P-actin transcript levels. ** P<0.01 vs. normoxia. C and D: Western blot analyses of Kvl .5 and 2.1 in normoxia and hypoxia. ** J°<0.01 vs. normoxia (Reproduced from Ref. 80).

As demonstrated in Figure 5, chronic hypoxia downregulates the mRNA (Fig. 5A and B) and protein (Fig. 5C and D) expression of several pore-forming a subunits of Kv channels in rat PASMC, while no appreciable expression changes are seen in mesenteric artery smooth muscle cells (MASMC) (80, 105). These data indicate that: i) the chronic hypoxia-induced downregulation of Kv channels is specific or unique to PASMC (in comparison to systemic arterial smooth muscle cells), and ii) the inhibitory effect of chronic hypoxia only occurs on the pore-forming a subunits in PASMC but not on the regulatory P subunits (Fig. 5A and B). The decreased Kv channel a subunit expression would be expected to decrease the number of sarcolemmal Kv channels and decrease whole-cell /K(V) (because of decreased AO. The unsuppressed regulatory P subunit expression would be expected to further limit the activity of existing pore-forming a subunits (because of decreased ¡Kv and/or Popen), thereby further limiting Kv channel activity and the ability of the cell to maintain hyperpolarized.

Figure 6. Hypoxia-induced regulation of /K(V), Em, and [Ca2+]cyl in PASMC. Representative and summarized data showing the effect of hypoxia on /K(V) in PASMC (A) and MASMC (B). C: Distribution histogram showing the range of resting Em values recorded in PASMC under normoxic (top) and hypoxic (bottom) conditions. D: Summarized data (means±SE) showing resting Em in PASMC and MASMC in normoxia (Nor) and hypoxia (Hyp). ***P<0.001 vs. normoxia. E: Resting [Ca2+]cyl is increased in PASMC by 60-hr exposure to hypoxia. * * * P<0.001 vs. normoxia (Reproduced from Ref. 80).

Figure 6. Hypoxia-induced regulation of /K(V), Em, and [Ca2+]cyl in PASMC. Representative and summarized data showing the effect of hypoxia on /K(V) in PASMC (A) and MASMC (B). C: Distribution histogram showing the range of resting Em values recorded in PASMC under normoxic (top) and hypoxic (bottom) conditions. D: Summarized data (means±SE) showing resting Em in PASMC and MASMC in normoxia (Nor) and hypoxia (Hyp). ***P<0.001 vs. normoxia. E: Resting [Ca2+]cyl is increased in PASMC by 60-hr exposure to hypoxia. * * * P<0.001 vs. normoxia (Reproduced from Ref. 80).

As shown in Figure 6, indeed, chronic hypoxia significantly reduced whole-cell fK(V), caused membrane depolarization, and increased [Ca2+]cyt in PASMC, but had little effect on /K(V) and Em in MASMC. The selective effect of chronic hypoxia on PASMC, in comparison to MASMC, indicates that pulmonary and systemic vascular smooth muscle cells are regulated by chronic hypoxia through different cellular and molecular mechanisms. The hypoxia-induced sustained membrane depolarization and increase in [Ca2+]cyt in PASMC would trigger pulmonary vasoconstriction and contribute to the excessive PASMC proliferation or pulmonary arterial medial hypertrophy observed in lungs from chronically hypoxic animals as well as patients with hypoxic cardiopulmonary diseases. The sustained pulmonary vasoconstriction and vascular remodeling are two of the major causes for the development of pulmonary hypertension in humans and animals exposed to chronic hypoxia.

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