Decreased Expression of Maxi-K ⁺ Channel β ₁ -Subunit and Altered Vasoregulation in Hypoxia

Abstract

Background-Hypertension, a major cause of cardiovascular morbidity and mortality, can result from chronic hypoxia; however, the pathogenesis of this disorder is unknown. We hypothesized that downregulation of the maxi-K ϩ channel ␤ 1 -subunit by hypoxia decreases the ability of these channels to hyperpolarize arterial smooth muscle cells, thus favoring vasoconstriction and hypertension. Methods and Results-Lowering O 2 tension produced a decrease of maxi-K ϩ ␤ 1 -subunit mRNA levels in rat (aortic and basilar) and human (mammary) arterial myocytes. This was paralleled by a reduction of the ␤ 1 -subunit protein level as determined by immunocytochemistry and flow cytometry. Exposure to hypoxia also produced a decrease of open probability, mean open time, and sensitivity to the xenoestrogen tamoxifen of single maxi-K ϩ channels recorded from patch-clamped dispersed myocytes. The number of channels per patch and the single-channel conductance were not altered. The vasorelaxing force of maxi-K ϩ channels was diminished in rat and human arterial rings exposed to low oxygen tension. Conclusions-These

Hypoxia Inducible Factor-2α Stabilization and Maxi-K + Channel β 1 -Subunit Gene Repression by Hypoxia in Cardiac Myocytes

“…We used cultured mammalian cardiomyocytes to test whether, as it occurs in vascular smooth muscle cells, 13 maxi-K ␤ 1 -subunit mRNA is also downregulated by hypoxia. Both conventional PCR and Northern blot ( Figure 1A) analyses demonstrated that hypoxia (1% O 2 ) induces a marked downregulation of the ␤ 1 -subunit mRNA in neonatal rat cardiomyocytes.…”

“…This is in accord with a previous publication from our laboratory reporting that the decrease of ␤ 1 -subunit mRNA levels induced by hypoxia in vascular smooth muscle alters the function of native maxi-K channels in a way compatible with a reduced ␤ 1 protein expression. 13 The mechanism underlying the O 2 tension-dependent ␤ 1 -subunit gene repression was unknown. We have shown that it occurs at the transcriptional level and is mimicked by DMOG and cobalt, inhibitors of prolyl hydroxylases.…”

“…12 We have found that the ␤ 1 -subunit (KCNMB1) of the Ca 2ϩ -and voltage-dependent K ϩ (maxi-K) channel is downregulated by hypoxia in vascular smooth muscle cells 13 and human leukocytes. 14 The ␤ 1 -subunit modifies the Ca 2ϩ and voltage sensitivity of the pore-forming ␣-subunit, and its inhibition results in vasoconstriction.…”

“…14 The ␤ 1 -subunit modifies the Ca 2ϩ and voltage sensitivity of the pore-forming ␣-subunit, and its inhibition results in vasoconstriction. 13,15 The mechanism whereby hypoxia downregulates the ␤ 1 -subunit gene is unknown.…”

Human β-Defensin 2 Is a Novel Opener of Ca 2+ -Activated Potassium Channels and Induces Vasodilation and Hypotension in Monkeys

“…BK Ca -type channels have diverse physiological roles; for example, the β1 subunit in SMCs plays a vital role in coupling Ca 2+ influx with BK Ca currents responsible for hypertension. [11][12][13] The openers of BK Catype channels, especially of the mSlo+β1 channel, have received a great deal of attention attributable to the fact that they can be used to treat various cardiovascular diseases. Up to now, no peptidyl opener of BK Ca -mSlo+β1 channels has been reported, Abstract-Human β-defensin 2 (HBD2) is a cysteine-rich cationic antimicrobial peptide known for its important role in innate immune system.…”