scholarly journals Dehydroepiandrosterone promotes pulmonary artery relaxation by NADPH oxidation-elicited subunit dimerization of protein kinase G 1α

2014 ◽  
Vol 306 (4) ◽  
pp. L383-L391 ◽  
Author(s):  
Dhara Patel ◽  
Sharath Kandhi ◽  
Melissa Kelly ◽  
Boon Hwa Neo ◽  
Michael S. Wolin
Keyword(s):  
Pulmonary Hypertension ◽  
Protein Kinase ◽  
Pulmonary Arteries ◽  
Activation Mechanism ◽  
Protein Kinase G ◽  
Beneficial Effects ◽  
Vasp Phosphorylation ◽  
Vasodilator Activity ◽  
Nadph Oxidation ◽  
Knockin Mouse

The activity of glucose-6-phosphate dehydrogenase (G6PD) controls a vascular smooth muscle relaxing mechanism promoted by the oxidation of cytosolic NADPH, which has been associated with activation of the 1α form of protein kinase G (PKG-1α) by a thiol oxidation-elicited subunit dimerization. This PKG-1α-activation mechanism appears to contribute to responses of isolated endothelium-removed bovine pulmonary arteries (BPA) elicited by peroxide, cytosolic NADPH oxidation resulting from G6PD inhibition, and hypoxia. Dehydroepiandrosterone (DHEA) is a steroid hormone with pulmonary vasodilator activity, which has beneficial effects in treating pulmonary hypertension. Because multiple mechanisms have been suggested for the vascular effects of DHEA and one of the known actions of DHEA is inhibiting G6PD, we investigated whether it promoted relaxation associated with NADPH oxidation, PKG-1α dimerization, and PKG activation detected by increased vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Relaxation of BPA to DHEA under aerobic or hypoxic conditions was associated with NADPH oxidation, PKG-1α dimerization, and increased VASP phosphorylation. The vasodilator activity of DHEA was markedly attenuated in pulmonary arteries and aorta from a PKG knockin mouse containing a serine in place of a cysteine involved in PKG dimerization. DHEA promoted increased PKG dimerization in lungs from wild-type mice, which was not detected in the PKG knockin mouse model. Thus PKG-1α dimerization is a major contributing factor to the vasodilator actions of DHEA and perhaps its beneficial effects in treating pulmonary hypertension.

scholarly journals Roles for cytosolic NADPH redox in regulating pulmonary artery relaxation by thiol oxidation-elicited subunit dimerization of protein kinase G1α

2013 ◽  
Vol 305 (3) ◽  
pp. H330-H343 ◽  
Author(s):  
Boon Hwa Neo ◽  
Dhara Patel ◽  
Sharath Kandhi ◽  
Michael S. Wolin
Keyword(s):  
Protein Kinase ◽  
Redox Regulation ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Thiol Oxidation ◽  
Hypoxic Conditions ◽  
Vasp Phosphorylation ◽  
Thioredoxin 1 ◽  
Nadph Oxidation ◽  
Glucose 6 Phosphate Dehydrogenase

The activity of glucose-6-phosphate dehydrogenase (G6PD) appears to control a vascular smooth muscle relaxing mechanism regulated through cytosolic NADPH oxidation. Since our recent studies suggest that thiol oxidation-elicited dimerization of the 1α form of protein kinase G (PKG1α) contributes to the relaxation of isolated endothelium-removed bovine pulmonary arteries (BPA) to peroxide and responses to hypoxia, we investigated whether cytosolic NADPH oxidation promoted relaxation by PKG1α dimerization. Relaxation of BPA to G6PD inhibitors 6-aminonicotinamide (6-AN) and epiandrosterone (studied under hypoxia to minimize basal levels of NADPH oxidation and PKG1α dimerization) was associated with increased PKG1α dimerization and PKG-mediated vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Depletion of PKG1α by small inhibitory RNA (siRNA) inhibited relaxation of BPA to 6-AN and attenuated the increase in VASP phosphorylation. Relaxation to 6-AN did not appear to be altered by depletion of soluble guanylate cyclase (sGC). Depletion of G6PD, thioredoxin-1 (Trx-1), and Trx reductase-1 (TrxR-1) in BPA with siRNA increased PKG1α dimerization and VASP phosphorylation and inhibited force generation under aerobic and hypoxic conditions. Depletion of TrxR-1 with siRNA inhibited the effects of 6-AN and enhanced similar responses to peroxide. Peroxiredoxin-1 depletion by siRNA inhibited PKG dimerization to peroxide, but it did not alter PKG dimerization under hypoxia or the stimulation of dimerization by 6-AN. Thus regulation of cytosolic NADPH redox by G6PD appears to control PKG1α dimerization in BPA through its influence on Trx-1 redox regulation by the NADPH dependence of TrxR-1. NADPH regulation of PKG dimerization may contribute to vascular responses to hypoxia that are associated with changes in NADPH redox.

scholarly journals Roles for soluble guanylate cyclase and a thiol oxidation-elicited subunit dimerization of protein kinase G in pulmonary artery relaxation to hydrogen peroxide

2010 ◽  
Vol 299 (4) ◽  
pp. H1235-H1241 ◽  
Author(s):  
Boon Hwa Neo ◽  
Sharath Kandhi ◽  
Michael S. Wolin
Keyword(s):  
Nitric Oxide ◽  
Hydrogen Peroxide ◽  
Protein Kinase ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Protein Kinase G ◽  
Thiol Oxidation ◽  
Organoid Culture ◽  
Vasp Phosphorylation

We have previously provided evidence that hydrogen peroxide (H2O2) stimulates soluble guanylate cyclase (sGC) under conditions where it relaxes isolated endothelium-removed bovine pulmonary arteries (BPAs). Since it was recently reported that H2O2 induces coronary vasorelaxation associated with a nitric oxide/cGMP-independent thiol oxidation/subunit dimerization-elicited activation of protein kinase G (PKG), we investigated whether this mechanism participates in the relaxation of BPAs to H2O2. BPAs precontracted with serotonin (incubated under hypoxia to lower endogenous H2O2) were exposed to increasing concentrations of H2O2. It was observed that 0.1–1 mM H2O2 caused increased PKG dimerization and relaxation. These responses were associated with increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at the serine-239 site known to be mediated by PKG. Treatment of BPAs with 1 mM DTT attenuated PKG dimerization, VASP phosphorylation, and relaxation to H2O2. An organoid culture of BPAs for 48 h with 10 μM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a heme oxidant inhibitor of sGC activation, depleted sGC expression by 85%, associated with a 67% attenuation of VASP phosphorylation and 48% inhibition of relaxation elicited by 100 μM H2O2. Thus both a sGC activation/cGMP-dependent and a thiol oxidation subunit dimerization/cGMP-independent activation of PKG appear to contribute to the relaxation of BPAs elicited by H2O2.

scholarly journals Roles for redox mechanisms controlling protein kinase G in pulmonary and coronary artery responses to hypoxia

2011 ◽  
Vol 301 (6) ◽  
pp. H2295-H2304 ◽  
Author(s):  
Boon Hwa Neo ◽  
Sharath Kandhi ◽  
Michael S. Wolin
Keyword(s):  
Coronary Arteries ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Protein Kinase G ◽  
Organoid Culture ◽  
Vasp Phosphorylation ◽  
Contrast Exposure ◽  
Nadph Oxidation ◽  
Interfering Rna ◽  
Stimulation Of

We previously reported that isolated endothelium-removed bovine pulmonary arteries (BPAs) contract to hypoxia associated with removal of peroxide- and cGMP-mediated relaxation. In contrast, bovine coronary arteries (BCAs) relax to hypoxia associated with cytosolic NADPH oxidation coordinating multiple relaxing mechanisms. Since we recently found that H2O2 relaxes BPAs through PKG activation by both soluble guanylate cyclase (sGC)/cGMP-dependent and cGMP-independent thiol oxidation/subunit dimerization mechanisms, we investigated if these mechanisms participate in BPA contraction and BCA relaxation to hypoxia. The contraction of BPA (precontracted with 20 mM KCl) to hypoxia was associated with decreased PKG dimerization and PKG-mediated vasodilator-stimulated phosphoprotein (VASP) phosphorylation. In contrast, exposure of 20 mM KCl-precontracted endothelium-removed BCAs to hypoxia caused relaxation and increased dimerization and VASP phosphorylation. Depletion of sGC by organoid culture of BPAs with an oxidant of the sGC heme (10 μM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) increased aerobic force generation, decreased VASP phosphorylation, and inhibited further contraction to hypoxia and changes in VASP phosphorylation. Thiol reduction with dithiothreitol increased aerobic force in BPAs and decreased PKG dimerization, VASP phosphorylation, and the contraction to hypoxia. Furthermore, PKG-1α and sGC β1-subunit small interfering RNA-transfected BPAs demonstrated increased aerobic K+ force and inhibition of further contraction to hypoxia, associated with an attenuation of H2O2-elicited relaxation and VASP phosphorylation. Thus, decreases in both a sGC/cGMP-dependent and a dimerization-dependent activation of PKG by H2O2 appear to contribute to the contraction of BPAs elicited by hypoxia. In addition, stimulation of PKG activation by dimerization may be important in the relaxation of coronary arteries to hypoxia.

scholarly journals Protein kinase G deficiency induces pulmonary hypertension in mice and humans

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
You‐Yang Zhao ◽  
Muhammad K Mirza ◽  
Sophie Sun ◽  
Kristen Wasiukanis ◽  
Stephen M Vogel ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Protein Kinase ◽  
Protein Kinase G

Punicalagin Prevents Hypoxic Pulmonary Hypertension via Anti-Oxidant Effects in Rats

2016 ◽  
Vol 44 (04) ◽  
pp. 785-801 ◽  
Author(s):  
Jingyun Shao ◽  
Peng Wang ◽  
An Liu ◽  
Xusheng Du ◽  
Jie Bai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Pulmonary Arteries ◽  
Pomegranate Juice ◽  
No Production ◽  
Protective Effects ◽  
Hypoxic Pulmonary Hypertension ◽  
Beneficial Effects ◽  
Anti Oxidant

Punicalagin (PG), a major bioactive ingredient in pomegranate juice, has been proven to have anti-oxidative stress properties and to exert protective effects on acute lung injuries induced by lipopolysaccharides. This study aimed to investigate the effects of PG treatment on hypoxic pulmonary hypertension (HPH) and the underlying mechanisms responsible for the effects. Rats were exposed to 10% oxygen for 2 wk (8 h/day) to induce the HPH model. PG (5, 15, 45[Formula: see text]mg/kg) was orally administered 10[Formula: see text]min before hypoxia each day. PG treatments at the doses of 15 and 45[Formula: see text]mg/kg/d decreased the mean pulmonary arterial pressure (mPAP) and alleviated right ventricular hypertrophy and vascular remodeling in HPH rats. Meanwhile, PG treatment attenuated the hypoxia-induced endothelial dysfunction of pulmonary artery rings. The beneficial effects of PG treatment were associated with improved nitric oxide (NO)-cGMP signaling and reduced oxidative stress, as evidenced by decreased superoxide generation, gp91[Formula: see text] expression and nitrotyrosine content in the pulmonary arteries. Furthermore, tempol’s scavenging of oxidative stress also increased NO production and attenuated endothelial dysfunction and pulmonary hypertension in HPH rats. Combining tempol and PG did not exert additional beneficial effects compared to tempol alone. Our study indicated for the first time that PG treatment can protect against hypoxia-induced endothelial dysfunction and pulmonary hypertension in rats, which may be induced via its anti-oxidant actions.

scholarly journals Nebivolol has a beneficial effect in monocrotaline-induced pulmonary hypertension

2016 ◽  
Vol 94 (7) ◽  
pp. 758-768 ◽  
Author(s):  
Edward A. Pankey ◽  
Justin A. Edward ◽  
Kevin W. Swan ◽  
Camille R.T. Bourgeois ◽  
Matthew J. Bartow ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Beneficial Effect ◽  
Adrenergic Receptor ◽  
Pulmonary Arteries ◽  
Blocking Agent ◽  
Current Treatment ◽  
Systemic Arterial Pressure ◽  
No Production ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity

Pulmonary hypertension is a rare disorder that, without treatment, is progressive and fatal within 3–4 years. Current treatment involves a diverse group of drugs that target the pulmonary vascular bed. In addition, strategies that increase nitric oxide (NO) formation have a beneficial effect in rodents and patients. Nebivolol, a selective β1 adrenergic receptor-blocking agent reported to increase NO production and stimulate β3 receptors, has vasodilator properties suggesting that it may be beneficial in the treatment of pulmonary hypertension. The present study was undertaken to determine whether nebivolol has a beneficial effect in monocrotaline-induced (60 mg/kg) pulmonary hypertension in the rat. These results show that nebivolol treatment (10 mg/kg, once or twice daily) attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension. This study demonstrates the presence of β3 adrenergic receptor immunoreactivity in pulmonary arteries and airways and that nebivolol has pulmonary vasodilator activity. Studies with β3 receptor agonists (mirabegron, BRL 37344) and antagonists suggest that β3 receptor-mediated decreases in systemic arterial pressure occur independent of NO release. Our results suggest that nebivolol, a selective vasodilating β1 receptor antagonist that stimulates β3 adrenergic receptors and induces vasodilation by increasing NO production, may be beneficial in treating pulmonary hypertensive disorders.

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