Effect of dietary fish oil on lung lipid profile and hypoxic pulmonary hypertension

Archer, Stephen L.; Johnson, Gerhard J.; Gebhard, Roger L.; Castleman, W. L.; Levine, Allen S.; Westcott, Jay Y.; Voelkel, NF; Nelson, Daniel S.; Weir, Ε. Kenneth

doi:10.1152/jappl.1989.66.4.1662

Cited by 40 publications

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“…Intrapulmonary resistance PAs were subcategorized based on relationship to airway structures and diameter: large (associated with bronchi, Ͼ100 m), intermediate (associated with alveolar ducts, 40 to 100 m), and small (surrounded by alveoli, Ͻ40 m). 29 …”

Section: Definitionsmentioning

confidence: 99%

Preferential Expression and Function of Voltage-Gated, O ₂ -Sensitive K ⁺ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

Archer

Thébaud

et al. 2004

Circulation Research

180

178

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Abstract-Hypoxic pulmonary vasoconstriction (HPV) is initiated by inhibition of O 2 -sensitive, voltage-gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs). Kv inhibition depolarizes membrane potential (E M ), thereby activating Ca 2ϩ influx via voltage-gated Ca 2ϩ channels. HPV is weak in extrapulmonary, conduit pulmonary arteries (PA) and strong in precapillary resistance arteries. We hypothesized that regional heterogeneity in HPV reflects a longitudinal gradient in the function/expression of PASMC O 2 -sensitive Kv channels. In adult male Sprague Dawley rats, constrictions to hypoxia, the Kv blocker 4-aminopyridine (4-AP), and correolide, a Kv1.x channel inhibitor, were endothelium-independent and greater in resistance versus conduit PAs. Moreover, HPV was dependent on Kvinhibition, being completely inhibited by pretreatment with 4-AP. Kv1.2, 1.5, Kv2.1, Kv3.1b, Kv4.3, and Kv9.3. mRNA increased as arterial caliber decreased; however, only Kv1.5 protein expression was greater in resistance PAs. Resistance PASMCs had greater K ϩ current (I K ) and a more hyperpolarized E M and were uniquely O 2 Ϫ and correolide-sensitive. The O 2 -sensitive current (active at Ϫ65 mV) was resistant to iberiotoxin, with minimal tityustoxin sensitivity. In resistance PASMCs, 4-AP and hypoxia inhibited I K 57% and 49%, respectively, versus 34% for correolide. Intracellular administration of anti-Kv1.5 antibodies inhibited correolide's effects. The hypoxia-sensitive, correolide-insensitive I K (15%) was conducted by Kv2.1. Anti-Kv1.5 and anti-Kv2.1 caused additive depolarization in resistance PASMCs (Kv1.5ϾKv2.1) and inhibited hypoxic depolarization. Heterologously expressed human PASMC Kv1.5 generated an O 2 Ϫ and correolide-sensitive I K like that in resistance PASMCs. In conclusion, Kv1.5 and Kv2.1 account for virtually all the O 2 -sensitive current. HPV occurs in a Kv-enriched resistance zone because resistance PASMCs preferentially express O 2 -sensitive Kv-channels. Key Words: immunoelectropharmacology Ⅲ laser capture microdissection Ⅲ voltage-gated channels Ⅲ pulmonary circulation Ⅲ adenoviral gene transfer T he adult pulmonary circulation is a low-resistance circuit designed for gas exchange that is perfused by a thinwalled, afterload-intolerant right ventricle. The pulmonary vasculature consists of large, elastic, extraparenchymal "conduit" arteries and small, muscular intrapulmonary arteries, which control regional distribution of blood flow and largely determine pulmonary vascular resistance (PVR). Hypoxic pulmonary vasoconstriction (HPV) is a widely conserved mechanism for ventilation-perfusion matching. 1 With segmental hypoxia (eg, atelectasis), resistance pulmonary arteries (PAs) serving the hypoxic lobes constrict, diverting blood to better-oxygenated segments, thereby optimizing systemic PO 2 , without increasing PVR. 2,3 Microangiography 4 and micropuncture 5 reveal that HPV primarily occurs in resistance PAs (Ͻ200 mol/L diameter, division 4, and distal), with lesser contributions from larger i...

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Section: Definitionsmentioning

confidence: 99%

Preferential Expression and Function of Voltage-Gated, O ₂ -Sensitive K ⁺ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

Archer

Thébaud

et al. 2004

Circulation Research

180

178

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“…The RV/(LVϩseptum) ratio, a measure of right ventricular hypertrophy (RVH), was measured as previously described. 18 …”

Section: Hemodynamic Measurementsmentioning

confidence: 99%

“…Medial thickness was measured in small and medium-size PAs (nϭ88 from 4 rats per group) by investigators blinded to the treatment groups, as previously described. 18 …”

Section: Histologymentioning

confidence: 99%

Dichloroacetate, a Metabolic Modulator, Prevents and Reverses Chronic Hypoxic Pulmonary Hypertension in Rats

et al. 2002

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Background-Chronic hypoxic pulmonary hypertension (CH-PHT) is associated with suppressed expression and function of voltage-gated K ϩ channels (Kv) in pulmonary artery (PA) smooth muscle cells (SMCs) and a shift in cellular redox balance toward a reduced state. We hypothesized that dichloroacetate (DCA), a metabolic modulator that can shift redox balance toward an oxidized state and increase Kv current in myocardial cells, would reverse CH-PHT. Methods and Results-We studied 4 groups of rats: normoxic, normoxicϩDCA (DCA 70 mg · kg Ϫ1 · d Ϫ1 PO), chronically hypoxic (CH), and CHϩDCA. CH and CHϩDCA rats were kept in a hypoxic chamber (10% FiO 2 ) for 2 to 3 weeks. DCA was given either at day 1 to prevent or at day 10 to reverse CH-PHT. We used micromanometer-tipped catheters and measured hemodynamics in closed-chest rats on days 14 to 18. CHϩDCA rats had significantly reduced pulmonary vascular resistance, right ventricular hypertrophy, and PA remodeling compared with the CH rats. CH inhibited I K , eliminated the acute hypoxia-sensitive I K , and decreased Kv2.1 channel expression. In the short term, low-dose DCA (1 mol/L) increased I K in CH-PASMCs. In a mammalian expression system, DCA activated Kv2.1 by a tyrosine kinase-dependent mechanism. When given long-term, DCA partially restored I K and Kv2.1 expression in PASMCs without altering right ventricular pyruvate dehydrogenase activity, suggesting that the beneficial effects of DCA occur by nonmetabolic mechanisms. Conclusions-DCA both prevents and reverses CH-PHT by a mechanism involving restoration of expression and function of Kv channels. DCA has previously been used in humans and may potentially be a therapeutic agent for pulmonary hypertension. (Circulation. 2002;105:244-250.)

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“…7 Selective delivery of a dominant-negative construct to the small PAs (using an inhaled adenovirus) induces apoptosis, decreases proliferation in the media, and reverses PAH. 7 Also, inhibition of the PDGF pathway either by fish oil 24 or imatinib 6 reverses PAH in animals. In summary, early PAH is characterized by increased apoptosis in the endothelial layer.…”

Section: An Apoptosis-based Theory For the Development Of Pah: Being mentioning

confidence: 99%

Spatio-Temporal Diversity of Apoptosis Within the Vascular Wall in Pulmonary Arterial Hypertension

Michelakis

2006

Circulation Research

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A lthough pulmonary arterial hypertension (PAH) was originally thought to be a disease of increased pulmonary arterial (PA) tone, we now know that vasoconstriction is important only in a minority of patients. 1 PAH is characterized by increased proliferation of PA endothelial cells (PAECs) and PA smooth muscle cells (PASMCs), leading to narrowing or even obliteration of the PA lumen, increased pulmonary vascular resistance (PVR), right ventricular failure and premature death. 1 Voelkel and Tuder suggested that the proliferative remodeling in the PAs resembles cancer. 2 Several features, in addition to excessive proliferation, make this hypothesis attractive. For example, as in cancer, the development of PAH appears to result from a "multiple-hit" mechanism, where environmental factors (virus, inflammation, anorexigens, shunt-induced shear stress, etc) interact with a genetic predisposition (loss-of-function mutations in the bone morphogenetic protein receptor II, BMPR-II) culminating in disease. 1 That PAH is characterized by a cancer-like apoptosis resistance is supported by recent reports that proapoptotic therapies can reverse PAH, similarly to cancer, where proapoptotic chemotherapies are the mainstay of treatment. Several experimental PAH treatments (including dichloroacetate, 3 simvastatin, 4 sildenafil, 5 imatinib, 6 anti-survivin, 7 and K ϩ channel replacement gene therapies 8 ) induce apoptosis of PASMCs, leading to reversal of vascular remodeling and PAH. In sharp contrast, strategies designed to promote survival and inhibit apoptosis of PAECs (cell-based gene transfer of angiopoietin-1 9 or eNOS, 10 caspase inhibitors 11 ) also improve PAH, particularly at early stages. These apparently conflicting reports can be rationalized by the hypothesis that vascular apoptosis is regulated in a compartment-specific manner.The role of apoptosis in the pathogenesis of PAH is also supported by the discovery that mutations in BMPR-II predispose patients to familial PAH. 12 Like most mediators involved in embryological development, BMPs are important regulators of apoptosis. It was initially assumed that loss-offunction BMPR-II mutations would suppress apoptosis and increase proliferation in the PA wall, perhaps fully explaining the vascular remodeling in PAH. However it is now recognized that although most familial PAH patients carry mutations, they are found in only Ϸ10% of patients with sporadic idiopathic PAH (iPAH) and their presence confers only a 15% to 20% chance of PAH in a carrier's lifetime. 12 Nevertheless, this discovery offered new insights into the biology of PAH. BMP Signaling in the Pulmonary CirculationBMP4 inhibits growth of PASMC from normal but not iPAH patients 13 and, similarly, BMP2 and -7 induce more apoptosis in normal than in iPAH PASMCs. 14 Interestingly, these human data are not supported by transgenic models. Heterozygous knockout mice lacking exons 4 to 5 of the BMPR-II gene have only mild pulmonary hypertension at baseline and, surprisingly, after exposure to chronic hypoxia the muscu...

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Effect of dietary fish oil on lung lipid profile and hypoxic pulmonary hypertension

Cited by 40 publications

References 0 publications

Preferential Expression and Function of Voltage-Gated, O ₂ -Sensitive K ⁺ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

Preferential Expression and Function of Voltage-Gated, O ₂ -Sensitive K ⁺ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

Dichloroacetate, a Metabolic Modulator, Prevents and Reverses Chronic Hypoxic Pulmonary Hypertension in Rats

Spatio-Temporal Diversity of Apoptosis Within the Vascular Wall in Pulmonary Arterial Hypertension

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Effect of dietary fish oil on lung lipid profile and hypoxic pulmonary hypertension

Cited by 40 publications

References 0 publications

Preferential Expression and Function of Voltage-Gated, O 2 -Sensitive K + Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

Preferential Expression and Function of Voltage-Gated, O 2 -Sensitive K + Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

Dichloroacetate, a Metabolic Modulator, Prevents and Reverses Chronic Hypoxic Pulmonary Hypertension in Rats

Spatio-Temporal Diversity of Apoptosis Within the Vascular Wall in Pulmonary Arterial Hypertension

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About

Preferential Expression and Function of Voltage-Gated, O ₂ -Sensitive K ⁺ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

Preferential Expression and Function of Voltage-Gated, O ₂ -Sensitive K ⁺ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction