Hypoxic Pulmonary Vascular Remodeling Research Articles

The relationship between acidosis and hypercapnia with Cor pulmonale in patients with chronic obstructive pulmonary disease

Introduction: Cor pulmonale or right ventricular (RV) enlargement is cardiovascular complication of the chronic obstructive pulmonary disease (COPD). Hypoxic pulmonary vasoconstriction, hypercapnia, acidosis and pulmonary vascular remodeling are suggested as possible mechanisms of cor pulmonale. In this study, we aimed to evaluate the correlation between acidosis and hypercapnia with corpulmonale in patients with COPD. Methods: In this cross-sectional analytical study, 100 patients (56 men and 44 women with mean age of 66.53 ± 10.63 years) with moderate to severe COPD exacerbation were included. Complete history taking and physical examination as well as atrial blood gas, pulmonary function test (PFT) and echocardiography were performed. Disease severity was defined according to global initiative for obstructive lung disease (GOLD), Modified Medical Research Council (mMRC) and COPD Assessment Test (CAT) criteria. Patients with cor pulmonale were defined and findings were compared between patients with and without cor pulmonale. Results: Forty-two patients had cor pulmonale. There was no significant difference in hypercapnia between groups. Cor pulmonale patients, compared to non-cor pulmonale, had significantly lower forced expiratory volume in the first second (FEV1) (P = 0.020), higher tricuspid regurgitation (TR) (P = 0.001) and pulmonary hypertension (P = 0.020). There was significantly negative correlation between RV thickness with FEV1/forced vital capacity (FCV) (r = -0.239, P = 0.010) and RV size with FEV1/FVC (r = -0.312, P = 0.002) and positive correlation with partial pressure of carbon dioxide (PaCO2) (r = 0.312, P = 0.002) and bicarbonate (HCO3) (r = 0.258, P = 0.009). Conclusion: Cor pulmonale in the course of COPD accompanies with adverse outcome. These patients have worse spirometry and left ventricle echocardiographic findings, but have no difference in arterial blood gas (ABG) findings.

MiR-125a regulates mitochondrial homeostasis through targeting mitofusin 1 to control hypoxic pulmonary vascular remodeling.

Hypoxia leads to upregulation of mitofusin 1 (Mfn1) both in vivo and in vitro. Mfn1 is involved in hypoxia-induced PASMCs proliferation. Mfn1-mediated mitochondrial homeostasis is regulated by miR-125a. MiR-125a plays a role in PASMCs oxidative phosphorylation and glycolysis.

HIF2α–arginase axis is essential for the development of pulmonary hypertension

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.

SENP‑1 enhances hypoxia‑induced proliferation of rat pulmonary artery smooth muscle cells by regulating hypoxia‑inducible factor‑1α.

Hypoxic pulmonary vascular remodeling (HPSR) has an important role in the development of hypoxic pulmonary hypertension. HPSR is predominantly mediated by the proliferation of pulmonary artery smooth muscle cells (PASMCs). Our previous study demonstrated that hypoxia-inducible factor (HIF)-1α was able to promote the proliferation of PASMCs. Small ubiquitin-like modifier (SUMO)ylation is a post-translational modification that is important in various cellular processes. It has previously been demonstrated that HIF-1α may be SUMOylated by SUMO. Conversely, SUMO-specific protease 1 (SENP-1) was able to increase the stability of HIF-1α by decreasing SUMOylation of HIF-1α. In order to investigate whether SUMOylation of HIF-1α has a role in the proliferation of PASMCs, the present study cultured PASMCs in hypoxic and normoxic chambers in vitro. The proliferation ability of PASMCs was measured using the Cell Counting kit-8 and 5-ethynyl-2′-deoxyuridine cell proliferation assays. In addition, short hairpin RNA lentiviral particles were used to knockdown the expression of SENP-1, and the expression levels of HIF-1α, SENP-1 and vascular endothelial growth factor (VEGF) were detected at the mRNA and protein levels using semi-quantitative polymerase chain reaction and western blotting, respectively. The present study demonstrated that SENP-1 was able to enhance the proliferative ability of PASMCs by initiating deSUMOylation of HIF-1α and increasing the expression of its downstream responsive gene, VEGF.

Effect of panax notoginseng saponins on pulmonary artery pathology of pulmonary hypertension rats

Objective To observe the effect of panax notoginseng saponins on pulmonary artery pathology in chronic hypoxic pulmonary hypertensionp (HPH) rats models, discuss the role and possible mechanisms of panax notoginseng saponins in prevention of chronic hypoxic pulmonary hypertension. Methods Forty male Sprague-Dawley (SD) rats were randomly divided into four groups (n=10). Group C: control group; Group H: rats were treated with hypoxia only; Group HC: rats were treated with hypoxia and captopril; and Group HP: rats were treated with hypoxia and panax notoginseng saponins. To observe the effect of panax notoginseng saponins prophylactic treatment in chronic hypoxic pulmonary hypertension rats, after the establishment of the model of hypoxic rat animal pulmonary hypertension models, transthoracic direct pulmonary artery intubation was measured in rat pulmonary arterial systolic pressure and mean pulmonary artery pressure, at the end of separation and cut for pulmonary artery to observe the pathological changes of pulmonary artery, results were recorded and statistically analyzed. Results ⑴Transthoracic direct pulmonary artery intubation was measured in rat pulmonary arterial systolic pressure and mean pulmonary artery pressure: pulmonary artery systolic pressure (PASP) and mean pulmonary arterial pressure (MPAP) were significantly higher in Group H than in Group C (P<0.05), Group HP was no significant difference relative to Group C. ⑵Pathological section shew that the primary pathological change of group H is vascular intimal hyperplasia and the proliferation of smooth muscle cells, medial hypertrophy, extracellular matrix increased, thickening of the vessel wall and the vascular stenos. Conclusions Panax notoginseng saponins inhibit the formation of chronic hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats, and have the effect of prevention and treatment of pulmonary hypertension. Key words: SANCHINOSIDE/PD; Hypertension, pulmonary/DT/PA; Pulmonary artery/PA; Anoxia

Mast cell stabilization with sodium cromoglycate modulates pulmonary vessel wall remodeling during four-day hypoxia in rats

ABSTRACTAim of the study: In rats, the environment with low content of oxygen induces hypoxic pulmonary hypertension. Remodeling of pulmonary resistance arteries is particularly triggered by the mast cell degranulation products, e.g., rodent-like interstitial collagenase (matrix metalloproteinase 13). Administration of sodium cromoglycate leads to stabilization of mast cell granules, and thus to the modified remodeling process. Materials and Methods: During four-day hypoxia, we treated rats with sodium cromoglycate. Pulmonary vascular remodeling was assessed as well as counts of periarterial pulmonary mast cells, both total and matrix metalloproteinase 13-positive ones. Results: Four-day hypoxia induced remodeling of both resistance arteries and large conduit arteries. We have found increase in the tunica media thickness of resistance arteries. Tunica adventitia thickness of both resistance arteries and large conduit arteries with a diameter of over 300 μm increased as well; the latter ones revealed increase in the number of vasa vasorum in their walls. Mast cell stabilization suppressed hypoxic pulmonary vascular remodeling in resistance pulmonary arteries. Four-day hypoxia led to changes in distribution of toluidine blue-detected and MMP-13 positive periarterial mast cells; this redistribution was also influenced by the administration of sodium cromoglycate. Conclusions: The number of pulmonary periarterial mast cells seemingly decreases during hypoxia due to their degranulation, which disables their identification. Large conduit arteries do not affect final blood pressure in the pulmonary vascular bed; however, their structure changes substantially under hypoxia. Such remodeling changes are not mediated by mast cell products only since they have occurred in spite of stabilization of mast cell granules.

Pathophysiology and treatment of high-altitude pulmonary vascular disease.

It is estimated that >140 million people live above 2500 m in various regions of the world.1 There are many challenges to living at high altitude, but chronic exposure to alveolar hypoxia is prominent among them. Inspired Po2 falls from ≈150 mm Hg at sea level to ≈100 mm Hg at 3000 m and 43 mm Hg on the summit of Everest (8400 m).2,3 The body responds by hyperventilating, increasing resting heart rate, and stimulating red cell production in an attempt to maintain the oxygen content of arterial blood at or above sea level values.2 However, hypoxic pulmonary vasoconstriction (HPV) and vascular remodeling, together with increased erythropoiesis, place an increased pressure load on the right ventricle (RV). How well healthy humans adapt to hypoxia depends on their rate of ascent to altitude, the severity and duration of their exposure, and their genetic background. ### Pulmonary Vascular Response to Hypoxia For most mammals, including humans, a rise in pulmonary artery pressure (PAP) is an early and inevitable consequence of ascent to high altitude. Resting mean PAP increases along a parabolic curve from 15 mm Hg at 2000 m to ≈30 mm Hg at 4500 m.4 The exceptions and interindividual variation in the magnitude of response offer a natural experiment that might provide insight into fundamental underlying mechanisms ( vide infra ). The initial rise in PAP on exposure to hypoxia is attributed to HPV. With chronic hypoxia, other mechanisms that likely drive vascular remodeling soon contribute to the elevated pressure (Figure 1A). After 2 or 3 weeks of hypoxia, there is little response to rebreathing 100% oxygen, indicating a structural resistance to pulmonary blood flow rather than one based solely on increased vasomotor tone.6 A fall in PAP on re-exposure to a normal oxygen environment is evident in rats monitored by telemetry over days …

Possible role of lysophosphatidic acid in rat model of hypoxic pulmonary vascular remodeling.

Pulmonary hypertension is characterized by cellular and structural changes in the vascular wall of pulmonary arteries. We hypothesized that lysophosphatidic acid (LPA), a bioactive lipid, is implicated in this vascular remodeling in a rat model of hypoxic pulmonary hypertension. Exposure of Wistar rats to 10% O2 for 3 weeks induced an increase in the mean serum levels of LPA, to 40.9 (log-detransformed standard deviations: 23.4-71.7) μM versus 21.6 (11.0-42.3) μM in a matched control animal group (P = 0.037). We also observed perivascular LPA immunohistochemical staining in lungs of hypoxic rats colocalized with the secreted lysophospholipase D autotaxin (ATX). Moreover, ATX colocalized with mast cell tryptase, suggesting implication of these cells in perivascular LPA production. Hypoxic rat lungs expressed more ATX transcripts (2.4-fold) and more transcripts of proteins implicated in cell migration: β2 integrin (1.74-fold), intracellular adhesion molecule 1 (ICAM-1; 1.84-fold), and αM integrin (2.70-fold). Serum from the hypoxic group of animals had significantly higher chemoattractant properties toward rat primary lung fibroblasts, and this increase in cell migration could be prevented by the LPA receptor 1 and 3 antagonists. LPA also increased adhesive properties of human pulmonary artery endothelial cells as well as those of human peripheral blood mononuclear cells, via the activation of LPA receptor 1 or 3 followed by the stimulation of gene expression of ICAM-1, β-1, E-selectin, and vascular cell adhesion molecule integrins. In conclusion, chronic hypoxia increases circulating and tissue levels of LPA, which might induce fibroblast migration and recruitment of mononuclear cells in pulmonary vasculature, both of which contribute to pulmonary vascular remodeling.

Hypoxia activates 15‐PGDH and its metabolite 15‐KETE to promote pulmonary artery endothelial cells proliferation via ERK1/2 signalling

Dysfunction and injury of endothelial cells in the pulmonary artery play critical roles in the hypertension induced by chronic hypoxia. One consequence of hypoxia is increased activity of 15-hydroxyprostaglandin dehydrogenase (PGDH). Here, we have explored, in detail, the effects of hypoxia on the proliferation of pulmonary artery endothelial cells. We used bromodeoxyuridine incorporation, cell-cycle analysis, immunohistochemistry and Western blot analysis to study the effects of hypoxia, induced 15-PGDH) activity and its product, 15-keto-6Z, 8Z, 11Z, 13E-eicosatetraenoic acid (15-KETE), on endothelial cell proliferation. Scratch-wound and tube formation assays were also used to study migration of endothelial cells. 15-KETE increased DNA synthesis and enhanced the transition from the G0 /G1 phase to the S phase in hypoxia. Inhibition of 15-PGDH or siRNA for 15-PGDH reversed these effects. 15-KETE also activated the ERK1/2 signalling pathway. 15-KETE-induced cell migration and tube formation were reversed by blocking ERK1/2, but not the p38 MAPK pathway. Hypoxia-induced endothelial proliferation and migration, an important underlying mechanism contributing to hypoxic pulmonary vascular remodelling, appears to be mediated by 15-PGDH and 15-KETE, via the ERK1/2 signalling pathway.

Altered expressions of alkane monooxygenase and hypoxia inducible factor-1α expression in lung tissue of rat hypoxic pulmonary hypertension

To explore the altered expressions of alkane monooxygenase (AlkB) and hypoxia-inducible factor-1α (HIF-1α) in a rat model of hypoxic pulmonary arterial hypertension. Twenty Wistar rats were divided randomly into normal control and hypoxia groups after 1-week adaptive feeding. Hypoxia group was raised in a homemade organic glass tank with a 24-h continuous supply of air and nitrogen atmospheric mixed gas. And the oxygen concentration of (10.0 ± 0.5)% was controlled by oxygen monitoring control system. The control group was maintained in room air. Both groups stayed in the same room with the same diet. After 8 weeks, the level of mean pulmonary pressure (mPAP) was measured by right-heart catheterization, right ventricular hypertrophy index (RVHI) calculated by the ratio of right ventricle to left ventricle plus septum and hypoxic pulmonary vascular remodeling (HPSR) observed under microscope. And the levels of AlkB and HIF-1α mRNA and protein in lungs were measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot. At 8 weeks post-hypoxia, compared with the control group [11.0 ± 0.7 mm Hg (1 mm Hg = 0.133 kPa), 0.210 ± 0.035], the levels of mPAP and RVHI in hypoxia group (33.3 ± 1.3 mm Hg, 0.448 ± 0.013) increased significantly (both P < 0.05), the expressions of AlkB mRNA and protein in pulmonary tissue decreased significantly (0.338 ± 0.085 vs 0.688 ± 0.020, P < 0.01) (0.483 ± 0.052 vs 0.204 ± 0.010, P < 0.01), and the expressions of HIF-1α mRNA and protein increased significantly (0.790 ± 0.161 vs 0.422 ± 0.096, P < 0.01) (0.893 ± 0.080 vs 0.346 ± 0.008, P < 0.01). The down-regulation of AlkB in lung tissue may increase the activity of HIF-1 to participate in the occurrence and development of pulmonary hypertension.

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Differential Regulation of Pulmonary Vascular Cell Growth by Hypoxia-Inducible Transcription Factor–1α and Hypoxia-Inducible Transcription Factor–2α

Hypoxia-inducible transcription factors HIF-1α and HIF-2α can contribute to pulmonary hypertension and vascular remodeling, but their mechanisms remain unknown. This study investigated the role of HIF-1α and HIF-2α in pulmonary artery endothelial and smooth muscle cells. The exposure of human pulmonary artery endothelial cells (HPAECs) to hypoxia (10% O₂ or 5% O₂) increased proliferation over 48 hours, compared with cells during normoxia (21% O₂). The adenovirus-mediated overexpression of HIF-2α that is transcriptionally active during normoxia (mutHIF-2α) increased HPAEC proliferation, whereas the overexpression of HIF-1α, which is transcriptionally active during normoxia (mutHIF-1α), exerted no effect. The knockdown of HIF-2α decreased proliferation during both hypoxia and normoxia. Both HIFs increased migration toward fibrinogen, used as a chemoattractant. In an angiogenesis tube formation assay, mutHIF-2α-transduced cells demonstrated increased tube formation, compared with the mutHIF-1α-transduced cells. In addition, the tubes formed in HIF-2α-transduced cells were more enduring than those in the other groups. In human pulmonary artery smooth muscle cells (HPASMCs), chronic exposure to hypoxia increased proliferation, compared with cells during normoxia. For HPASMCs transduced with adenoviral HIFs, HIF-1α increased proliferation, whereas HIF-2α exerted no such effect. Thus, HIF-1α and HIF-2α exert differential effects in isolated cells of the human pulmonary vasculature. This study demonstrates that HIF-2α plays a predominant role in the endothelial growth pertinent to the remodeling process. In contrast, HIF-1α appears to play a major role in pulmonary smooth muscle growth. The selective targeting of each HIF in specific target cells may more effectively counteract hypoxic pulmonary hypertension and vascular remodeling.

Intermedin modulates hypoxic pulmonary vascular remodeling by inhibiting pulmonary artery smooth muscle cell proliferation

BackgroundHypoxic pulmonary arterial hypertension (PAH) is a disabling disease with limited treatment options. Hypoxic pulmonary vascular remodeling is a major cause of hypoxic PAH. Pharmacological agents that can inhibit the remodeling process may have great therapeutic value. ObjectiveTo examine the effect of intermedin (IMD), a new calcitonin gene-related peptide family of peptide, on hypoxic pulmonary vascular remodeling. MethodsRats were exposed to normoxia or hypoxia (∼10% O2), or exposed to hypoxia and treated with IMD, administered by an implanted mini-osmotic pump (6.5 μg/rat/day), for 4 weeks. The effects of IMD infusion on the development of hypoxic PAH and right ventricle (RV) hypertrophy, on pulmonary vascular remodeling, on pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis, and on the activations of l-arginine nitric oxide (NO) pathway and endoplasmic reticulum stress apoptotic pathway were examined. ResultsRats exposed to hypoxia developed PAH and RV hypertrophy. IMD treatment alleviated PAH and prevented RV hypertrophy. IMD inhibited hypoxic pulmonary vascular remodeling as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia-exposed rats. IMD treatment inhibited PASMC proliferation and promoted PASMC apoptosis. IMD treatment increased tissue level of constitutive NO synthase activity and tissue NO content in lungs, and enhanced l-arginine uptake into pulmonary vascular tissues. IMD treatment increased cellular levels of glucose-regulated protein (GRP) 78 and GRP94, two major markers of endoplasmic reticulum (ER) stress, and increased caspase-12 expression, the ER stress-specific caspase, in lungs and cultured PASMCs. ConclusionsThese results demonstrate that IMD treatment attenuates hypoxic pulmonary vascular remodeling, and thereby hypoxic PAH mainly by inhibiting PASMC proliferation. Promotion of PASMC apoptosis may also contribute to the inhibitory effect of IMD. Activations l-arginine–NO pathway and of ER stress-specific apoptosis pathway could be the mechanisms mediating the anti-proliferative and pro-apoptotic effects of IMD.

Pulmonary hypertension and the right ventricle in hypoxia

Hypoxia causes pulmonary vasoconstriction. Regional hypoxic vasoconstriction improves the matching of perfusion to alveolar ventilation. Global hypoxic vasoconstriction increases right ventricular afterload. The hypoxic pulmonary pressor response is universal in mammals and in birds, but with considerable interspecies and interindividual variability. Chronic hypoxia induces pulmonary hypertension in proportion to initial vasoconstriction. Prolonged hypoxic exposure is also associated with an increase in red blood cell mass, which aggravates pulmonary hypertension by an increase in blood viscosity. Hypoxic pulmonary hypertension in humans is usually mild to moderate, but pulmonary vascular pressure-flow relationships are steep, which corresponds to a substantial afterload on the right ventricle during exercise. A partial recovery of 10-25% of the hypoxia-induced decrease in maximal oxygen uptake has been reported with intake-specific pulmonary vasodilating interventions. Hypoxia has been reported to decrease myocardial fibre contractility in vitro. However, the acutely hypoxic right ventricle remains able to preserve the coupling of its contractility to increased afterload in intact animals. Echocardiographic studies of the right ventricle in healthy hypoxic human subjects show altered diastolic function, but systolic function that is preserved or even increased acutely and slightly depressed chronically. These findings are more pronounced in patients with chronic mountain sickness. Their clinical significance remains incompletely understood. Almost no imaging studies of right ventricular function have been reported in a minority of subjects who develop severe pulmonary hypertension and clinical right ventricular failure in hypoxia. No imaging studies of right ventricular function during hypoxic exercise in normal subjects are yet available. Thus, while it is plausible that the right ventricle limits exercise capacity in hypoxia, this still needs to be firmly established.

MicroRNA-138 plays a role in hypoxic pulmonary vascular remodelling by targeting Mst1

Unbalanced apoptosis is a major cause of structural remodelling of vasculatures associated with PAH (pulmonary arterial hypertension), whereas the underlying mechanisms are still elusive. miRNAs (microRNAs) regulate the expression of several proteins that are important for cell fate, including differentiation, proliferation and apoptosis. It is possible that these regulatory RNA molecules play a role in the development of PAH. To test this hypothesis, we studied the effect of several miRNAs on the apoptosis of cultured PASMCs (pulmonary artery smooth muscle cells) and identified miR-138 to be an important player. miR-138 was expressed in PASMCs, and its expression was subjected to regulation by hypoxia. Expression of exogenous miR-138 suppressed PASMC apoptosis, prevented caspase activation and disrupted Bcl-2 signalling. The serine/threonine kinase Mst1, an amplifier of cell apoptosis, seemed to be a target of miR-138, and the activation of the Akt pathway was necessary for the anti-apoptotic effect of miR-138. Therefore the results of the present study suggest that miR-138 appears to be a negative regulator of PASMC apoptosis, and plays an important role in HPVR (hypoxic pulmonary vascular remodelling).

Implication of lysophosphatidic acid in hypoxic pulmonary vascular remodeling: effects on cell adhesion and migration

Pulmonary hypertension is characterized by cellular and structural changes in vascular wall of pulmonary arteries. Intimal thickening, fibrosis, medial hypertrophy, adventitial fibroblast activation involve progenitors cells and fibrocytes. We hypothesized that lysophosphatidic acid (LPA), a bioactive lipid, is implicated in this vascular remodeling. We investigated the rat model of hypoxic pulmonary hypertension. Chronic hypoxic exposure induced increase of serum levels of circulating LPA (21.6 (11.0 – 42.3) μM vs 40.9 (23.4 – 71.7) μM, p=0.037). In addition, we observed perivascular LPA immunohistochemical staining in lungs of hypoxic rats (antibody against LPA provided by L‐Path Inc.), which co‐localized with lysophospholipase D. Serum from the hypoxic group of animals had significantly higher chemoattractant properties towards rat primary lung fibroblasts, and this increase in cell migration could be prevented by the LPA receptor 1 and 3 antagonist, VPC12249. LPA increased also adhesive properties of human pulmonary artery endothelial cells and of human peripheral blood mononuclear cells via the activation LPA receptor (1 or 3). We suggest that chronic hypoxia increases circulating and tissue level of LPA which might induce fibroblast migration and recruitment of mononuclear cells in pulmonary vasculature that contributes to pulmonary vascular remodeling.

99 TANSHINONE IIA ATTENUATED HYPOXIA-INDUCED PULMONARY HYPERTENSION VIA UPGRADING KV CHANNELS AND P27KIP1

Objectives: Pulmonary hypertension induced by hypoxia is the characterized by hypoxic pulmonary vasoconstriction (HPV) and pulmonary vascular structure remodeling (PVSR). Tanshinone IIA (TIIA) has numerous biological protective effects. Purpose of the paper is to investigated whether KV channels and P27kip1 were responsible for the protective effect of TIIA on HPV and PVSR. Basic procedures and methods: Effects of TIIA on intrapulmonary arteriole (IPA) rings and the IKV currents of pulmonary artery smooth muscle cells (PASMCs) isolated from rats in acute hypoxia experiments and chronic hypoxia experiments were determined. Main findings: results showed that TIIA attenuated acute hypoxia-induced IPA rings vasoconstriction which may be partially through recovering the down- regulation of IKV currents in PASMCs. TIIA markedly alleviated the increased weight of right ventricle/left ventricle plus septum ratio, medial width of pulmonary arterioles, decreased expression of Kv2.1 and Kv1.5 and the down-regulation of IKV currents induced by chronic hypoxia. In addition, TIIA increased the p27kip1 protein amount, but did not affect the p27kip1 mRNA amount. TIIA kept p27kip1 from being degraded through repressing the activity of Akt and decreasing the production of Skp-2. Conclusions: Principle conclusions: these data demonstrates that TIIA significantly attenuated acute and chronic hypoxia-induced HPV and PVSR, which were probably through up-regulation KV channels and p27kip1.

Promotion of Apoptosis Does Not Necessarily Mean Inhibition of Remodeling

To the Editor: Hypoxic pulmonary hypertension is a serious disease characterized by hypoxic pulmonary vasoconstriction and pulmonary vascular remodeling.1 In the article “The MicroRNA-328 Regulates Hypoxic Pulmonary Hypertension by Targeting at Insulin Growth Factor 1 Receptor and l-Type Calcium Channel-1C,”2 the authors have drawn a conclusion that miR-328 is downregulated in pulmonary arteries from hypoxic rats and patients with pulmonary hypertension, affecting hypoxic pulmonary vasoconstriction and pulmonary vascular remodeling by targeting Cav1.2 and insulin-like growth factor 1 receptor, leading to hypoxic pulmonary hypertension.2 However, from the data presented, the authors claimed only that miR-328 induced pulmonary artery smooth muscle cell (PASMC) …

Silencing of Sodium–Hydrogen Exchanger 1 Attenuates the Proliferation, Hypertrophy, and Migration of Pulmonary Artery Smooth Muscle Cells via E2F1

We previously found that deficiency of the sodium-hydrogen exchanger 1 (NHE1) gene prevented hypoxia-induced pulmonary hypertension and vascular remodeling in mice, which were accompanied by a significantly reduced proliferation of pulmonary artery smooth muscle cells (PASMCs), and which decreased the medial-wall thickness of pulmonary arteries. That finding indicated the involvement of NHE1 in the proliferation and hypertrophy of PASMCs, but the underlying mechanism was not fully understood. To define the mechanism by which the inhibition of NHE1 decreases hypoxic pulmonary hypertension and vascular remodeling, we investigated the role of E2F1, a nuclear transcription factor, in silencing the NHE1 gene-induced inhibition of the proliferation, hypertrophy, and migration of human PASMCs. We found that: (1) silencing of NHE1 by short, interfering RNA (siRNA) significantly inhibited PASMC proliferation and cell cycle progression, decreased hypoxia-induced hypertrophy (in terms of cell size and protein/DNA ratio) and migration (in terms of the wound-healing and migration chamber assays); (2) hypoxia induced the expression of E2F1, which was reversed by NHE1 siRNA; and (3) the overexpression of E2F1 blocked the inhibitory effect of NHE1 siRNA on the proliferation, hypertrophy, and migration of PASMCs. The present study determined that silencing the NHE1 gene significantly inhibited the hypoxia-induced proliferation, hypertrophy, and migration of human PASMCs via repression of the nuclear transcription factor E2F1. This study revealed a novel mechanism underlying the regulation of hypoxic pulmonary hypertension and vascular remodeling via NHE1.

Decreased Neprilysin and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease

Studies with genetically engineered mice showed that decreased expression of the transmembrane peptidase neprilysin (NEP) increases susceptibility to hypoxic pulmonary vascular remodeling and hypertension; in hypoxic wild-type mice, expression is decreased early in distal pulmonary arteries, where prominent vascular remodeling occurs. Therefore, in humans with smoke- and hypoxia-induced vascular remodeling, as in chronic obstructive pulmonary disease (COPD), pulmonary activity/expression of NEP may likewise be decreased. To test whether NEP activity and expression are reduced in COPD lungs and pulmonary arterial smooth muscle cells (SMCs) exposed to cigarette smoke extract or hypoxia and begin to investigate mechanisms involved. Control and advanced COPD lung lysates (n = 13-14) were analyzed for NEP activity and protein and mRNA expression. As a control, dipeptidyl peptidase IV activity was analyzed. Lung sections were assessed for vascular remodeling and oxidant damage. Human pulmonary arterial SMCs were exposed to cigarette smoke extract, hypoxia, or H₂O₂, and incubated with antioxidants or lysosomal/proteasomal inhibitors. COPD lungs demonstrated areas of vascular rarification, distal muscularization, and variable intimal and prominent medial/adventitial thickening. NEP activity was reduced by 76%; NEP protein expression was decreased in alveolar walls and distal vessels; mRNA expression was also decreased. In SMCs exposed to cigarette smoke extract, hypoxia, and H₂O₂, NEP activity and expression were also reduced. Reactive oxygen species inactivated NEP activity; NEP protein degradation appeared to be substantially induced. Mechanisms responsible for reduced NEP activity and protein expression include oxidative reactions and protein degradation. Maintaining or increasing lung NEP may protect against pulmonary vascular remodeling in response to chronic smoke and hypoxia.