RESUMEN
ABSTRACT: Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by excessive proliferation and vasoconstriction of small pulmonary artery vascular smooth muscle cells (PASMCs). Coptidis rhizoma (CR) because of the complexity of the components, the underlying pharmacological role and mechanism of it on PAH remains unknown. In this article, the network pharmacological analysis was used to screen the main active constituents of CR and the molecular targets that these constituents act on. Then, we evaluated the importance of berberine and quercetin (biologically active components of CR) on the proliferation and migration of PASMCs and vascular remodeling in experimental models of PAH. Our results showed that berberine and quercetin effectively inhibited the proliferation and migration of hypoxia-induced PASMCs in a manner likely to be mediated by the suppression of MAPK1, NADPH oxidase 4 (NOX4), and cytochrome P450 1B1 (CYP1B1) expression. Furthermore, berberine and quercetin treatment attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension in rat models. In conclusion, this research demonstrates CR might be a promising treatment option for PAH, and the network pharmacology approach can be an effective tool to reveal the potential mechanisms of Chinese herbal medicine.
Asunto(s)
Antihipertensivos/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Hipertensión Arterial Pulmonar/prevención & control , Remodelación Vascular/efectos de los fármacos , Animales , Antihipertensivos/aislamiento & purificación , Berberina/aislamiento & purificación , Berberina/farmacología , Células Cultivadas , Coptis chinensis , Citocromo P-450 CYP1B1/metabolismo , Bases de Datos Genéticas , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/aislamiento & purificación , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Hipertrofia Ventricular Derecha/prevención & control , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , NADPH Oxidasa 4/metabolismo , Farmacología en Red , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/patología , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Quercetina/aislamiento & purificación , Quercetina/farmacología , Ratas Sprague-Dawley , Transducción de Señal , Función Ventricular Derecha/efectos de los fármacosRESUMEN
High altitude (hypobaric hypoxia) triggers several mechanisms to compensate for the decrease in oxygen bioavailability. One of them is pulmonary artery vasoconstriction and its subsequent pulmonary arterial remodeling. These changes can lead to pulmonary hypertension and the development of right ventricular hypertrophy (RVH), right heart failure (RHF) and, ultimately to death. The aim of this review is to describe the most recent molecular pathways involved in the above conditions under this type of hypobaric hypoxia, including oxidative stress, inflammation, protein kinases activation and fibrosis, and the current therapeutic approaches for these conditions. This review also includes the current knowledge of long-term chronic intermittent hypobaric hypoxia. Furthermore, this review highlights the signaling pathways related to oxidative stress (Nox-derived O2.- and H2O2), protein kinase (ERK5, p38α and PKCα) activation, inflammatory molecules (IL-1ß, IL-6, TNF-α and NF-kB) and hypoxia condition (HIF-1α). On the other hand, recent therapeutic approaches have focused on abolishing hypoxia-induced RVH and RHF via attenuation of oxidative stress and inflammatory (IL-1ß, MCP-1, SDF-1 and CXCR-4) pathways through phytotherapy and pharmacological trials. Nevertheless, further studies are necessary.
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Insuficiencia Cardíaca/patología , Hipertrofia Ventricular Derecha/patología , Hipoxia/fisiopatología , Inflamación/complicaciones , Estrés Oxidativo , Proteínas Quinasas/metabolismo , Animales , Insuficiencia Cardíaca/inmunología , Insuficiencia Cardíaca/metabolismo , Humanos , Hipertrofia Ventricular Derecha/inmunología , Hipertrofia Ventricular Derecha/metabolismo , Inflamación/inmunología , Inflamación/patologíaRESUMEN
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular remodeling leading to elevation of pulmonary artery pressure, right ventricular hypertrophy, and death. Currently, there are no cure exists for PAH. Magnesium lithospermate B (MLB) is the major component of Salvia przewalskii water extracts with treating angina and cardiovascular damage, anti-inflammation, anti-oxidation and anti-apoptosis. However, the effects of MLB on PAH still unclear. This study we investigated the efficacy of MLB in the hypobaric hypoxia-induced rat model of PAH. The results showed that MLB relieved mean pulmonary arterial pressure (mPAP) and right ventricular hypertrophy index (RVHI). Meanwhile, MLB significantly reduced pulmonary vascular remodeling. Additionally, MLB inhibited hypobaric hypoxia-induced α-smooth muscle actin (α-SMA) expression, cell apoptosis, and α-SMA and von Willebrand factor (vWF) co-expression in lung, suggesting that MLB could inhibit hypobaric hypoxia-induced endothelial-to-mesenchymal transition (EndMT). Furthermore, after treatment with MLB, the expression of hypoxia inducible factor-1α (HIF-1α), nuclear factor-kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase 4 (CDK4), CyclinD1, RhoA, rho-associated protein kinase 1 (ROCK1) and ROCK2 was decreased. Further, CHK1, PIM1, STK6, LKHA4, PDE5A, BRAF1, PLK1, AKT1, PAK6, PAK7 and ELNE may be the potential targets of MLB. Taken together, our findings suggest that MLB ameliorates hypobaric hypoxia-induced PAH by inhibiting EndMT in rats, and has potential value in the preventment and treatment of PAH.
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Medicamentos Herbarios Chinos/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipoxia/complicaciones , Animales , Biomarcadores , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Endotelio Vascular/patología , Expresión Génica , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Ratas , Transducción de SeñalRESUMEN
There is an increase in oxidative stress and apoptosis signaling during the transition from hypertrophy to right ventricular (RV) failure caused by pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). In this study, it was evaluated the action of copaiba oil on the modulation of proteins involved in RV apoptosis signaling in rats with PAH. Male Wistar rats (±170 g, n = 7/group) were divided into 4 groups: control, MCT, copaiba oil, and MCT + copaiba oil. PAH was induced by MCT (60 mg/kg intraperitoneally) and, 7 days later, treatment with copaiba oil (400 mg/kg by gavage) was given for 14 days. Echocardiographic and hemodynamic measurements were performed, and the RV was collected for morphometric evaluations, oxidative stress, apoptosis, and cell survival signaling, and eNOS protein expression. Copaiba oil reduced RV hypertrophy (24%), improved RV systolic function, and reduced RV end-diastolic pressure, increased total sulfhydryl levels and eNOS protein expression, reduced lipid and protein oxidation, and the expression of proteins involved in apoptosis signaling in the RV of MCT + copaiba oil as compared to MCT group. In conclusion, copaiba oil reduced oxidative stress, and apoptosis signaling in RV of rats with PAH, which may be associated with an improvement in cardiac function caused by this compound.
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Apoptosis/efectos de los fármacos , Fármacos Cardiovasculares/farmacología , Fabaceae , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/prevención & control , Monocrotalina , Miocardio , Aceites de Plantas/farmacología , Disfunción Ventricular Derecha/prevención & control , Función Ventricular Derecha/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Fármacos Cardiovasculares/aislamiento & purificación , Modelos Animales de Enfermedad , Fabaceae/química , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Miocardio/metabolismo , Miocardio/patología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Aceites de Plantas/aislamiento & purificación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Hypoxia-induced pulmonary hypertension (HPH) is a severe condition associated with significant morbidity and mortality in people living at high altitude. Tsantan Sumtang, a traditional Tibetan medicine, has been routinely used for the treatment of cardiopyretic disease, as well as stenocardia. Interestingly, our previous research found that Tsantan Sumtang improved HPH in rats maintaining in a hypobaric chamber. We performed a series of experiments to test the indexes of vasoconstriction and vascular remodeling, the key pathophysiological characteristics of HPH. Our results showed that Tsantan Sumtang relaxed noradrenaline (NE)-precontracted rat pulmonary artery rings in a concentration-dependent manner in vitro. The PGI2-cAMP (prostaglandin I2-cyclic adenosine monophosphate) pathway, NO-cGMP (nitric oxide-cyclic guanosine monophosphate) pathway, and the opening of K+ channels (inward rectifier K+ channels, large conductance Ca2+-activated K+ channels, and voltage-dependent K+ channels) might play major roles in the vasorelaxation effect. In vivo, the administration of Tsantan Sumtang resulted in a substantial decrease in the rat mean pulmonary artery pressure (mPAP) and the right ventricular hypertrophy index (RVHI). The reduction of thickness of small pulmonary arterial wall and the WT% (the ratio of the vascular wall thickness to the vascular diameter) were observed. The smooth muscle muscularization of the arterials was alleviated by Tsantan Sumtang treatment at the same time. Tsantan Sumtang also reduced remodeling of pulmonary arterioles by suppressing the expression of proliferating cell nuclear antigen (PCNA), α-smooth muscle actin (α-SMA), cyclin D1, and cyclin-dependent kinase 4 (CDK4) through inhibition of p27Kip1 degradation. Therefore, Tsantan Sumtang could be applied as a preventative medication for HPH, which would be a new use for this traditional medicine.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Hipertensión Pulmonar , Hipertrofia Ventricular Derecha , Hipoxia , Plantas Medicinales , Arteria Pulmonar , Animales , Enfermedad Crónica , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Hipoxia/complicaciones , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Hipoxia/parasitología , Masculino , Medicina Tradicional Tibetana , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Ratas , Ratas Sprague-Dawley , Remodelación VascularRESUMEN
Ozone (O3)-related cardiorespiratory effects are a growing public health concern. Ground level O3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O3-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O2) or hypoxia (10.0% O2), followed by a 4-h exposure to either 1ppm O3 or filtered air (FA). As an additional experimental intervention fasudil (20mg/kg) was administered intraperitoneally prior to and after O3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O3-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability.
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1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Contaminantes Atmosféricos/toxicidad , Lesión Pulmonar/tratamiento farmacológico , Ozono/toxicidad , Inhibidores de Proteínas Quinasas/uso terapéutico , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/uso terapéutico , Animales , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/patología , Hiperreactividad Bronquial/fisiopatología , Líquido del Lavado Bronquioalveolar/citología , Recuento de Células , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Hipoxia/complicaciones , Hipoxia/tratamiento farmacológico , Hipoxia/patología , Hipoxia/fisiopatología , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/fisiopatología , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/patología , Lesión Pulmonar/fisiopatología , Masculino , Ratones Endogámicos C57BL , Tamaño de los Órganos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Función Ventricular Derecha/efectos de los fármacos , Presión Ventricular/efectos de los fármacos , Quinasas Asociadas a rho/antagonistas & inhibidoresRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Carthamus tinctorius L. is a traditional herbal medicine native to China with properties of promoting blood circulation and removing blood stasis, which is used for the treatment of cerebrovascular and cardiovascular diseases. Hydroxysafflor yellow A (HSYA) is the main constituent isolated from the flower of Carthamus tinctorius L. which is used as a marker substance in the quality control of Carthamus tinctorius L. in Chinese Pharmacopeia. AIM OF THE STUDY: This study is to investigate the hypertension attenuating effect of HSYA on hypoxia-induced pulmonary artery hypertension model rats, and the possible mechanism. MATERIALS AND METHODS: The animal models were made by treating adult male Wistar rats (of the same age with the same weight of 200±25g) under hypoxia 24h per day for 9 days with or without administration of HSYA. The pulmonary arterial pressure of rats was measured after anesthetization; The right ventricular hypotrophy was evaluated by the right ventricular hypotrophy index (RVHI=[RV/(LV+S)]) as well as histomorphology assay with Hematoxylin and Eosin (HE) staining; The reducing of pulmonary artery remodelling was evaluated by histomorphology assay with HE staining; The proliferation of pulmonary artery smooth muscle cells (PASMCs) was evaluated by immunohistochemistry assays (PCNA and Ki67) and MTT assay. Cell cycle analysis and Weston-blot analysis were also performed in the study. RESULTS: HSYA reduced the mean right ventricular systolic pressure (RVSP) of rats with hypoxic pulmonary arterial hypertension (HPH) in a manner of concentration dependency. It significantly inhibited the PASMCs proliferation and attenuated the remodelling of the pulmonary artery and right ventricular hypertrophy. CONCLUSION: These findings suggested that HSYA protected against hypoxic induced pulmonary hypertension by reversing the remodelling of the pulmonary artery through inhibiting the proliferation and hypertrophy of PASMCs. This is in accordance with our previous finding that HSYA protects against the pulmonary artery vascular constriction. All these results suggest that HSYA may be a promising candidate for HPH treatment.
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Chalcona/análogos & derivados , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Quinonas/uso terapéutico , Animales , Carthamus tinctorius , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Chalcona/farmacología , Chalcona/uso terapéutico , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Hipoxia/complicaciones , Masculino , Miocitos del Músculo Liso/efectos de los fármacos , Fitoterapia , Arteria Pulmonar/citología , Arteria Pulmonar/patología , Quinonas/farmacología , Ratas Wistar , Remodelación Vascular/efectos de los fármacosRESUMEN
BACKGROUND: The Chinese herbal Bufei Jianpi formula (BJF) provides an effective treatment option for chronic obstructive pulmonary disease (COPD). However, the systems-level mechanism underlying the clinical effects of BJF on COPD remains unknown. METHODS: In this study, a systems pharmacology model based on absorption filtering, network targeting, and systems analyses was applied specifically to clarify the active compounds and therapeutic mechanisms of BJF. Then, a rat model of cigarette smoke- and bacterial infection-induced COPD was used to investigate the therapeutic mechanisms of BJF on COPD and its comorbidity. RESULTS: The pharmacological system successfully identified 145 bioactive ingredients from BJF and revealed 175 potential targets. There was a significant target overlap between the herbal constituents of BJF. These results suggested that each herb of BJF connected with similar multitargets, indicating potential synergistic effects among them. The integrated target-disease network showed that BJF probably was efficient for the treatment of not only respiratory tract diseases but also other diseases, such as nervous system and cardiovascular diseases. The possible mechanisms of action of BJF were related to activation of inflammatory response, immune responses, and matrix metalloproteinases, among others. Furthermore, we demonstrated that BJF treatment could effectively prevent COPD and its comorbidities, such as ventricular hypertrophy, by inhibition of inflammatory cytokine production, matrix metalloproteinases expression, and other cytokine production in vivo. CONCLUSION: This study using the systems pharmacology method, in combination with in vivo experiments, helped us successfully dissect the molecular mechanism of BJF for the treatment of COPD and predict the potential targets of the multicomponent BJF, which provides a new approach to illustrate the synergetic mechanism of the complex prescription and discover more effective drugs against COPD.
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Antiinflamatorios/farmacología , Medicamentos Herbarios Chinos/farmacología , Pulmón/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Medicina Tradicional China , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Biología de Sistemas/métodos , Animales , Antiinflamatorios/análisis , Citocinas/metabolismo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/análisis , Femenino , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Hipertrofia Ventricular Derecha/enzimología , Hipertrofia Ventricular Derecha/patología , Mediadores de Inflamación/metabolismo , Pulmón/enzimología , Pulmón/microbiología , Pulmón/fisiopatología , Masculino , Inhibidores de la Metaloproteinasa de la Matriz/análisis , Fitoterapia , Plantas Medicinales , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/enzimología , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Ratas Sprague-Dawley , Fumar/efectos adversos , Factores de TiempoRESUMEN
The present work adopted a systems pharmacology-based approach to provide new insights into the active compounds and therapeutic targets of Bufei Yishen formula (BYF) for the treatment of chronic obstructive pulmonary disease (COPD). In addition, we established a rat model of cigarette smoke- and bacterial infection-induced COPD to validate the mechanisms of BYF action that were predicted in systems pharmacology study. The systems pharmacology model derived 216 active compounds from BYF and 195 potential targets related to various diseases. The compound-target network showed that each herbal drug in the BYF formula acted on similar targets, suggesting potential synergistic effects among these herbal drugs. The ClueGo assay, a Cytoscape plugin, revealed that most targets were related to activation of MAP kinase and matrix metalloproteinases. By using target-diseases network analysis, we found that BYF had great potential to treatment of multiple diseases, such as respiratory tract diseases, immune system, and cardiovascular diseases. Furthermore, we found that BYF had the ability to prevent COPD and its comorbidities, such as ventricular hypertrophy, in vivo. Moreover, BYF inhibited the inflammatory cytokine, and hypertrophic factors expression, protease-antiprotease imbalance and the collagen deposition, which may be the underlying mechanisms of action of BYF.
Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Animales , Colágeno/metabolismo , Citocinas/metabolismo , Medicamentos Herbarios Chinos/farmacología , Hipertrofia Ventricular Derecha/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Medicina Tradicional China , Miocardio/patología , Miocardio/ultraestructura , Fitoterapia , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
BACKGROUND: Pulmonary hypertension and subsequent right ventricular (RV) failure are associated with high morbidity and mortality. Prognosis is determined by occurrence of RV failure. Currently, adequate treatment for RV failure is lacking. Further research into the molecular basis for the development of RV failure as well as the development of better murine models of RV failure are therefore imperative. We hypothesize that adding a low-copper diet to chronic hypoxia in mice reinforces their individual effect and that the combination of mild pulmonary vascular remodeling and capillary rarefaction, induces RV failure. METHODS: Six week old mice were subjected to normoxia (N; 21% O2) or hypoxia (H; 10% O2) during a period of 8 weeks and received either a normal diet (Cu+) or a copper depleted diet (Cu-). Cardiac function was assessed by echocardiography and MRI analysis. RESULTS AND CONCLUSION: Here, we characterized a mouse model of chronic hypoxia combined with a copper depleted diet and demonstrate that eight weeks of chronic hypoxia (10%) is sufficient to induce RV hypertrophy and subsequent RV failure. Addition of a low copper diet to hypoxia did not have any further deleterious effects on right ventricular remodeling.
Asunto(s)
Cobre/metabolismo , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Hipoxia , Remodelación Ventricular , Animales , Biomarcadores/metabolismo , Dieta , Suplementos Dietéticos , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Hipertensión Pulmonar/complicaciones , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Masculino , Ratones , Estrés Fisiológico , Volumen SistólicoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Different parts of Mimosa pigra (MPG) are used in traditional medicine in Madagascar, tropical Africa, South America and Indonesia for various troubles including cardiovascular disorders. AIM OF THE STUDY: To investigate the mechanisms underlying the vascular effects of MPG by assessing in vitro its antioxidant and anti-inflammatory properties, and its vascular relaxing effects, and in vivo, its action on hypoxic pulmonary hypertension (PAH) in rats. MATERIAL AND METHODS: The antioxidant activity of MPG leaf hydromethanolic extract was determined by using both the 1,1-diphenyl-2-picrylhydrazyl radical scavenging and the oxygen radical absorbance capacity in vitro assays. Anti-inflammatory properties were assayed on TNFα-induced VCAM-1 expression in endothelial cells. The vasorelaxant effect of MPG extract was studied on rat arterial rings pre-contracted with phenylephrine (1µM) in the presence or absence of the endothelium. In vivo MPG extract effects were analyzed in chronic hypoxic PAH, obtained by housing male Wistar rats, orally treated or not with MPG extract (400mg/kg/d), in a hypobaric chamber for 21 days. RESULTS: MPG leaf extract had antioxidant and anti-inflammatory properties. It induced endothelium-dependent, NO-mediated relaxation of rat aorta and pulmonary artery. In vivo, chronic MPG treatment reduced hypoxic PAH in rat by decreasing by 22.3% the pulmonary arterial pressure and by 20.0% and 23.9% the pulmonary artery and cardiac remodelling, respectively. This effect was associated with a restoration of endothelium function and a 2.3-fold increase in endothelial NO synthase phosphorylation. MPG leaf hydromethanolic extract contained tryptophan and flavonoids, including quercetin glycosides. Both compounds also efficiently limit hypoxia-induced PAH. CONCLUSIONS: Our results show endothelial protective action of MPG leaf hydromethanolic extract which is likely to be due to its antioxidant action. MPG successfully attenuated the development of PAH, thus demonstrating the protective effect of MPG on cardiovascular diseases.
Asunto(s)
Antioxidantes/uso terapéutico , Cardiotónicos/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Mimosa , Extractos Vegetales/uso terapéutico , Vasodilatadores/uso terapéutico , Animales , Antioxidantes/farmacología , Aorta/efectos de los fármacos , Aorta/fisiología , Cardiotónicos/farmacología , Células Cultivadas , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/fisiología , Humanos , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Hipoxia/complicaciones , Técnicas In Vitro , Masculino , Fitoterapia , Extractos Vegetales/farmacología , Hojas de la Planta , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Arteria Pulmonar/fisiología , Ratas , Ratas Wistar , Vasodilatadores/farmacologíaRESUMEN
Although right ventricular failure (RVF) is the hallmark of pulmonary arterial hypertension (PAH), the mechanism of RVF is unclear. Development of PAH-induced RVF is associated with an increased reactive oxygen species (ROS) production. Increases in oxidative stress lead to generation of nitro-tyrosine residues in tissue inhibitor of metalloproteinase (TIMPs) and liberate active matrix metalloproteinase (MMPs). To test the hypothesis that an imbalance in MMP-to-TIMP ratio leads to interstitial fibrosis and RVF and whether the treatment with folic acid (FA) alleviates ROS generation, maintains MMP/TIMP balance, and regresses interstitial fibrosis, we used a mouse model of pulmonary artery constriction (PAC). After surgery mice were given FA in their drinking water (0.03 g/l) for 4 wk. Production of ROS in the right ventricle (RV) was measured using oxidative fluorescent dye. The level of MMP-2, -9, and -13 and TIMP-4, autophagy marker (p62), mitophagy marker (LC3A/B), collagen interstitial fibrosis, and ROS in the RV wall was measured. RV function was measured by Millar catheter. Treatment with FA decreased the pressure to 35 mmHg from 50 mmHg in PAC mice. Similarly, RV volume in PAC mice was increased compared with the Sham group. A robust increase of ROS was observed in RV of PAC mice, which was decreased by treatment with FA. The protein level of MMP-2, -9, and -13 was increased in RV of PAC mice in comparison with that in the sham-operated mice, whereas supplementation with FA abolished this effect and mitigated MMPs levels. The protein level of TIMP-4 was decreased in RV of PAC mice compared with the Sham group. Treatment with FA helped PAC mice to improve the level of TIMP-4. To further support the claim of mitophagy occurrence during RVF, the levels of LC3A/B and p62 were measured by Western blot and immunohistochemistry. LC3A/B was increased in RV of PAC mice. Similarly, increased p62 protein level was observed in RV of PAC mice. Treatment with FA abolished this effect in PAC mice. These results suggest that FA treatment improves MMP/TIMP balance and ameliorates mitochondrial dysfunction that results in protection of RV failure during pulmonary hypertension.
Asunto(s)
Autofagia/fisiología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/fisiopatología , Arteria Pulmonar/fisiopatología , Remodelación Ventricular/fisiología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Autofagia/efectos de los fármacos , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Ácido Fólico/farmacología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Masculino , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Especies Reactivas de Oxígeno/metabolismo , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Remodelación Ventricular/efectos de los fármacos , Complejo Vitamínico B/farmacología , Inhibidor Tisular de Metaloproteinasa-4RESUMEN
BACKGROUND: The endocardial substrate for ventricular arrhythmias in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is thought to be caused by a progressive degenerative process. Many clinical decisions and treatment plans are guided by this pathophysiologic assumption, but the extent of progression of macroscopic endocardial scar and right ventricular (RV) dilatation have not been assessed. METHODS AND RESULTS: Eleven patients with ARVD/C and ventricular tachycardia had 2 detailed sinus rhythm electroanatomic endocardial voltage maps (average, 291+/-122 points per map; range, 114 to 558 points) performed a mean of 57 months apart (minimum, 9 months) as part of ventricular tachycardia ablation procedures. Voltage-defined scar (<1.5 mV) and RV volume were measured by area and volume measurement software and compared. Two of the 11 patients had a clear increase in scar area (47 cm(2); 32 cm(2)) confirmed by visual inspection. The remaining 9 (81%; 95% CI, 48% to 98%) patients had no increase (<10-cm(2) difference) in scar area between studies. In contrast, 10 of the 11 patients had a significant increase in RV volume, with an average increase of 24% (212+/-67 mL to 263+/-52 mL; P< or =0.01). CONCLUSIONS: In patients with ARVD/C and ventricular tachycardia, progressive RV dilatation is the rule, and rapid progression of significant macroscopic endocardial scar occurs in only a subset of patients. These results have important management implications, suggesting that efforts to prevent RV dilatation in this population are needed and that an aggressive substrate-based ablation strategy offers the potential to provide long-term ventricular tachycardia control.
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Displasia Ventricular Derecha Arritmogénica/cirugía , Ablación por Catéter , Cicatriz/patología , Endocardio/patología , Hipertrofia Ventricular Derecha/prevención & control , Taquicardia Ventricular/cirugía , Cicatrización de Heridas , Adolescente , Adulto , Displasia Ventricular Derecha Arritmogénica/complicaciones , Displasia Ventricular Derecha Arritmogénica/patología , Cicatriz/etiología , Electrocardiografía , Técnicas Electrofisiológicas Cardíacas , Femenino , Humanos , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/patología , Masculino , Persona de Mediana Edad , Recurrencia , Reoperación , Taquicardia Ventricular/etiología , Taquicardia Ventricular/patología , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Atrial arrhythmia is often encountered in chronic pulmonary disease with pulmonary hypertension (PH), but few studies have investigated the electrical remodeling of atrial Ca(2+) channels under PH. METHODS AND RESULTS: Wistar rats were injected with monocrotaline (MCT), resulting in PH with right atrial and ventricular hypertrophy. The L-type Ca(2+) channel current density was significantly decreased in right atrial cells of MCT-treated rats, accompanied by a significant reduction in mRNA expression of the CaV1.2 (alpha(1C)) subunit and accessory beta(2) subunit. Conversely, the low voltage-activated Ca(2+) current was more marked in the right atrial cells of MCT-treated rats than in those of control rats. The current-voltage relationship and the time course of inactivation closely resembled those of T-type Ca(2+) channels, although the current was only slightly inhibited by 10-100 micromol/L Ni(2+). No significant differences were observed in the mRNA expression levels of CaV3.1 (alpha(1G)) and CaV3.2 (alpha(1H)) or the protein level of the CaV3.1 subunit. In left atrial cells, the electrophysiological molecular properties of Ca(2+) channels were unaffected by MCT treatment. CONCLUSIONS: PH causes right atrial hypertrophy, associated with alteration of the electrophysiological molecular properties of Ca(2+) channels.
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Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo T/metabolismo , Atrios Cardíacos/metabolismo , Hipertensión Pulmonar/metabolismo , Animales , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo T/genética , Modelos Animales de Enfermedad , Técnicas Electrofisiológicas Cardíacas , Atrios Cardíacos/patología , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/patología , Hipertrofia/metabolismo , Hipertrofia/patología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Monocrotalina , Técnicas de Placa-Clamp , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
Ginsenosides have been reported to release nitric oxide (NO) and decrease intracellular free Ca(2+) in cardiovascular system, which play important roles in antihypertrophic effect. This study investigated the potential inhibitory effect of total ginsenosides (TG) on right ventricular hypertrophy induced by monocrotaline (MCT, 60 mg/kg/d) and examined the possible antihypertrophic mechanism in male Sprague Dawley rats. MCT-intoxicated animals were treated with TG (20, 40, 60 mg/kg/d) for 18 d. TG treatment ameliorated MCT-induced elevations in right ventricular peak systolic pressure, right ventricular hypertrophy and the expression of atrial natriuretic peptide; N(G)-nitro-L-arginine-methyl ester (L-NAME), an NO synthase (NOS) inhibitor, had no influence on these inhibitory effects of TG 40 mg/kg/d, and TG at this dose had no any effect on the eNOS mRNA expression, suggesting the limited rule of NO in TG's effects. To further examine the mechanisms of the protection, the expression of calcineurin and its catalytic subunit CnA, as well as extracellular signal-regulated kinase-1 (ERK-1) and mitogen-activated protein kinase (MAPK) Phosphatase-1 (MKP-1) was examined. TG treatment significantly suppressed MCT-induced elevations of these signaling pathways in a dose-dependent manner. In summary, TG is effective in protecting against MCT-induced right ventricle hypertrophy, possibly through lowering pulmonary hypertension. Multiple molecular mechanisms appeared to be involved in this protection, such as the suppression of MCT-activated calcineurin and ERK signaling pathways.
Asunto(s)
Ginsenósidos/farmacología , Hipertrofia Ventricular Derecha/prevención & control , Monocrotalina/antagonistas & inhibidores , Monocrotalina/toxicidad , Venenos/toxicidad , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Western Blotting , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/prevención & control , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/patología , Pulmón/patología , Masculino , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Miocardio/metabolismo , Miocardio/patología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Panax/química , Circulación Pulmonar/efectos de los fármacos , ARN/biosíntesis , ARN/aislamiento & purificación , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacosRESUMEN
The pulmonary arteries (PA) in pulmonary arterial hypertension (PAH) are constricted and remodeled;. They have suppressed apoptosis, partly attributable to suppression of the bone morphogenetic protein axis and selective downregulation of PA smooth muscle cell (PASMC) voltage-gated K+ channels, including Kv1.5. The Kv downregulation-induced increase in [K+]i, tonically inhibits caspases, further suppressing apoptosis. Mitochondria control apoptosis and produce activated oxygen species like H2O2, which regulate vascular tone by activating K+ channels, but their role in PAH is unknown. We show that dichloroacetate (DCA), a metabolic modulator that increases mitochondrial oxidative phosphorylation, prevents and reverses established monocrotaline-induced PAH (MCT-PAH), significantly improving mortality. Compared with MCT-PAH, DCA-treated rats (80 mg/kg per day in drinking water on day 14 after MCT, studied on day 21) have decreased pulmonary, but not systemic, vascular resistance (63% decrease, P<0.002), PA medial thickness (28% decrease, P<0.0001), and right ventricular hypertrophy (34% decrease, P<0.001). DCA is similarly effective when given at day 1 or day 21 after MCT (studied day 28) but has no effect on normal rats. DCA depolarizes MCT-PAH PASMC mitochondria and causes release of H2O2 and cytochrome c, inducing a 10-fold increase in apoptosis within the PA media (TUNEL and caspase 3 activity) and decreasing proliferation (proliferating-cell nuclear antigen and BrdU assays). Immunoblots, immunohistochemistry, laser-captured microdissection-quantitative reverse-transcription polymerase chain reaction and patch-clamping show that DCA reverses the Kv1.5 downregulation in resistance PAs. In summary, DCA reverses PA remodeling by increasing the mitochondria-dependent apoptosis/proliferation ratio and upregulating Kv1.5 in the media. We identify mitochondria-dependent apoptosis as a potential target for therapy and DCA as an effective and selective treatment for PAH.
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Apoptosis/efectos de los fármacos , Ácido Dicloroacético/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Animales , División Celular/efectos de los fármacos , Células Cultivadas/efectos de los fármacos , Ácido Dicloroacético/farmacología , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/prevención & control , Hemodinámica/efectos de los fármacos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/patología , Canal de Potasio Kv1.5 , Mitocondrias/efectos de los fármacos , Monocrotalina/toxicidad , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Especificidad de Órganos , Fosforilación Oxidativa/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/genética , Canales de Potasio con Entrada de Voltaje/metabolismo , Arteria Pulmonar/citología , Ratas , Canales de Potasio Shab , Resistencia Vascular/efectos de los fármacosRESUMEN
The purpose of the present study was to evaluate the effectiveness of fish oil in preventing tissue pathologies associated with monocrotaline (MCT) toxicity. Twenty-four weanling rats were randomly assigned to one of two groups: (1) 12 to a group fed a diet containing 15% (w/w) corn oil (control) and (2) 12 to a group fed a diet containing fish oil (13%) and corn oil (2%) as the source of fat. Rats were fed for 4 weeks prior to MCT treatment. Six rats in each group were subcutaneously injected with MCT and six injected with its vehicle (water) and all were continued on their respective diets. All rats were sacrificed 3 weeks after injection. In rats receiving MCT, we observed severe interstitial pneumonia, septal fibrosis, vasculitis with virtual obliteration of the lumen of the small arteries and arterioles, right ventricular hypertrophy (RVH), and hepatomegaly and hepatocyte vacuole formation. Dietary fish oil significantly reduced septal fibrosis and development of pneumonia. There was a slight, but statistically insignificant decrease in vasculitis and fish oil did not prevent RVH (pulmonary hypertension). In addition, fish oil effectively protected the MCT-treated rats from development of hepatocyte vacuoles (steatosis), hepatic inflammation and vasculitis, increased presence of fibroblasts and collagen deposition in the centrilobular and, to a lesser extent, in the periportal spaces. These results suggest that lung parenchymal inflammation can be attenuated without altering the course of development of pulmonary hypertension in the MCT model. These results also indicate that fish oil protects against inflammation and fibrosis in the lung and liver, and against hepatocyte vacuole formation in MCT-treated rats.
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Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Grasas de la Dieta/farmacología , Aceites de Pescado/farmacología , Monocrotalina/toxicidad , Neumonía/prevención & control , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Grasas de la Dieta/metabolismo , Ácidos Grasos Insaturados/metabolismo , Aceites de Pescado/metabolismo , Histocitoquímica , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/patología , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Cirrosis Hepática/prevención & control , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Monocrotalina/metabolismo , Neumonía/inducido químicamente , Neumonía/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/prevención & control , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
Some studies have indicated that the injury induced by the hepato- and pneumotoxin monocrotaline (MCT) is in part mediated by oxidation. Because beta-carotene is a potent antioxidant, we hypothesized that it would protect the lung and liver parenchyma against MCT-induced injury. Twenty rats were assigned randomly to four groups. All rats were fed a standard AIN93G diet with or without beta-carotene. After 1 week on the purified diets, half of the rats fed the control (standard) diet and half of the rats fed the beta-carotene-supplemented diet were injected subcutaneously with 60 mg MCT/kg body weight or its vehicle (water). All rats were sacrificed at 4 weeks. Histological examination showed that beta-carotene alone did not affect lung or liver structure. On the other hand, lungs of MCT-treated rats had severe focal pneumonia, extensive deposition of collagen in the septa, marked inflammation of the small arteries and arterioles, and arterialization of the small venules. Livers of MCT-treated rats showed some fatty infiltration and diffuse hemorrhages, more prominent sometimes in the centrilobular area and sometimes in the periportal region. Concomitant treatment with beta-carotene protected the lung parenchyma from the inflammatory reaction and the septal fibrosis, but did not prevent cardiac right ventricular hypertrophy and only slightly reduced the thickening of the wall of small arteries and arterioles. Incidence of steatosis and hemorrhages was decreased in the liver. These results indicate that MCT-induced pulmonary vascular remodeling occurs in the absence of inflammatory cell infiltration. Furthermore, beta-carotene prevented inflammation and protected the lung and liver parenchyma of MCT-treated rats.
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Antídotos/farmacología , Antioxidantes/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/prevención & control , Monocrotalina/antagonistas & inhibidores , Monocrotalina/toxicidad , Venenos/toxicidad , beta Caroteno/farmacología , Animales , Antídotos/administración & dosificación , Antioxidantes/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Colágeno/metabolismo , Dieta , Hígado Graso/inducido químicamente , Hígado Graso/patología , Hígado Graso/prevención & control , Hemorragia/inducido químicamente , Hemorragia/patología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/prevención & control , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Enfermedades Pulmonares/patología , Masculino , Ratas , Ratas Sprague-Dawley , beta Caroteno/administración & dosificaciónRESUMEN
Light microscopic and morphometric methods along with the measurement of right ventricular systolic pressure (RVSP) and right ventricle hypertrophy index (RBHI) were performed by the authors in studying the inhibitory effects of Radix Peucedani (RP) on structural remodeling of intraacinar pulmonary arteries (IAPA) and pulmonary hypertension (PHT) in hypoxic rats. The results showed that, RP could not only antagonize IAPA contraction caused by hypoxia and lower the resistance of pulmonary circulation, inhibit the cell proliferation and hypertrophy of adventitial cells of pulmonary artery, but also reverse the change in structure and function of pulmonary artery. It suggests that RA plays a key role in inhibiting hypoxic structural remodeling of IAPA and pulmonary hypertension.