Effect of menthol on hypobaric hypoxia-induced pulmonary arterial hypertension in mice and its mechanism / 中国药理学通报

Aim To study the effect of menthol on hypobaric hypoxia-induced pulmonary arterial hypertension and explore the underlying mechanism in mice. Methods 10 to 12 weeks old wild type (WT) mice and TRPM8 gene knockout (TRPM8

The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-κB signaling pathway / 药学学报

Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg·kg-1), and positive control sildenafil group (100 mg·kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% ± 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF-κB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF-κB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3) by DYY.

Effects of atorvastatin in suppressing pulmonary vascular remodeling in rats with chronic obstructive pulmonary disease

Abstract Objective To investigate the effects of atorvastatin calcium on pulmonary vascular remodeling, the authors explored the regulatory mechanism of Histone Deacetylation Enzyme-2 (HDAC2) in rats with Chronic Obstructive Pulmonary Disease (COPD), and provided a new direction for drug treatment in the progression of vascular remodeling. Methods Eighteen female SD rats were randomly divided into control (Group S1), COPD (Group S2), and atorvastatin calcium + COPD (Group S3) groups. A COPD rat model was established by passive smoking and intratracheal injection of Lipopolysaccharide (LPS). Haematoxylin and eosin staining and Victoria Blue + Van Gibson staining were used to observe pathological changes in the lung tissue. The pulmonary vascular inflammation score was calculated, and the degree of pulmonary vascular remodeling was evaluated. The ratio of Muscular Arteries in lung tissue (MA%), the ratio of the vessel Wall Area to the vessel total area (WA%), and the ratio of the vessel Wall Thickness to the vascular outer diameter (WT%) were measured using imaging software. The expression of HDAC2 was measured using western blotting, ELISA (Enzyme-Linked Immunosorbent Assay), and qPCR (Real-time PCR). Results Compared with the control group, the degree of pulmonary vascular inflammation and pulmonary vascular remodeling increased in rats with COPD. The WT%, WA%, and lung inflammation scores increased significantly; the expression of HDAC2 and HDAC2mRNA in the serum and lung tissue decreased, and the level of Vascular Endothelial Growth Factor (VEGF) in the lung tissues increased (p< 0.05). Compared with the COPD group, the lung tissues from rats in the atorvastatin group had fewer inflammatory cells, and the vascular pathological changes were significantly relieved. The WT%, WA%, and lung inflammation scores decreased significantly; the expression of HDAC2 and HDAC2mRNA in the serum and lung tissues increased, and the level of VEGF in the lung tissues decreased (p< 0.05). Conclusion The present study revealed that atorvastatin calcium could regulate the contents and expression of HDAC2 in serum and lung tissues and inhibit the production of VEGF, thereby regulating pulmonary vascular remodeling in a rat model with COPD.

Progress on the mechanism of PDGF-BB signaling pathway in the pulmonary vascular remodeling of neonatal hypoxic pulmonary hypertension / 国际儿科学杂志

Neonatal hypoxic pulmonary hypertension(HPH)is a common acute critical disease in NICU, and is one of the diseases leading to neonatal death.At present, the specific pathogenesis is still unclear.Current studies have shown that pulmonary vascular remodeling is an important pathological feature of pulmonary hypertension, and the excessive proliferation and migration of pulmonary artery smooth muscle cell is the main cause of pulmonary vascular remodeling.Platelet-derived growth factor(PDGF-BB)is a powerful mitogenic factor which involved in cell proliferation and migration.Currently, plenty of studies have found that PDGF-BB plays an important role in multiple diseases, including tumor, atherosclerosis, pulmonary hypertension and pulmonary fibrosis.In view of the mechanism of PDGF-BB, this article reviews the possible mechanism of PDGF-BB in pulmonary vascular remodeling with neonatal HPH, aiming to provide a new direction for the therapies of reversing pulmonary vascular remodeling with neonatal HPH.

Overview of miRNA involved in PASMCs phenotypic switching in pulmonary hypertension / 中国药理学通报

Pulmonary hypertension ( PH) is occult, with no distinctive clinical manifestations and poor prognosis.Pulmonary vascular remodelling is an important pathological feature in which pulmonary artery smooth muscle cell ( PASMCs) pheno- typic switching plays a crucial role.MicroRNA (miRNA) is a class of evolutionary highly conserved single-stranded small non-coding RNA.Recently, an increasing number of scholars have found that miRNA can play an important role in the occurrence and development of PH by regulating the phenotypic switching of PASMCs, which is expected to be a potential target for the prevention and treatment of PH.It has been found that miR NA such as miR-221 , miR-24, miR-15b, miR-96, miR-23a.miR-9, miR-214, miR-20a can promote the phenotypic switching of PASMCs, while miRNA such as miR-21, miR-132, miR-182, miR-449, miR-206 .miR-124, miR-30c, miR-140.miR-17-92 cluster can inhibit it.This article aims to review the research progress on miRNA that mediates PASMCs phenotypic switching in PH from both growth factor-related miRNA and hy- poxia-related miRNA.

Research progress on hypoxia-induced imbalance of calcium homeostasis in pulmonary artery smooth muscle cells and its treatment / 中国药理学通报

Chronic hypoxic lung diseases are major causes of disability and mortality worldwide, which are typically aggravated by hypoxic pulmonary hypertension.The pathogenesis of hypoxic pulmonary hypertension is complex, and its mechanism has not been fully elucidated.The previous studies have shown abnormally elevated levels of free Ca + in the cytoplasm of pulmonary artery smooth muscle cells to be the predominant drivers of pulmonary hypertension , causing continuous contraction and remodeling of the pulmonary vessels.This article briefly summarizes the mechanism of hypoxia-induced imbalance in calcium homeostasis in pulmonary artery smooth muscle cells, together with its related drug research, based on the existing literature.Hypoxia induces an imbalance in calcium homeostasis in pulmonary artery smooth muscle cells by regulating hypoxia-inducible factor-1, K+ , store-operated calcium channel, receptor-operated calcium channel, the Ca +-sensing myosin contractile mechanism by binding to calmodulin, leading to pulmonary vasoconstriction.Ca + can also activate PKC/ MAPKs and PI3K/Akt/mTOR pathways, leading to pulmonary vascular remodeling.

Research progress on mechanisms and therapeutic drugs of hypoxic pulmonary hypertension / 中国药理学通报

Hypoxic pulmonary hypertension ( HPH) is a complex mechanism of HPH is complex, and it has a high mortality rate cardiopulmonary disease eaused by hypoxia.The pathological of disability.Clinically the diug of treatment for HPH is unspe-cialized, mainly relying on traditional vasomotor dnrgs, inclu¬ding prostaglandin 12 receptor agonists, endothelin receptor an¬tagonists and phosphodiesterase-5 inhibitors, but their efficacy cannot be achieved.To meet the clinical need, it is of great sig¬nificance to develop targeted anti-HPH dnigs.To provide ideas for the discovery of HPH treatment drugs, the pathophysiological mechanism of HPH and the current status of dmg development are reviewed in the paper.

Research progress on therapeutic strategies for improving pulmonary vascular remodeling in pulmonary hypertension / 中国药理学通报

Pulmonary hypertension(PH)is a chronic,progressive,high-mortality disease characterized by a continuous increase in pulmonary vascular pressure. All types of PH have the same characteristics,i.e.,the excessive proliferation,anti-apoptosis and inflammation of pulmonary artery endothelial cells and smooth muscle cells,which leads to progressive thickening of pulmonary small vessels,resulting in pulmonary vascular remodeling and increased pulmonary vascular resistance,ultimately leading to right ventricular hypertrophy,heart failure,and death. The drugs used to treat PH mainly include L-type calcium channel blockers,phosphodiesterase 5 inhibitors,guanosine cyclase activators,endothelin receptor antagonists,and synthetic prostacyclin and its analogues. These drugs reduce pulmonary artery pressure by relaxing pulmonary blood vessels but do not cure the patient,and their prognosis remains poor. Therefore,the development of drugs that can effectively improve or even reverse pulmonary vascular remodeling is the key to treating PH. In recent years,studies on pulmonary vascular remodeling mainly included(1)the synthesis of new small-molecule compounds;(2)the transformation of mature drugs,such as the use of drug combinations and dosage form transformation,etc.;(3)the pharmacodynamic evaluation of traditional Chinese medicines and derived compounds based on the theory of "lung distension";(4)research into monomers of traditional Chinese medicine; and(5)research into new targets.

Treatment of pulmonary hypertension based on inhibition of pulmonary vascular cell proliferation / 药学学报

Pulmonary hypertension is a rapidly progressing disease of the lung vasculature with poor prognosis, ultimately leading to right heart failure and death. The remodeling of small pulmonary arteries represents an important pathological characteristic of pulmonary hypertension. Pulmonary arterial smooth muscle cells (PASMCs) located in the middle layer of pulmonary artery exhibit hyperproliferation and resistance to apoptosis, which is the main initiator of pulmonary vascular remodeling and similar to that seen in tumor cells. In this review we focus on the signaling pathways that play a key role in PASMCs proliferation and the latest research progress on inhibitors targeting cell proliferation pathways to provide a new perspective for the treatment of PH．

The substitution of SERCA2 redox cysteine 674 promotes pulmonary vascular remodeling by activating IRE1α/XBP1s pathway

Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling, in which hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) plays an important role. The cysteine 674 (C674) in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is the critical redox regulatory cysteine to regulate SERCA2 activity. Heterozygous SERCA2 C674S knock-in mice (SKI), where one copy of C674 was substituted by serine to represent partial C674 oxidative inactivation, developed significant pulmonary vascular remodeling resembling human PH, and their right ventricular systolic pressure modestly increased with age. In PASMCs, substitution of C674 activated inositol requiring enzyme 1 alpha (IRE1α) and spliced X-box binding protein 1 (XBP1s) pathway, accelerated cell cycle and cell proliferation, which reversed by IRE1α/XBP1s pathway inhibitor 4μ8C. In addition, suppressing the IRE1α/XBP1s pathway prevented pulmonary vascular remodeling caused by substitution of C674. Similar to SERCA2a, SERCA2b is also important to restrict the proliferation of PASMCs. Our study articulates the causal effect of C674 oxidative inactivation on the development of pulmonary vascular remodeling and PH, emphasizing the importance of C674 in restricting PASMC proliferation to maintain pulmonary vascular homeostasis. Moreover, the IRE1α/XBP1s pathway and SERCA2 might be potential targets for PH therapy.

Increasing angiotensin-converting enzyme (ACE) 2/ACE axes ratio alleviates early pulmonary vascular remodeling in a porcine model of acute pulmonary embolism with cardiac arrest / 世界急诊医学杂志（英文）

@#BACKGROUND: Acute pulmonary embolism (APE) with cardiac arrest (CA) is characterized by high mortality in emergency due to pulmonary arterial hypertension (PAH). This study aims to determine whether early pulmonary artery remodeling occurs in PAH caused by massive APE with CA and the protective effects of increasing angiotensin-converting enzyme (ACE) 2-angiotensin (Ang) (1-7)-Mas receptor axis and ACE-Ang II-Ang II type 1 receptor (AT1) axis (ACE2/ACE axes) ratio on pulmonary artery lesion after return of spontaneous circulation (ROSC). METHODS: To establish a porcine massive APE with CA model, autologous thrombus was injected into the external jugular vein until mean arterial pressure dropped below 30 mmHg (1 mmHg=0.133 kPa). Cardiopulmonary resuscitation and thrombolysis were delivered to regain spontaneous circulation. Pigs were divided into four groups of five pigs each: control group, APE-CA group, ROSC-saline group, and ROSC-captopril group, to examine the endothelial pathological changes and expression of ACE2/ACE axes in pulmonary artery with or without captopril. RESULTS: Histological analysis of samples from the APE-CA and ROSC-saline groups showed that pulmonary arterioles were almost completely occluded by accumulated endothelial cells. Western blotting analysis revealed a decrease in the pulmonary arterial ACE2/ACE axes ratio and increases in angiopoietin-2/angiopoietin-1 ratio and expression of vascular endothelial growth factor (VEGF) in the APE-CA group compared with the control group. Captopril significantly suppressed the activation of angiopoietin-2/angiopoietin-1 and VEGF in plexiform lesions formed by proliferative endothelial cells after ROSC. Captopril also alleviated endothelial cell apoptosis by increasing the B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X (Bax) ratio and decreasing cleaved caspase-3 expression. CONCLUSION: Increasing the ACE2/ACE axes ratio may ameliorate pulmonary arterial remodeling by inhibiting the apoptosis and proliferation of endothelial cells after ROSC induced by APE.

Manifestaciones pulmonares y sistémicas de la hipertensión arterial pulmonar: Un enfoque panvascular

La hipertensión arterial pulmonar (HAP) es una grave enfermedad cuyo resultado final de la interacción entre el tono vascular y la alteración progresiva de la remodelación de las arterias pulmonares provoca insuficiencia cardíaca derecha y muerte. El remodelado vascular pulmonar es la alteración estructural clave en la hipertensión pulmonar. Este proceso implica cambios en la íntima, media, adventicia y espacio perivascular, a menudo con la interacción de células inflamatorias. Los mecanismos fisiopatológicos de la HAP abarcan una serie de modificaciones vasculares que producen un aumento de la resistencia vascular pulmonar. Las modificaciones vasculares que se producen en la HAP incluyen: la vasoconstricción, la proliferación del músculo liso, la inflamación, la apoptosis endotelial, la proliferación endotelial resistente a la apoptosis, la fibrosis, la trombosis in-situ, y finalmente, las lesiones plexiformes. Hasta hace poco, la HAP se consideraba una enfermedad restringida a la circulación pulmonar. Sin embargo, existe una creciente evidencia de que los pacientes con HAP también exhiben disfunción vascular sistémica, como lo demuestra la alteración de la dilatación mediada por el flujo de la arteria braquial, el flujo sanguíneo cerebral anormal, la miopatía esquelética y la enfermedad renal intrínseca. Los datos recientes apoyan un vínculo con los eventos genéticos y moleculares detrás de la patogénesis de la HAP. Esta revisión sirve de introducción a los principales hallazgos sistémicos en la HAP y la evidencia que apoya un vínculo común con la fisiopatología de la HAP. Sobre la base de la evidencia disponible, proponemos un paradigma en el que las anomalías metabólicas, la lesión genética y la disfunción vascular sistémica contribuyen a las manifestaciones sistémicas de la HAP. Este concepto no sólo abre interesantes posibilidades de investigación, sino que también anima a considerar las manifestaciones extrapulmonares en el tratamiento de los pacientes con HAP, pues la disfunción vascular sistémica contribuiría a las manifestaciones sistémicas de la HAP.

Pulmonary arterial hypertension (PAH) is a serious disease whose end result of the interaction between vascular tone and the progressive alteration of the remodeling of the pulmonary arteries causes right heart failure and death. Pulmonary vascular remodeling is the key structural alteration in pulmonary hypertension. This process involves changes in the intima, media, adventitia, and perivascular space, often with the interaction of inflammatory cells. The pathophysiological mechanisms of PAH include a series of vascular modifications that produce an increase in pulmonary vascular resistance. Vascular modifications that occur in PAH include: vasoconstriction, proliferation of smooth muscle, inflammation, Endothelial apoptosis, apoptosis-resistant endothelial proliferation, fibrosis, in-situ thrombosis, and finally, plexiform lesions. Until recently, PAH was considered a disease restricted to the pulmonary circulation. However, there is growing evidence that patients with PAH also exhibit systemic vascular dysfunction, as evidenced by impaired brachial artery flow-mediated dilation, abnormal cerebral blood flow, skeletal myopathy, and intrinsic kidney disease. Recent data support a link to the genetic and molecular events behind the pathogenesis of PAH. This review serves as an introduction to the main systemic findings in PAH and the evidence supporting a common link with the pathophysiology of PAH. Based on the available evidence, we propose a paradigm in which metabolic abnormalities, genetic injury, and systemic vascular dysfunction contribute to the systemic manifestations of PAH. This concept not only opens up interesting research possibilities, but also encourages consideration of extrapulmonary manifestations in the treatment of patients with PAH, since systemic vascular dysfunction would contribute to the systemic manifestations of PAH.

A hipertensão arterial pulmonar (HAP) é uma doença grave cujo resultado final da interação entre o tônus vascular e a alteração progressiva da remodelação das artérias pulmonares causa insuficiência cardíaca direita e morte. A remodelação vascular pulmonar é a principal alteração estrutural na hipertensão pulmonar. Esse processo envolve mudanças na íntima, média, adventícia e espaço perivascular, muitas vezes com a interação de células inflamatórias. Os mecanismos fisiopatológicos da HAP incluem uma série de modificações vasculares que produzem um aumento na resistência vascular pulmonar. As modificações vasculares que ocorrem na HAP incluem: vasoconstrição, proliferação do músculo liso, inflamação, apoptose endotelial, proliferação endotelial resistente à apoptose, fibrose, trombose in situ e, finalmente, lesões plexiformes. Até recentemente, a HAP era considerada uma doença restrita à circulação pulmonar. No entanto, há evidências crescentes de que os pacientes com HAP também apresentam disfunção vascular sistêmica, conforme evidenciado pela dilatação prejudicada mediada pelo fluxo da artéria braquial, fluxo sanguíneo cerebral anormal, miopatia esquelética e doença renal intrínseca. Dados recentes suportam uma ligação com os eventos genéticos e moleculares por trás da patogênese da HAP. Esta revisão serve como uma introdução aos principais achados sistêmicos em HAP e as evidências que apoiam uma ligação comum com a fisiopatologia da HAP. Com base nas evidências disponíveis, propomos um paradigma em que anormalidades metabólicas, lesão genética e disfunção vascular sistêmica contribuem para as manifestações sistêmicas da HAP. Esse conceito não apenas abre possibilidades interessantes de pesquisa, mas também incentiva a consideração das manifestações extrapulmonares no tratamento de pacientes com HAP, uma vez que a disfunção vascular sistêmica contribuiria para as manifestações sistêmicas da HAP.

Role of secretory protein GREM1 in systemic-to-pulmonary shunt associated pulmonary arterial hypertension / 中国胸心血管外科临床杂志

@#Objective    To explore the possibility that GREM1, a bone morphogenetic protein (BMP) antagonist, is a mechanical explanation for BMP signal suppression in congenital heart disease associated pulmonary arterial hypertension (CHD/PAH) patients. Methods    Systemic-to-pulmonary shunt induced PAH was surgically established in rats. At the postoperative 12th week, right heart catheterization and echocardiography evaluation were performed to evaluate hemodynamic indexes and morphology of right heart system. Right heart hypotrophy index and pulmonary vascular remodeling were evaluated. Changes of BMP signal pathway related proteins and GREM1 in lungs and plasma GREM1 concentration were detected. The effect of GREM1 on the proliferation and apoptosis of pulmonary arterial endothelial cells (PAECs) was also explored. Results    The hypertensive status was successfully reproduced in rats with systemic-to-pulmonary shunt model. BMP signal pathway was suppressed but GREM1 was up-regulated with no change in hypoxia inducible factor-1 in lungs exposed to systemic-to-pulmonary shunt, while this trend was reversed by systemic-to-pulmonary shunt correction (P<0.05). Immunohistochemical staining demonstrated enhanced staining of GREM1 in remodeled pulmonary arteries. In vitro experiments found that BMP signal was down-regulated but GREM1 expression and secretion were up-regulated in proliferative PAECs (P<0.05). Furthermore, BMP2 significantly inhibited PAECs proliferation and promoted PAECs apoptosis (P<0.05), which could be antagonized by GREM1. In addition, plasma level of GREM1 in rats with systemic-to-pulmonary shunt was also increased and positively correlated with pulmonary hemodynamic indexes. Conclusion    Systemic-to-pulmonary shunt induces the up-regulation of GREM1 in lungs, which promotes pulmonary vascular remodeling via antagonizing BMP cascade. These results present a new mechanical explanation for BMP pathway suppression in lungs of CHD/PAH patients.

Effects of hydrogen sulfide on pulmonary vascular remodeling and its inhibitors in rats with pulmonary hypertension / 解剖学报

Objective To explore the effects of hydrogen sulfide on pulmonary vascular remodeling and its inhibitors in rats with pulmonary hypertension ( PH). Methods Thirty male SD rats were randomly divided into control group ( 10 rats) , model group ( 10 rats) and H2S intervention group ( 10 rats) , PH model was induced by Lilium Wilfordii in model group, on the basis of model group, rats in H2S intervention group were injected with NaHS (56 u,mol/kg) intraperitoneally, while rats in control group were injected with normal saline at the same dose. Four weeks later, the hemodynamic parameters were measured, the right ventricular hypertrophy index (RVHI) was calculated, the pathological changes of pulmonary vessels were detected by HE staining, and the expressions of p38 and c-Jun N-terminal kinase( JNK) proteins in the mitogen-activated protein kinase (MAPK) family were detected by Western blotting and Real-time PCR. Results There were significant differences in hemodynamics, RVHI, wall thickness as a percentage of vessel diameter ( WT) % , pulmonary vessel wall area as a percentage of vascular cross-sectional area( WA) % , p38 and JNK in each group (P<0. 05). The expression levels of MSAP, MPAP, RVHI, WT%, WA%, p38 mRNA and JNK mRNA in the model group and H2S intervention group were significantly higher than those in the control group (P<0. 05) , while the levels of MSAP , MPAP , RVHI, WT% , WA% , p38 mRNA and JNK mRNA in H2S intervention group were significantly lower than those in the model group (P<0. 05). The pulmonary artery morphology showed that the wall thickness and lumen stenosis of the model group and the H2S intervention group increased compared with the control group, but the lumen thickness and lumen stenosis of the H2S intervention group were significantly reduced compared with the model group; Western blotting showed that the expressions of p38 and JNK in model group and H2S intervention group were higher than those in control group, while the expressions of p38 and JNK in H2S intervention group were lower than those in model group. Conclusion H2S can improve hemorheology, right ventricular hypertrophy index, alleviate pulmonary artery wall thickening and lumen stenosis, and inhibit pulmonary vascular remodeling in PH rats. Its mechanism may be related to the down-regulation of JNK and p38 protein expression in MAPK signaling pathway by H2S.

Advances in research on notch signaling pathway in pulmonary vascular remodeling of pulmonary arterial hypertension / 中国药理学通报

Pulmonary hypertension is a cardiovascular disease characterized by persistent elevation of pulmonary artery pressure and pulmonary vascular resistance, causing pulmonary vascular remodeling. Notch signaling pathway is a highly conserved signaling pathway involved in the occurrence and development of cardiovascular, neurological and tumor diseases mainly by regu-lating cell proliferation, differentiation and apoptosis. TTiis paper mainly reviews the molecular mechanism of Notch signaling path way involved in pulmonary vascular remodeling, contributing to provide a new strategy for the treatment of pulmonary arterial hypertension.

Research progress of bone morphogenetic protein-4 in pulmonary vascular remodeling in patients with pulmonary hypertension / 中国胸心血管外科临床杂志

@#Pulmonary hypertension is a disease characterized by pulmonary artery pressure increased, with or without small artery pathological change, which ultimately leads to right heart failure or even death. Pulmonary hypertension seriously threatens to human health, however, the pathogenesis of pulmonary hypertension is unclear. Previous studies have found that bone morphogenetic protein (BMP) signaling system played an important role in the progress of pulmonary hypertension. In the current review, we describe the mechanism of BMP4 in the development of pulmonary hypertension.

Expression change of NBL1 in rats with pulmonary arterial hypertension / 中国药理学通报

Aim To study the expression pattern of neuroblastoma, suppression of tumorigenicity 1 (NBL1) in pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). Methods Forty rats were randomly allocated into control group (n = 10) and MCT group (n= 30). Intraperitoneal injection of 60mg 'kg"1 MCT for MCT group or equal volume normal saline for control group was performed. The changes of NBL1 in lungs and plasma of the 3 rd, 4 th and 5 th week after MCT injection were detected respectively. NBL1 levels in rat plasma were detected by enzyme linked immunosorbent assay. Results At the 3 rd, 4 th, and 5 th week after MCT injection, the mRNA level of NBL1 decreased by 70%, 81% and 89% , the protein level decreased by 36% , 78% and 99% , and the plasma concentration of NBL1 decreased from (2. 82 ± 0. 58) xg L"1 (control rats) to (1. 90±0.55) fig L-1, (1.51 ±0.43) jxg L'1, (0.64 ±0. 34)ug L-l and presented a negative correlation with pulmonary hemodynamic indices and right ventricular hypertrophy. Immunohistochernical staining demonstrated that NBL1 was mainly expressed in small pulmonary arteries in normal lungs from control group but seldom detected in severely remodeled pulmonary arteries from MCT group. Furthermore, NBL1 significantly inhibited the activation of BMP signal in pulmonary artery endothelial cells induced by BMP2/4. Conclusions NBL1 level demonstrates a stepwise decrease in MCT induced PAH, implying its vital roles in the pulmonary vascular remodeling process and the possibility of NBL1 to be a potential biomarker for PAH.

Therapeutic Effects of Transthoracic Pulmonary Artery Denervation in a Rat Model of Pulmonary Arterial Hypertension / 中国循环杂志

Objectives:The aim of this study was to observe whether transthoracic pulmonary artery denervation (TPADN) could reduce the pulmonary arterial pressure and attenuate pulmonary vascular remodeling in rats with pulmonary arterial hypertension induced by monocrotaline. Methods:Twenty-four healthy male SD rats were randomly divided into control group, sham operation group and operation group (n=8 per group). Rats in sham operation group and operation group received single subcutaneous injection of monocrotaline (MCT, 60 mg/kg). After four weeks, the mean pulmonary arterial pressure (mPAP) and other hemodynamic parameters were measured with the right heart catheter in rats of these two groups. Then, operation group received the surgery of TPADN, which included thoracotomy in left 2-3 rib, exposing pulmonary artery, and removing the near connective tissue of the pulmonary artery trunk. After two weeks of operation, the mPAP and other hemodynamic parameters were measured again by the right heart catheter. The microstructure changes of the heart and pulmonary vessels was observed by immunohistochemistry and immunofluorescence. Meanwhile, RV cardiomyocyte cross-sectional area (CSA) and the right hearthy pertrophy index (RVHI= RV/[LV+S]) were used to evaluate the degree of right ventricular hypertrophy. Results:After four weeks of injection of MCT, the mPAP was significantly higher in the operation group and the sham operation group than in control group (P＜0.01). Two weeks after the surgery of TPADN, the mPAP was significantly reduced in the operation group than compared in the sham group(P＜0.01). Meanwhile, the percentage of medial thickness to outer diameter of the small pulmonary arterioles, right ventricular myocardial cell cross-sectional area and RVHI were also significantly decreased in the operation group compared to sham operation group(all P＜0.01). Conclusions:Our results show that TPADN could reduce the mean pulmonary arterial pressure and attenuate the hypertrophy of medial thickness of small pulmonary arterioles and of right ventricle in PAH rats induced by monocrotaline.

Effects of long-term cigarette smoke exposure on pulmonary vascular re-modeling and TGF-β1 expression in rat pulmonary vessels / 中国病理生理杂志

[ ABSTRACT] AIM:To observe the effects of long-term cigarette smoke exposure on pulmonary vascular remode-ling and the protein expression of transforming growth factor-β1 ( TGF-β1 ) in the rats, and to explore the mechanism. METHODS:SD rats (n=36) were randomly divided into control group, 2-week smoke exposure (S-2W) group and 12-week smoke exposure (S-12W) groups.HE staining andα-smooth muscle actin staining were performed to observe the pul-monary vascular remodeling.The protein expression of proliferating cell nuclear antigen ( PCNA) and TGF-β1 in the pulmo-nary arteries was determined by the method of immunohistochemistry.The mRNA expression of TGF-β1 in the pulmonary arteries was evaluated by RT-qPCR.RESULTS:Compared with control group, ratio of pulmonary vessel wall thickness to vessel diameter ( WT%) and percentage of muscularized vessels were significantly increased in S-2W group and S-12W group ( P<0.01) .Significant increases in the protein expression of PCNA and TGF-β1 in smoke exposure groups were ob-served compared with control group.There was significant difference between 2 model groups (P<0.01).Compared with control group, the mRNA expression of TGF-β1 in pulmonary artery walls obviously increased in smoke exposure groups. There was significantly difference between S-2W and S-12W groups (P<0.05).The mRNA expression of TGF-β1 was positively correlated with pulmonary vascular muscularization, WT% and the protein expression of PCNA.CONCLU-SION:Long-term cigarette smoke exposure results in pulmonary artery remodeling in rats.The possible mechanism is that cigarette smoking exposure induces the over-expression of TGF-β1 at mRNA level in pulmonary vessels and promotes the proliferation of pulmonary vascular smooth muscle cells in rats.

Pulmonary vascular remodeling after left lung pneumonectomy in rats / 中国实验动物学报

Objective To investigate the existence of pulmonary vascular remodeling after left pneumonectomy in rats and the role of hypoxia inducible factor-lα( HIF-1α) and vascular endothelial growth factor ( VEGF) in pulmonary vascular remodeling.Methods Twenty-four healthy male Sprague-Dawley rats were randomly divided into experimental and control groups, 12 in each group.The rat models of pulmonary vascular remodeling were created by open-chest left pneumonectomy.After 12 weeks of feeding, the mean pulmonary artery pressure ( mPAP) and partial pressure of arterial oxygen ( PaO2 ) of each rat were measured.The ultrastructure of small arteries in the lung specimens were examined by e-lectron microscopy.Muscularized degree of three kinds of small pulmonary vessels ( muscularized artery MA, partially mus-cularized artery PMA, and non-muscularized artery NMA) were observed by light microscopy, and the percentage of each kind of pulmonary arteries ( MA%, PMA%, NMA%) were calculated.Arterial external diameter, media thickness of ves-sel ( MTV) , total vascular area, media area of vessel ( MAV) , MTV%and MAV%were calculated as indicators of pul-monary vascular remodeling.The expressions of HIF-1αand VEGF in artery were detected by immunohistochemistry.Re-sults The values of mPAP, MA%, PMA%, MTV, MAV, MTV% and MAV% in the experimental group were signifi-cantly higher than those in the control group (P<0.01), but the value of PaO2 and NMA%were significantly lower than those in the control group (P<0.01).The IOD value of HIF-1αand VEGF expressed in the pulmonary arterial wall of the experimental group were 26.47 ±4.16 and 42.04 ±3.79, respectively, significantly higher than those in the control group (6.12 ±2.14 and 11.53 ±2.29, P<0.01).Linear correlation analysis showed that the expression of HIF-1αand VEGF was positively correlated with MTV% and MAV%, negatively correlated with PaO2 , and the HIF-1αexpression was posi-tively correlated with VEGF expression.Conclusions A rat model of pulmonary vascular remodeling can be successfully established by left pneumonectomy.Hypoxia is a key factor in the development of pulmonary vascular remodeling, HIF-1αand VEGF may play an important role in its pathogenesis.