1.Impact of high pulmonary blood flow on pulmonary vascular structure and human urotensin II in intrapulmonary arteries of rats.
Jian-Guang QI ; Jun-Bao DU ; Jian LI ; Bing WEI ; Chao-Shu TANG
Chinese Journal of Applied Physiology 2003;19(3):274-277
AIMTo study human urotensin II (hUII) expression in intrapulmonary arteries of rats with pulmonary hypertension induced by high pulmonary blood flow and explore the role of hU II in the development of pulmonary hypertension induced by left to right shunt.
METHODSAortocaval shunting was produced for 11 weeks in rats. Pulmonary artery mean pressure (PAMP) of each rat was evaluated using right cardiac catheterization. The pulmonary vascular structural changes, including the percentage of muscularized arteries of small pulmonary vessels and relative medial thickness of intra-acinar pulmonary arteries were examined. Meanwhile, the expression of hU II by pulmonary arteries was detected by immunohistochemistry.
RESULTSAfter 11-week aortocaval shunting, PAMP was significantly increased. The percentage of muscularized arteries of small pulmonary vessels and relative medial thickness of pulmonary arteries were obviously increased in shunting rats compared with controls (P < 0.01, respectively). Meanwhile, hU II expression by pulmonary artery endothelial cells and smooth muscle cells was significantly augmented in rats of shunt group, which was positively correlated with PAMP and the structural changes in pulmonary arteries.
CONCLUSIONThe up-regulation of hU II in pulmonary arteries might be involved in the development of pulmonary vascular structural remodeling and pulmonary hypertension induced by high pulmonary blood flow.
Animals ; Humans ; Hypertension, Pulmonary ; metabolism ; Male ; Pulmonary Artery ; metabolism ; physiopathology ; Pulmonary Circulation ; Rats ; Rats, Sprague-Dawley ; Urotensins ; metabolism
2.The expression and possible role of SENP1 in the pulmonary vascular wall of rat during the development of hypoxic pulmonary hypertension.
Hua TIAN ; Ai-Guo DAI ; Dai-Yan FU ; Rui-Cheng HU ; Li-Ming ZHU
Chinese Journal of Applied Physiology 2012;28(2):123-127
OBJECTIVETo investigate the dynamic expression and role of SENP1 (SUMO-specific proteases-1) in the pulmonary vascular wall of rat during the development of hypoxic pulmonary hypertension (HPH).
METHODSForty adult male Wistar rats were randomly divided into 5 groups (n = 8), and exposed to normoxia (Control group) or exposed to hypoxia for 3, 7, 14 or 21 d, respectively. The HPH models were established by normobaric intermittent hypoxia. Mean pulmonary arterial pressure (mPAP), right ventricle hypertrophy index (RVHI), and vessel morphometry were measured. Reverse transcriptase-polymerase chain reaction(RT-PCR) and in situ hybridization were used to determine the mRNA expression of SENP1. Immunohistochemistry and Western blot were used to determine the protein expression of SENP1.
RESULTSThe hypoxic rats developed pulmonary vascular remodeling in pulmonary arterioles after 7 d of hypoxia exposure. Pulmonary vascular remodeling in pulmonary arterioles significantly increased after 14 d of hypoxia. The level of mPAP in hypoxic rats increased significantly after 7 d of hypoxia, reached its peak after 14 d of hypoxic exposure. RVHI was markedly increased after 14 d of hypoxia. In situ hybridization and immunohistochemical analysis showed that SENP1 mRNA and protein were positively stained in control. SENP1 mRNA expression had little changes after exposure to hypoxia compared with the control, however, SENP1 protein expression was declined gradually after 7 d of hypoxia. The results of RT-PCR and Western blot showed that the same dynamic expression of SENP1 mRNA and protein in lung tissues of rats. Linear correlation analysis showed that SENP1 protein were negatively correlated with mPAP, pulmonary vascular remodeling index and RVHI.
CONCLUSIONUnder chronic hypoxia, SENP1 protein can be degradated. The dynamic expression of SENP1 protein may play a role in implicating in the development of HPH.
Animals ; Endopeptidases ; metabolism ; Hypertension, Pulmonary ; etiology ; metabolism ; Hypoxia ; complications ; metabolism ; Male ; Pulmonary Artery ; metabolism ; Rats ; Rats, Wistar
3.Expression of connective tissue growth factor in pulmonary artery at the early-stage of pulmonary fibrosis.
Mao-Xiang CUI ; Xiao-Ling CHEN ; Cun-Ling HUO ; Xiao-Jie HU ; Jie AI
Acta Physiologica Sinica 2008;60(4):535-540
To ascertain whether connective tissue growth factor (CTGF) participates in the remodeling of pulmonary artery at the early-stage of bleomycin (BLM)-induced pulmonary fibrosis, mean pulmonary arterial pressure, the expression of type I and type III collagens, and the expression and location of CTGF in pulmonary artery and arteriole were investigated in the present study. Sprague-Dawley rats received instillation of BLM [5 mg/kg body weight, in 0.5 mL of normal saline (NS)] or instillation of the same amount of NS as control. Mean pulmonary arterial pressure was detected via a catheter in the pulmonary artery. Type I and type III collagens were examined with Sirius red staining under polarized light. CTGF expression was investigated by using immunohistochemistry, and was represented as average optical density and percentage of positive area of CTGF. The mean pulmonary arterial pressure was higher in rats on day 14 after BLM instillation [(19.5+/-2.9) mmHg] than that in the control rats [(14.8+/-1.2) mmHg] (P<0.05). The type I and type III collagens were increased both in pulmonary artery and arteriole of rats on day 14 after BLM instillation, compared with those in the control rats (P<0.05, P<0.01, respectively). The ratio of type I/III collagens in pulmonary artery was also higher in BLM-treated rats than that in the control rats (P<0.05). The values of average optical density of positive CTGF staining were increased both in pulmonary artery (0.37+/-0.02) and arteriole (0.40+/-0.03) of rats on day 14 after BLM instillation, compared with those in the control rats (artery, 0.34+/-0.01; arteriole, 0.29+/-0.01) (both P<0.05). The percentages of positive area of CTGF were higher in pulmonary artery (8.40+/-1.13) and arteriole (12.4+/-2.0) of rats on day 14 after BLM instillation than those in the control rats (artery: 1.42+/-0.63; arteriole: 1.16+/-0.34), respectively (both P<0.05). The increased positive CTGF staining areas were mainly located in the endothelium and smooth muscle layer. It is therefore concluded that CTGF expression increases in the endothelium and smooth muscle layer of pulmonary artery and arterioles during high pulmonary arterial pressure and remodeling of pulmonary artery at the early-stage of BLM-induced pulmonary fibrosis, and that the increased CTGF might be one of the mechanisms of maintenance and development of pulmonary hypertension.
Animals
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Bleomycin
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Collagen Type I
;
metabolism
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Collagen Type III
;
metabolism
;
Connective Tissue Growth Factor
;
metabolism
;
Hypertension, Pulmonary
;
Pulmonary Artery
;
metabolism
;
Pulmonary Fibrosis
;
metabolism
;
Rats
;
Rats, Sprague-Dawley
4.Dynamic changes of urotensin II receptor in pulmonary artery and arterioles of rats chronically exposed to hypoxia-hypercapnia.
Yong-Sheng GONG ; Xiao-Fang FAN ; Xiao-Mai WU ; Yu-Qi GAO ; Liang-Gang HU ; Hong HUANG ; Shan-Shan JIA
Chinese Journal of Applied Physiology 2005;21(4):377-381
AIMTo investigate the dynamic changes and functions of urotensin II (U lI) receptor (UT) in pulmonary arteries of rats chronically exposed to hypoxia-hypercapnia.
METHODSIn rats with hypoxia-hypercapnia at 1, 2 and 4 weeks U II receptor binding of pulmonary arteries sarcolemma was determined by radioligand assay. U II mRNA and UTmRNA in various grades of pulmonary arterioles were measured by in situ hybridization.
RESULTS(1) Mean pulmonary pressure (mPAP) and weight ratio of right ventricle to left ventricle and septum (RV/LV + S) of 1-week group were higher than those of normal control (NC) group by 26.2% and 21.6% (P < 0.01), respectively, and 2-week group higher than 1-week group by 22.5% and 14.1% (respectively, P < 0.01). However, no significant changes were found between 4-week and 2-week group. (2) U Il receptor (Bmax) of 1-week group was higher than NC group by 38.8%, 2-week group higher than 1-week group by 23.2%, and 4-week group increased 7.3% compared with 2-week group (respectively, P < 0.01). The UT changes were time-dependent, while the affinity to U II (Kd) was no different among each group. (3) UII mRNA in each grade of pulmonary arterioles of 2-week group and 4-week group were higher than NC group (respectively, P < 0.01), and those of 2-week group were higher than 1-week group by 5.9% (P > 0.05), 16.4% and 9.1% (respectively, P < 0.01), while no differences existed between 2-week group and 4-week group. (4) UT mRNA in each grade of pulmonary arterioles of all hypoxia-hypercapnia groups was higher than NC group (respectively, P < 0.01), and those of two abaxial grade vessels in 1-week group were the highest. No differences existed between 2-week group and 4-week group. (5) The pulmonary vessels remodeling were time-dependently aggravated by hypoxia-hypercapnia.
CONCLUSIONThe dynamic changes of UT in pulmonary arterioles might have important contribution to the development of pulmonary hypertension and pulmonary arteriole remodeling induced by chronic hypoxia-hypercapnia in rats.
Animals ; Arterioles ; metabolism ; physiopathology ; Hypercapnia ; metabolism ; Hypertension, Pulmonary ; metabolism ; physiopathology ; Hypoxia ; metabolism ; Male ; Pulmonary Artery ; metabolism ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled ; metabolism
5.Role of myelin and lymphocyte protein in regulating pulmonary artery smooth muscle cell proliferation and apoptosis in pulmonary hypertension.
Jin Jun LIU ; Qing Qing LI ; Chao Chao ZENG ; Yue Xiang WANG ; Qing Tian HU ; Hong Ju WANG ; Shi Li WU
Journal of Southern Medical University 2022;42(10):1572-1577
OBJECTIVE:
To investigate the role of myelin and lymphocyte protein (MAL) in pulmonary hypertension (PAH).
METHODS:
Blood samples were collected from 50 patients with PAH (PAH group) and 50 healthy individuals for detection of plasma MAL expression using ELISA.According to the echocardiographic findings, the patients were divided into moderate/severe group (n=18) and mild group (n=32), and the correlation between MAL protein level and the severity of PAH was analyzed.In a pulmonary artery smooth muscle cell model of PAH with hypoxia-induced abnormal proliferation, the effects of mal gene knockdown and overexpression on cell growth, proliferation and starvation-induced apoptosis were observed; the changes in NK-κB signaling pathway in the transfected cells were detected to explore the molecular mechanism by which MAL regulates PAMSC proliferation and apoptosis.
RESULTS:
The plasma level of MAL was significantly higher in patients with PAH than in healthy individuals (P < 0.05), and the patients with moderate/severe PAH had significantly higher MAL level than those with mild PAH (P < 0.001).In PAMSCs, exposure to hypoxia significantly increased the mRNA and protein expression levels of MAL (P < 0.05), and MAL knockdown obviously inhibited hypoxia-induced proliferation and promoted starvation-induced apoptosis of the PAMSCs (P < 0.05).Knocking down mal significantly inhibited the activation of NK-κB signaling pathway that participated in regulation of PAMSC proliferation (P < 0.05).
CONCLUSION
The plasma level of MAL is elevated in PAH patients in positive correlation with the disease severity.MAL knockdown inhibits abnormal proliferation and promotes apoptosis of PAMSCs by targeted inhibition of the NF-κB signaling pathway to improve vascular remodeling in PAH.
Humans
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Pulmonary Artery
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Hypertension, Pulmonary
;
Myelin Sheath/metabolism*
;
Apoptosis
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Myocytes, Smooth Muscle
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Vascular Remodeling/genetics*
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Cell Proliferation
;
Hypoxia/metabolism*
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Lymphocytes
7.The role of endogenous carbon monoxide in vascular remodeling in hypoxic pulmonary hypertension.
Guo-hua ZHEN ; Zhen-xiang ZHANG ; Yong-jian XU
Chinese Journal of Applied Physiology 2002;18(4):374-377
AIMTo investigate the expression of heme oxygenase-1 gene and production of endogenous carbon monoxide in the rat lung tissue at different time points of chronic hypoxic pulmonary hypertension and the effect of hemin, an inducer of heme oxygenase, on the expression of HO-1 gene and production of endogenous carbon monoxide and pulmonary hypertension.
METHODSWe recreated a rat model of hypoxic pulmonary hypertension by intermittent normal pressure hypoxia (10% O2). The following assays were carried out: Reverse transcriptase polymerase chain reaction (RT-PCR) were performed to determine the level of HO-1 mRNA in rat lung tissue, double wave length spectrophotometry was used to evaluate the quantity of COHb in arterial blood, cardiac catheterization was used to measure the right ventricular systolic pressure (RVSP) and HE staining was performed in dissected lung tissue to observe the pathologic changes of the intra-acinar pulmonary arteries(IAPA).
RESULTS(DT here was low level of HO-1 mRNA in normal rat lung tissue, but the level of HO-1 mRNA increased by 2-4 times in the lung tissue of hypoxic rats (P < 0.01). The quantity of COHb was 2-3 times as those of control group (P < 0.01 or P < 0.05). These were accompanied by the increase of RVSP and the thickness of IAPA. (2) Hemin could maintain the HO-1 mRNA and COHb in the hypoxic rat lung tissue at a high level, and partially suppressed the increase of rat RVSP, ameliorated the pathologic changes of IAPA.
CONCLUSIONThe upregulation of the expression of HO-1 gene and production of CO in the rat lung of hypoxic pulmonary hypertension plays a role of inhibition in the development of hypoxic pulmonary hypertension. Hemin has a therapeutic effect on hypoxic pulmonary hypertension.
Animals ; Carbon Monoxide ; metabolism ; Heme Oxygenase (Decyclizing) ; metabolism ; Hemin ; pharmacology ; Hypertension, Pulmonary ; metabolism ; pathology ; physiopathology ; Hypoxia ; metabolism ; pathology ; Male ; Pulmonary Artery ; metabolism ; physiopathology ; Rats ; Rats, Wistar
8.Study on relativity of hypoxic pulmonary hypertension with levels of endothelin-1 and vascular endothelial growth factor in plasma of pulmonary artery and carotid artery.
Yu-fang HUANG ; Zhi-chao LI ; Li-li LUAN ; Ming-qing DONG ; Bo ZHANG
Chinese Journal of Applied Physiology 2007;23(4):473-477
AIMTo study the effects of endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) on the mechanism of hypoxic pulmonary hypertension (HPH).
METHODSWe studied 4 groups of age-controlled male rats, i.e., normal control for 2 weeks group (N2), normal control for 3 weeks group (N3), exposed to hypoxia for 2 weeks group (H2) and for 3 weeks group (H3). Chronic HPH rat models were established by chronic hypobaric hypoxia [(10.0% +/- 0.5% O2] for 2 and 3 weeks, respectively. The rats were anesthetized and fixed, and the levels of mean pulmonary artery pressure (mPAP) and carotid arterial pressure (CAP) were measured using catheters by a microcomputer via transducers. The weight ratio of right ventricle (RV) and left ventricle and septum (LV + S) [RV/ (LV+S)] were determined. The contents of ET-1 in plasma of pulmonary artery and carotid artery and in homogenates of lung and systemic arteries were determined by radioimmunoassay, and the contents of VEGF in serum of pulmonary artery and carotid artery were determined by ABC-ELISA.
RESULTSHPH rat models were established successfully. Compared with control groups, the values of ET-1 were both enhanced in carotid artery and pulmonary artery plasma in model groups (P < 0.01). In the HPH groups, the level of pulmonary artery plasma ET-1 was significantly lower than that of carotid artery plasma, but just the reverse was ET-1 in control rats. The levels of ET-1 in homogenates of lungs from HPH models were significantly higher than those in homogenates of lungs from control groups (P < 0.01), and markedly higher than those in homogenates of systemic arteries from HPH rats (P < 0.01) SThe values of VEGF in serum of pulmonary artery from H3 group were significantly higher than those from control groups and H2 group (P < 0.01). In serum of carotid artery, the values of VEGF from the HPH models were higher than those from the control groups (P < 0.01).
CONCLUSIONET-1 and VEGF play important roles in the pathogenesis of HPH. The result that ET-1 concentration around pulmonary arteries was significantly higher than that around systemic arteries may be one of the mechanisms accounting for the different reaction of them to hypoxia.
Animals ; Endothelin-1 ; metabolism ; Hypertension, Pulmonary ; metabolism ; physiopathology ; Hypoxia ; metabolism ; Male ; Pulmonary Artery ; metabolism ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Vascular Endothelial Growth Factor A ; metabolism
9.An experimental study on the regulation of pulmonary arterial remodeling by protein kinase C in chronic hypoxic rats.
Hao ZHOU ; Shao-Xian CHEN ; Liang-Xing WANG ; Yan-Fan CHEN ; Yu-Peng XIE
Chinese Journal of Applied Physiology 2002;18(1):38-42
AIMTo investigate the effect of protein kinase C regulating pulmonary arterial remodeling in chronic hypoxic rats.
METHODSElectron microscope, radioactivity, immunohistochemistry and image analyser were used.
RESULTS(1) Mean pulmonary arterial pressure (mPAP) and weight ratio of RV to LV + S were significantly higher than that of control group (P < 0.01). (2) WA/TA and SMC were significantly higher than that of control group (P < 0.01). Electron microscopy showed the proliferation of smooth muscle cells and the disposition of collagenous fiber in pulmonary arterioles induced by hypoxia. (3) The total, cytosolic, particulate fraction PKC activity and the ratio of particulate fraction to total PKC activity were significantly higher than that of control group (P < 0.01). (4) Expression of PKC, collagen I were significantly higher than that of control group (P < 0.01), the difference of collagen III was not significant between two groups (P > 0.05). (5) There were good correlation between the total, particulate fraction PKC activity, the ratio of particulate fraction to total PKC activity, expression of PKC and SMC, collagen I in pulmonary arterioles.
CONCLUSIONThe PKC regulates the proliferation of pulmonary artery smooth muscle cells and expression of pulmonary arterial collagen in chronic hypoxic rats, which may play an important role in the pathogenesis of pulmonary hypertension and structural remodeling of pulmonary arteries.
Animals ; Collagen ; metabolism ; Female ; Hypertension, Pulmonary ; metabolism ; physiopathology ; Hypoxia ; metabolism ; physiopathology ; Male ; Myocytes, Smooth Muscle ; metabolism ; Protein Kinase C ; metabolism ; Pulmonary Artery ; physiopathology ; Rats ; Rats, Sprague-Dawley
10.The vasoactive material and pulmonary vascular structural remodeling in rats.
Qiu-Hong CHEN ; Xiao-Qin WANG ; Man-Tang YU ; Xiao-Hong LI ; Jin WANG
Chinese Journal of Applied Physiology 2006;22(1):71-74
AIMTo investigate the role of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) on pulmonary vascular structural remodeling in rats and pika.
METHODSThe Wistar rats which reside at 2 260 m were carried to 3 417 m. After they were fed 24 hours,2 weeks and 3 weeks respectively, the level of VEGF and ET-1 were measured using a kit by ELISA method. Pulmonary tissue was taken out to stain with elastica-Van Gieson. The amount of pulmonary arteries (< 100 microm) and the component ratio of MA, PMA,and NMA were calculated by using a light microscope. The ratio of right ventricle weight to left ventricle plus septum weight (RV/LV + S) were measured.
RESULTSThe ET-1 was significantly different in pika as compared with 24 h, 2 weeks, 3 weeks hypoxic rats (P < 0.01) respectively. The levels of VEGF in 2 weeks, 3 weeks rats were much higher than that of pika but no difference was found between pika and 24 h hypoxic rats. The ratio of MA, PMA obviously increased, and NMA decreased significantly, right ventricular hypertrophy was developed in differ groups of hypoxic rats.
CONCLUSIONThe VEGF and ET-1 participate the muscularization of pulmonary vessels during hypoxia and play an important role in the process of hypoxic pulmonary hypertension in rats, however the VEGF and ET-1 may be maintainable only normal organic function in pika.
Animals ; Endothelin-1 ; metabolism ; Female ; Hypertension, Pulmonary ; metabolism ; Hypoxia ; metabolism ; Lagomorpha ; Lung ; blood supply ; Male ; Pulmonary Artery ; metabolism ; Rats ; Rats, Wistar ; Vascular Endothelial Growth Factor A ; metabolism