Hypoxia Induces Transforming Growth Factor-β1 Gene Expression in the Pulmonary Artery of Rats via Hypoxia-inducible Factor-1α

The present study was undertaken to investigate the dynamic expression of hypoxia induciblefactor-1 α (HIF-1α) and transforming growth factor-β1 (TGF-β1) in hypoxia-induced pulmonary hypertensionof rats.It was found that mean pulmonary arterial pressure (mPAP) increased significantly after 7 d ofhypoxia.Pulmonary artery remodeling index and right ventricular hypertrophy became evident after 14 d ofhypoxia.HIF-1α mRNA staining was less positive in the control,hypoxia for 3 d and hypoxia for 7 d,butbegan to enhance significantly after 14 d of hypoxia,then remained stable.Expression of HIF-1 α protein inthe control was less positive,but was up-regulated in pulmonary arterial tunica intima of all hypoxic rats.TGF-β1 mRNA expression in pulmonary arterial walls was increased significantly after 14 d of hypoxia, butshowed no obvious changes after 3 or 7 d of hypoxia.In pulmonary tunica adventitia and tunica media,TGF-β1 protein staining was less positive in control rats,but was markedly enhanced after 3 d of hypoxia,reaching its peak after 7 d of hypoxia,and then weakening after 14 and 21 d of hypoxia.Western blottingshowed that HIF- 1α protein levels increased significantly after 7 d of hypoxia and then remained at a highlevel. TGF-β1 protein level was markedly enhanced after 3 d of hypoxia,reaching its peak after 7 d ofhypoxia,and then decreasing after 14 and 21 d of hypoxia.Linear correlation analysis showed that HIF-1αmRNA, TGF-β1 mRNA, TGF-β1 protein were positively correlated with mPAP,vessel morphometry andright ventricular hypertrophy index.TGF-β1 protein (tunica adventitia) was negatively correlated withHIF-lα mRNA.Taken together,our results suggest that changes in HIF-lα and TGF-β1 expression afterhypoxia play an important role in hypoxia-induced pulmonary hypertension of rats.     

Differential and Reciprocal Regulation between Hypoxia-inducible Factor-α Subunits and Their Prolyl Hydroxylases in Pulmonary Arteries of Rat with Hypoxia-induced Hypertension

Hypoxia-inducible factor (HIF)-α subunits (HIF-1α,HIF-2α and HIF-3α),which play a pivotalrole during the development of hypoxia-induced pulmonary hypertension (HPH),are regulated through post-U'anslational hydroxylation by their three prolyl hydroxylase domain-containing proteins (PHD 1,PHD2 and PHD3).PHDs could also be regulated by HIF.But differential and reciprocal regulation between HIF-α and PHDs duringthe development of HPH remains unclear.To investigate this problem,a rat HPH model was established.Meanpulmonary arterial pressure increased significantly after 7 d of hypoxia.Pulmonary artery remodeling indexand right ventricular hypertrophy became evident after 14 d of hypoxia.HIF-1α and HIF-2α mRNA increasedslightly after 7 d of hypoxia,but HIF-3α increased significantly after 3 d of hypoxia.The protein expressionlevels of all three HIF-α were markedly upregulated after exposure to hypoxia.PHD2 mRNA and proteinexpression levels were upregulated after 3 d of hypoxia;PHD 1 protein declined after 14 d of hypoxia withoutsignificant mRNA changes.PHD3 mRNA and protein were markedly upregulated after 3 d of hypoxia,then themRNA remained at a high level,but the protein declined after 14 d of hypoxia.In hypoxic animals,HIF-lotproteins negatively correlated with PHD2 proteins,whereas HIF-2α and HIF-3α proteins showed negativecorrelations with PHD3 and PHD 1 proteins,respectively.All three HIF-α proteins were positively correlatedwith PHD2 and PHD3 mRNA.In the present study,HIF-α subunits and PHDs showed differential andreciprocal regulation,and this might play a key pathogenesis role in hypoxia-induced pulmonary hypertension.     

Expression and role of factor inhibiting hypoxia-inducible factor-1 in pulmonary arteries of rat with hypoxia-induced hypertension

Hypoxia-inducible factor-1alpha subunit (HIF-1alpha) plays a pivotal role during the development of hypoxia-induced pulmonary hypertension (HPH) by transactivating it' target genes. As an oxygen-sensitive attenuator, factor inhibiting HIF-1 (FIH) hydroxylates a conserved asparagine residue within the C-terminal transactivation domain of HIF-1alpha under normoxia and moderate hypoxia. FIH protein is downregulated in response to hypoxia, but its dynamic expression and role during the development of HPH remains unclear. In this study, an HPH rat model was established. The mean pulmonary arterial pressure increased significantly after 7 d of hypoxia. The pulmonary artery remodeling index became evident after 7 d of hypoxia, while the right ventricular hypertrophy index became significant after 14 d of hypoxia. The messenger RNA (mRNA) and protein expression of HIF-1alpha and vascular endothelial growth factor (VEGF), a well-characterized target gene of HIF-1alpha, were markedly upregulated after exposure to hypoxia in pulmonary arteries. FIH protein in lung tissues declined after 7 d of hypoxia and continued to decline through the duration of hypoxia. FIH mRNA had few changes after exposure to hypoxia compared with after exposure to normoxia. In hypoxic rats, FIH protein showed significant negative correlation with VEGF mRNA and VEGF protein. FIH protein was negatively correlated with mean pulmonary arterial pressure, pulmonary artery remodeling index and right ventricular hypertrophy index. Taken together, our results suggest that, in the pulmonary arteries of rat exposed to moderate hypoxia, a time-dependent decrease in FIH protein may contribute to the development of rat HPH by enhancing the transactivation of HIF-1alpha target genes such as VEGF.     

游泳运动对低氧性肺动脉高压大鼠肺组织apelin及其受体表达的影响

目的:探讨游泳运动对大鼠肺组织新的小分子活性肽apelin及其受体(APJ)表达的影响。方法:45只雄性大鼠随机分成三组:正常对照组、低氧组(七周)和游泳组(低氧+游泳锻炼七周组,低氧3周后,于每天入低氧舱前行无负重游泳运动60 min,每天1次)。七周后测定各组大鼠平均肺动脉压(mPAP)、右心室与左心室加室间隔的重量比[RV/(LV+S)]、肺细小动脉管壁面积/管总面积(WA/TA)、管腔面积/管总面积(CA/TA)及中膜厚度(PAMT)。免疫蛋白印迹与免疫组化法测定肺组织apelin/APJ的蛋白表达。结果:①低氧组mPAP和RV/(LV+S)比正常对照组分别高73.6%和31.2%(P均<0.01),而游泳组比低氧组分别低21.1%和8.9%(P均<0.05)。②低氧组WA/TA和PAMT较正常对照组分别高70.8%和102%,而游泳组较低氧组分别低24.8%和40.1%(P均<0.01)。低氧组CA/TA较正常对照组低15.1%,而游泳组较低氧组高10.3%(P均<0.01)。③低氧组肺组织apelin蛋白表达较正常对照组上调374%(P<0.01),而APJ蛋白表达下调87.1%(P均<0.01);游泳组肺组织apelin蛋白表达较低氧组下调48%,而APJ蛋白表达上调287%(P均<0.01)。④apelin蛋白主要在血管外膜及炎症细胞胞浆内表达,APJ蛋白主要在血管内膜、外膜及炎症细胞上表达。结论:游泳运动减缓肺动脉高压和肺血管重塑作用可能与调节肺组织apelin/APJ系统的表达有关。     

低氧诱导因子脯氨酰羟化酶与OS－9在大鼠低氧肺动脉高压中的协同作用

目的：研究HIF-1α、PHDs及OS-9的表达变化在低氧性肺动脉高压（HPH）中的作用和意义。方法：SD大鼠随机分5组（n=8）;对照组（C组）和低氧3、7、14和21d组,常压低氧复制HPH大鼠模型。原位杂交、RT-PCR检测mRNA表达,免疫组化、Westernblot检测蛋白质表达。结果：①HIF-1αmRNA对照纽和低氧3d无明显差异,低氧14d后表达明显增高;HIF-1α蛋白质低氧3d组表达明显增高,7d达高峰;②对照组PHD1mRNA呈阳性表达,各低氧组与对照组比较差异不显著,PHD1蛋白质在对照组强阳性表达,低氧14d下降,低氧21d保持较低水平;对照组PHD2mRNA呈阳性表达,低氧3d增高,14d达到高峰,21d维持高水平,其蛋白质表达趋势与mRNA相同;对照组PHD3mRNA和蛋白质表达不明显,低氧3dmRNA明显增高,蛋白质低氧3d明显增高,低氧7d保持高水平,低氧14d和21d下降。③OS-9mRNA在对照组呈强阳性表达,低氧3d后迅速降低,14d达到最低水平;其蛋白质表达趋势与mRNA相同。相关分析表明,肺小动脉壁OS-9蛋白质表达水平与OS-9mRNA呈正相关,与RVHI、mPAP、WA％及LA％呈负相关。结论：HIF-1α、PHDs及OS-9均在大鼠HPH的发病机制中发挥作用。OS-9可能通过增强PHDs的活性来调节HIF-1α的表达,从而在HPH的发生和发展中发挥作用。     

SENP1在大鼠低氧性肺动脉高压形成中肺血管壁中表达及可能作用

目的:探讨大鼠低氧性肺动脉高压(HPH)形成过程中SENP1在肺小动脉的动态表达变化及作用。方法:40只成年雄性Wistar大鼠随机分为5组(n=8):对照组和缺氧3 d、7 d、14 d2、1 d组,常压间断低氧复制HPH大鼠模型。测各组大鼠平均肺动脉压(mPAP)、右心室肥大指数(RVHI)、血管形态学指标;原位杂交、逆转录-聚合酶链反应(RT-PCR)检测肺内SUMO特异性蛋白酶-1(SUMO-specific proteases-1,SENP1)mRNA表达,免疫组化、Westernblot检测其蛋白质水平。结果:①缺氧7 d后,肺小动脉出现血管重塑,且mPAP明显上升;低氧14 d后,肺小动脉重塑更明显,mPAP达高峰。RVHI在低氧14 d后明显增加。②原位杂交显示,SENP1 mRNA在对照组肺小动脉壁呈阳性表达,低氧后其相对量无明显变化。RT-PCR显示肺组织SENP1 mRNA表达与原位杂交所观察到的肺小动脉壁SENP1 mRNA变化趋势一致;SENP1蛋白在对照组呈阳性表达,低氧7 d后其表达量开始呈进行性下降。Western blot显示肺组织内SENP1蛋白表达与免疫组化观察到的肺小动脉壁SENP1蛋白变化趋势一致。③SENP1蛋白与mPAP、重塑指数、RVHI均呈负相关。结论:慢性低氧诱导肺小动脉壁SENP1蛋白降解,进而可能在HPH发病过程中发挥一定的作用。     

低氧条件下大鼠肺动脉平滑肌细胞中活性氧与低氧诱导因子-1α和细胞增殖的关系

在低氧条件下,观察大鼠肺动脉平滑肌细胞（pulmonary arterial smooth muscle cells,PASMCs）中活性氧（reactive oxygen species,ROS）的变化,探讨ROS的变化是否通过调控低氧诱导因子-4α（hypoxia-inducible factor 1α, HIF-1α）的表达影响PASMCs的增殖。采用组织块法原代培养大鼠PASMCs,分成3组：常氧组（21％O2,24h）,低氧组（5％O2,24h）,低氧＋Mn-TBAP组（5％O2,24h,Mn-TBAP是一种ROS清除剂）。用激光共聚焦显微镜荧光染色法检测细胞内ROS的变化;用RT-PCR和免疫组织化学方法分别测定HIF-1α mRNA和蛋白的表达;用MTT法检测细胞增殖程度。结果显示：（1）低氧组PASMCs内ROS水平明显高于常氧组（P〈0．05）,低氧＋Mn-TBAP组ROS水平明显低于低氧组（P〈0．05）,但仍高于常氧组（P〈0．05）;（2）低氧组及低氧＋Mn-TBAP组的HIF-1α mRNA和蛋白表达均高于常氧组（P〈0．05）,且低氧组表达高于低氧＋Mn-TBAP组（P〈0．05）;（3）低氧组细胞增殖明显高于常氧组和低氧＋Mn-TBAP组（P〈0．05）,低氧＋Mn-TBAP组细胞增殖高于常氧组（P〈0．05）。结果表明：在低氧条件下大鼠PASMCs中ROS水平明显升高,RROS的变化能够调节HIF-1α的表达,进而影响平滑肌细胞的增殖,提示ROS可能在肺动脉高压的发病机制和低氧信号转导中具有重要作用。     

A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces haem oxygenase-1 expression in human cells through a mechanism independent of hypoxia-inducible factor-1alpha

Hypoxia-inducible factor (HIF)-1 is important for cellular homeostasis under hypoxia. Expression of haem oxygenase-1 (HO-1), an essential enzyme in haem catabolism, varies under hypoxia, depending on cell types. Here, we studied the role of HIF-1alpha, a component of HIF-1, in the regulation of HO-1 expression using three human cell lines: HeLa cervical cancer, and ARPE-19 and D407 retinal pigment epithelial cells. Under hypoxia (1% O(2)), the expression of HO-1 mRNA was decreased in HeLa cells, increased in D407 cells, and unchanged in ARPE-19 cells, while HIF-1alpha protein was accumulated in these cell lines. Thus, HIF-1alpha is unlikely to function as a key regulator for HO-1 expression under hypoxia. We then used ethyl-3,4-dihydroxybenzoate (EDHB), an inhibitor of prolyl hydroxylases, to accumulate HIF-1alpha protein under normoxia. Treatment with EDHB (250-500 microM) increased HIF-1alpha protein levels in HeLa and D407 cells, but not in ARPE-19 cells, whereas EDHB at lower concentrations (50-100 microM) consistently induced HO-1 mRNA expression (about 20-fold) in these three cell lines. Moreover, EDHB increased the HO-1 gene promoter activity via the enhancer that lacks a HIF-1-binding site. In conclusion, the signals evoked by hypoxia and after EDHB treatment differentially regulate HO-1 mRNA expression through HIF-1alpha-independent mechanisms.     

实验性肺纤维化大鼠发病过程中肺组织FIZZ1蛋白和mRNA表达的动态变化

为了探讨FIZZ1（found in inflammatory zone 1）在肺纤维化发病中的作用,应用博莱霉素（5mg／kg体重）气管内注入复制实聆性人鼠肺纤维化模犁,采用HE染色、Masson三联染色、羟脯氨酸含量测定、免疫组织化学染色、原位杂交等方法,观察实验性人鼠肺纤维化的发病过程及其肺组织中FIZZ1蛋白、mRNA表达水平的动态变化。结果显示：（1）实验性人鼠肺纤维化发病过程中,呈现舆型的肺泡炎（7d）、纤维组织增生（14～2ld）及稳定的肺纤维化（28d）等表现;（2）FIZZ1蛋白在正常肺组织表达较弱,存肺纤维化组7d时表达明显增强,14d时较7d时有所减弱,21及28d明显减弱;（3）FIZZ1 mRNA在正常肺组织巾表达较弱,在肺纤维化组7d时表达明显增强,14d时开始减弱,2l及28d明显减弱,但仍强于正常组。上述结果提示,FIZZ1蛋白和mRNA在实验性大鼠肺纤维化发病过程中呈现明显的动态变化,并可能参与了肺纤维化的发生。     

Transforming Growth Factor-β1 Induces Transdifferentiation of Fibroblasts into Myofibroblasts in Hypoxic Pulmonary Vascular Remodeling

The muscularization of non-muscular pulmonary arterioles is an important pathological feature of hypoxic pulmonary vascular remodeling. However, the origin of the cells involved in this process is still not well understood. The present study was undertaken to test the hypothesis that transforming growth factor-β1 （TGF-β1） can induce transdifferentiation of fibroblasts into myofibroblasts, which might play a key role in the muscularization of non-muscular pulmonary arterioles. It was found that mean pulmonary arterial pressure increased significantly after 7 d of hypoxia. Pulmonary artery remodeling index and fight ventricular hypertrophy became evident after 14 d of hypoxia. The distribution of nonmuscular, partially muscular, and muscular vessels was significantly different after 7 d of hypoxia. Immunocytochemistry results demonstrated that the expression of α-smooth muscle actin was increased in intra-acinar pulmonary arteries with increasing hypoxic time. TGF-β1 mRNA expression in pulmonary arterial walls was increased significantly after 14 d of hypoxia, but showed no obvious changes after 3 or 7 d of hypoxia. In pulmonary tunica adventitia and tunica media, TGF-β1 protein staining was poorly positive in control rats, but was markedly enhanced after 3 d of hypoxia, reaching its peak after 7 d of hypoxia. The myofibroblast phenotype was confirmed by electron microscopy, which revealed microfilaments and a well-developed rough endoplasmic reticulum. Taken together, our results suggested that TGF-β1 induces transdifferentiation of fibroblasts into myofibroblasts, which is important in hypoxic pulmonary vascular remodeling.     

Effects of perinatal exposure to hypoxia upon the pulmonary circulation of the adult rat

The hypothesis on Fetal and Infant Origins of Adult Disease proposes that an altered in utero environment may impair fetal development and physiological function, increasing susceptibility to disease in adulthood. Previous studies demonstrated that reduced fetal growth predisposes to adult cardiovascular diseases. Maternal smoking and high altitude are also linked to reduced fetal growth and adult disease, and both cause fetal hypoxia. We therefore wanted to determine whether fetal hypoxia produces alterations in the adult pulmonary vasculature. Body and ventricular weight, pulmonary arterial compliance and vasoreactivity to potassium chloride (KCl), prostaglandin F2alpha (PGF2alpha), acetylcholine (ACh) and sodium nitroprusside (SNP) were studied in adult rats exposed to 10 % hypoxia throughout the perinatal period, compared to age-matched controls. Rats exposed to perinatal hypoxia had reduced body weight (199+/-15 vs. 294+/-10 g, P<0.001), elevated right ventricular weight (70.3+/-8.8 vs. 51.4+/-1.2 mg/100 g, P<0.05), elevated left ventricular weight (281+/-27 vs. 232+/-5 mg/100 g, P<0.05), reduced pulmonary arterial compliance (35.2+/-2.0 vs. 46.4+/-2.4 microm/mN, P<0.05) and reduced maximal pulmonary vasoconstriction to KCl (1.74+/-0.14 vs. 2.63+/-0.31 mN/mm, P<0.01), and PGF2(2alpha) (1.40+/-0.14 vs. 2.47+/-0.44 mN/mm, P<0.05). Perinatal exposure to hypoxia had a profound effect upon the adult pulmonary circulation, which could predispose to cardiopulmonary diseases in adulthood.     

p38-MAPK信号通路在HHPH中的作用及三七总皂苷干预

目的:研究p38-MAPK信号通路在大鼠低O2高CO2性肺动脉高压(HHPH)发生发展中的动态变化;探讨三七总皂苷(PNS)防治低O2高CO2性肺动脉高压的机制。方法:复制慢性HHPH大鼠模型,分为正常组(N),低O2高CO23 d组(H3d)、1周组(H1w)、2周组(H2w)、4周组(H4w),及PNS治疗组(Hp),Hp组腹腔注射血塞通注射液(成分为PNS和生理盐水)。Western印迹法、免疫组织化学技术检测肺组织及肺血管P-p38、p38蛋白的表达。结果:①H1w、H2w、H4w和Hp组的WA/TA均高于N组(P均<0.05),但H3d组较N组增加不明显(P>0.05),Hp组WA/TA明显低于H4w组(P<0.05)。②肺组织P-p38蛋白在N组表达不明显,在H3d、H1w、H2w、H4w组均有高水平表达。③肺小动脉壁P-p38蛋白在N组和H3d组表达呈阴性或弱阳性,在H1w、H2w、H4w组有高水平表达,较N组差异有统计学意义(P<0.05)。④Hp组肺组织P-p38,肺小动脉壁P-p38蛋白表达较低O2高CO2组降低(P<0.05)。结论:p38-MAPK信号通路介导了大鼠HHPH的形成。PNS可减轻这一过程,其机制可能和PNS抑制P-p38表达有关。     

Intermedin/adrenomedullin 2及其受体在慢性低氧性肺动脉高压大鼠右心室的表达变化

本研究探讨了新发现的小分子生物活性肽intermedin／adrenomedullin 2（IMD／ADM2）及其受体在慢性低氧性肺动脉高压大鼠右心室中的变化和可能作用。用放射免疫分析法测定正常对照组和常压低氧4周组Sprague-Dawley大鼠血浆、右心室匀浆IMD／ADM2和肾上腺髓质素（adrenomednllin,ADM）蛋白水平;逆转录-多聚酶链反应法测定右心室IMD／ADM2、ADM及受体：降钙素受体样受体（calcitonin receptor-like receptor,CRLR）、受体活性修饰蛋白1,2,3（receptor activity modifying protein 1,2,3,RAMP1,RAMP2,RAMP3）mRNA表达。结果显示：低氧组平均肺动脉压、右心室与左心室加室间隔重量比[RV／（LV＋S）]显著高于对照组（均P〈0．01）;低氧组血浆和右心室组织匀浆ADM水平比对照组分别高1．26倍和1．68倍（P〈0．01）,IMD／ADM2水平则较对照组分别高0．90倍和1．19倍（P〈0．01）;与对照组相比,低氧组右心室IMD／ADM2、ADM mRNA表达均上调（P〈0．01）,RAMP2 mRNA表达增强（P〈0．05）,而两组间CRLR、RAMP1、RAMP3 mRNA的表达水平无显著性差异。结果表明,慢性低氧性肺动脉高压大鼠IMD／ADM2表达水平升高。     

缺氧诱导因子-1α在缺氧预处理预防心肌细胞损伤中的作用

本工作旨在研究缺氧预处理(hypoxic preconditioning,HPC)对于心肌细胞外信号调节激酶(extracellular signal-regulated proteinkinases,ERK)活性、缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)表达的影响,及其在缺氧复氧诱导心肌细胞损伤中的作用。通过在培养的SD乳鼠心肌细胞缺氧／复氧(H／R)模型上,观察HPC对于24h后H／R诱导心肌细胞损伤的影响,以台盼蓝排斥实验检测心肌细胞存活率、以TUNEL法检测细胞凋亡、并用荧光素染料Hoechst33258测定心肌细胞凋亡率：制备心肌细胞蛋白提取物,以磷酸化的ERK1／2抗体测定ERK1／2活性,以抗HIF-1α抗体检测HIF-1α的表达,并观察ERKs的上游激酶(MEK1／2)抑制剂PD98059对于HPC诱导的ERKs磷酸化、HIF-1α表达以及心肌细胞保护作用的影响,并分析细胞损伤与ERK1／2活性、HIF-1α表达量之间的相互关系。结果 显示缺氧复氧造成心肌细胞损伤,HPC可以增加心肌细胞H／R后存活率,降低凋亡率,并激活ERKll2,诱导HIF-1α表达：细胞凋亡与ERKs活性、HIF-1α表达量之间存在负相关,即ERKs活化、HIF-1α表达与预防细胞损伤有关：而ERKs活性与HIF-1α表达量之间存在正相关,ERKs的上游激酶MEK抑制剂PD98059可以消除HPC诱导的ERKs磷酸化、HIF-1α表达和心肌细胞保护作用。由此得出的结论是HPC可以提高乳鼠心肌细胞对于H／R的耐受性,其机制涉及ERKs介导的HIF-1α表达。     

Partial HIF-1alpha deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia

Chronic hypoxia depolarizes and reduces K+ current in pulmonary arterial smooth muscle cells (PASMCs). Our laboratory previously demonstrated that hypoxia-inducible factor-1 (HIF-1) contributed to the development of hypoxic pulmonary hypertension. In this study, electrophysiological parameters were measured in PASMCs isolated from intrapulmonary arteries of mice with one null allele at the Hif1a locus encoding HIF-1alpha [Hif1a(+/-)] and from their wild-type [Hif1a(+/+)] littermates after 3 wk in air or 10% O2. Hematocrit and right ventricular wall and left ventricle plus septum weights were measured. Capacitance, K+ current, and membrane potential were measured with whole cell patch clamp. Similar to our laboratory's previous results, hypoxia-induced right ventricular hypertrophy and polycythemia were blunted in Hif1a(+/-) mice. Hypoxia increased PASMC capacitance in Hif1a(+/+) mice but not in Hif1a(+/-) mice. Chronic hypoxia depolarized and reduced K+ current density in PASMCs from Hif1a(+/+) mice. In PASMCs from hypoxic Hif1a(+/-) mice, no reduction in K+ current density was observed, and depolarization was significantly blunted. Thus partial deficiency of HIF-1alpha is sufficient to impair hypoxia-induced depolarization, reduction of K+ current density, and PASMC hypertrophy.     

Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling

Chronic hypercapnia is commonly found in patients with severe hypoxic lung disease and is associated with a greater elevation of pulmonary arterial pressure than that due to hypoxia alone. We hypothesized that hypercapnia worsens hypoxic pulmonary hypertension by augmenting pulmonary vascular remodeling and hypoxic pulmonary vasoconstriction (HPV). Rats were exposed to chronic hypoxia [inspiratory O(2) fraction (FI(O(2))) = 0.10], chronic hypercapnia (inspiratory CO(2) fraction = 0.10), hypoxia-hypercapnia (FI(O(2)) = 0.10, inspiratory CO(2) fraction = 0.10), or room air. After 1 and 3 wk of exposure, muscularization of resistance blood vessels and hypoxia-induced hematocrit elevation were significantly inhibited in hypoxia-hypercapnia compared with hypoxia alone (P < 0.001, ANOVA). Right ventricular hypertrophy was reduced in hypoxia-hypercapnia compared with hypoxia at 3 wk (P < 0.001, ANOVA). In isolated, ventilated, blood-perfused lungs, basal pulmonary arterial pressure after 1 wk of exposure to hypoxia (20.1 +/- 1.8 mmHg) was significantly (P < 0.01, ANOVA) elevated compared with control conditions (12.1 +/- 0.1 mmHg) but was not altered in hypoxia-hypercapnia (13.5 +/- 0.9 mmHg) or hypercapnia (11.8 +/- 1.3 mmHg). HPV (FI(O(2)) = 0.03) was attenuated in hypoxia, hypoxia-hypercapnia, and hypercapnia compared with control (P < 0.05, ANOVA). Addition of N(omega)-nitro-L-arginine methyl ester (10(-4) M), which augmented HPV in control, hypoxia, and hypercapnia, significantly reduced HPV in hypoxia-hypercapnia. Chronic hypoxia caused impaired endothelium-dependent relaxation in isolated pulmonary arteries, but coexistent hypercapnia partially protected against this effect. These findings suggest that coexistent hypercapnia inhibits hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy, reduces HPV, and protects against hypoxia-induced impairment of endothelial function.