Atorvastatin attenuates involvement of RhoA/Rho-kinase pathway and NF-κB activation in hypoxic pulmonary hypertensive rats

Background Hypoxic pulmonary hypertension （HPH） contributes to the pathogenesis of cardiopulmonary diseases.Several lines of evidence indicate that the Rho A/Rho-kinase pathway play an important role in the progress of pulmonary hypertension.Stains have been shown exert numerous biological effects that are independent of their cholesterollowering property.We hypothesized that the Rho A/Rho-kinase pathway is involved in the pathogenesis of HPH,and that atorvastatin would attenuate involvement of the Rho A/Rho-kinase pathway in a HPH rat model.Methods Thirty-two Wistar rats were randomly divided into four groups：control group,hypoxic group,atovastatin group,and normal saline group.The control group was kept in a normoxia environment.The other groups were exposed to hypoxia for three weeks.Atovastatin was administered daily via a gastric gavage in the atovastatin group.We measured the mean pulmonary arterial pressure （mPAP）,the ratio of the right ventricular weight to the sum of the weights of the left heart ventricle and septum （RV/（LV＋S））,arteriole wall thickness/vascular external diameter （WT％）,vascular area/total vascular area （WA％）,expression of RhoA and phos-MYPT-1 protein in lung tissue,and NF-κB activation in pulmonary vascular smooth muscle cells.Results Compared with the control group,mPAP,RV/（LV＋S）,WT％,WA％,NF-κB activation,expression of RhoA,and phos-MYPT-1 were increased in the hypoxic and normal saline groups （P ＜0.05）.Compared with the hypoxic group,mPAP,RV/（LV＋S）,WT％,WA％,NF-κB activation,expression of RhoA,and phos-MYPT-1 were decreased in the atovastatin group （P ＜0.05）.Correlations between phos-MPTY-1 and mPAP,WA％,WT％,and NF-κB activation were all positive.Conclusions The Rho NRho-kinase pathway plays an important role in the development of HPH.Atorvastatin reversed HPH by inhibiting the activity of Rho A/Rho-kinase and NF-κB.

Inhibition of Expression of Hypoxia-inducible Factor-1α mRNA by Nitric Oxide in Hypoxic Pulmonary Hypertension Rats

In order to study the effect of nitric oxide (NO) on the expression of hypoxia inducible factor 1 alpha (HIF 1α) mRNA in hypoxic pulmonary hypertension (HPH) rats, 30 healthy male Wistar rats were randomly divided into normoxic control group, chronic hypoxic group and hypoxia plus L argine (L Arg) group. The animal model of HPH was developed. The mean pulmonary arterial pressure (mPAP) was measured by inserting a microcatheter into the pulmonary artery. The HIF 1α mRNA expression levels were detected by in situ hybridization (ISH) and semiquantitative RT PCR. It was found that after 14 days hypoxia, the mPAP in normoxic control group (17.6±2 7 mmHg,1 mmHg=0 133 kPa) was significantly lower than that in chronic hypoxic group(35.8±6.1 mmHg, t =0.2918, P <0.05) and mPAP in chronic hypoxic group was higher than that in hypoxia plus L argine group(24.4±3.8 mmHg, t =0.2563, P <0.05). ISH showed that the expression of HIF 1α mRNA in the intraacinar pulmonary arteriolae (IAPA) in normoxic control group (0.1076±0.0205) was markedly weaker than that in chronic hypoxic group (0.3317±0.0683, t =3.125, P <0.05) and that in chronic hypoxic group was stronger than that in hypoxia plus L argine group (0.1928±0.0381, t =2.844, P <0.05). RT PCR showed that the content of HIF 1α mRNA in chronic hypoxic group (2.5395±0.6449) was 2.16 times and 1.75 times higher than that in normoxic control group (1.1781±0.3628) and hypoxia plus L argine group (1.4511±0.3981), respectively. It is concluded that NO can reduce the mPAP by the inhibition of the expression of HIF 1α mRNA, which may be one of the mechanisms through which NO affects the pathogenesis of HPH.

Effect of Ligusticum Chuanxiong on Hypoxic Pulmonary Hypertension in Rats and Its Mechanism

Objective: To explore the mechanism of Chuanxiong in alleviating hypoxic pulmonary hypertension in rats by inhibiting pulmonary vascular remodeling. Methods: Thirty healthy and clean male SD rats weighing (180 - 220) g were randomly divided into three groups (n = 10): normoxia group (n), hypoxia group (H) and Chuanxiong group (L). Group N was fed in normoxic environment, and the other two groups were fed in hypoxic (9% 11% O2) environment for 4 weeks, 8 h/D, 6 days a week. Rats in group L were gavaged with Ligusticum chuanxiong solution diluted with normal saline at the concentration of 300 mg/kg, and rats in group H were gavaged with equal volume of normal saline. After 4 weeks, the mean pulmonary artery pressure was measured. After pulmonary perfusion, the right ventricular free wall and left ventricle plus ventricular septum were taken to measure the right ventricular hypertrophy index. The changes of pulmonary morphology and ultrastructure were observed under light microscope. Results: Compared with group n, the average pulmonary artery pressure and right ventricular hypertrophy index in the other two groups increased, and the thickening of pulmonary vascular wall was obvious under microscope (P Conclusion: Ligusticum chuanxiong can relieve pulmonary artery pressure in rats by inhibiting pulmonary vascular remodeling.

Reversal of Acute Hypoxic Pulmonary Hypertension with Inhalation of Nitric Oxide.

The effect of inhalation of nitric oxide（NO）gas on acute hypoxic pulmonary hypertension was studied.Eighteen mongrel dogs were divided into two groups; hypoxic control group（FIO=11％， n=10）and NO inhalation gloup（FIO=11％，NO inspiratory concentration=44ppm，n=8）.

The inhibitory effects of Radix Astragali on hypoxic pulmonary hypertension of rats

Objective To observe the inhibitory effects of Radix Astragali (RA) on hypoxic structural remodeling of intraacinar pulmonary arteries (IAPA) and pulmonary hypertension (PHT). Methods Sixty rats were divided into three groups: hypoxia group, hypoxia + RA group and normal control group. The rats of hypoxia group and hypoxia+RA group were fed in hypoxic environment under normal atmospheric pressure (10% O 2, 10 h/day). On the 15 th and 30 th day of hypoxia, right ventricular systolic pressure (RVSP) and right ventricle hypertrophy index (RVHI) were measured and pulmonary vessel changes were studied under light and electron microscope and with morphometric analysis. Results Compared with the result of hypoxia+RA group, RA could relieve IAPA wall cell injuries and dilate the constricted IAPA induced by hypoxia . RA could also inhibit hypertrophic changes in the tunica media and proliferation of adventitial cells of the IAPA and muscularization of nonmuscular arteries. Conclusion By preserving the IAPA wall cells and dilating IAPA, RA may play an important role in inhibiting the remodeling of IAPA and preventing PHT.