Activation of PPAR-γ ameliorates pulmonary arterial hypertension via inducing heme oxygenase-1 and p21WAF1: An in vivo study in rats

Elevated levels of norepinephrine (NE) occur in pulmonary arterial hypertension (PAH) and are determined, in part, by the activity of catechol- O -methyltransferase (COMT). COMT degrades catecholamines, is negatively regulated by calcium, and is expressed by pulmonary artery endothelial cells (PAEC). As hyperaldosteronism occurs in PAH and aldosterone (ALDO) influences calcium levels, we hypothesized that ALDO decreases COMT activity to increase NE levels in PAH. Accordingly, human PAEC were treated with ALDO (10 -7 mol/L), a level that is achieved clinically in PAH, for up to 72 h. Compared to vehicle-treated PAEC, ALDO decreased COMT activity by 59.2 ± 6.2% (p<0.01) to increase NE levels in the medium (122.4 ± 11.8 vs. 210.7 ± 15.5 pg/mL/mg protein, p<0.01). This occurred as a result of an ALDO-mediated decrease in COMT protein expression by 52.6 ± 9.3% (p<0.01) as well as an increase in intracellular calcium levels (102.9 ± 21.0 vs. 167.7 ± 17.8 nmol/L, p<0.05) to inhibit activity. These effects were abrogated by coincubation with spironolactone. To determine the in vivo relevance of these findings, COMT was examined in the rat monocrotaline model of PAH with confirmed hyperALDO. COMT was decreased (47.6 ± 10.2 %control, p<0.05) in remodeled pulmonary arterioles with a concomitant increase in lung NE levels (432.8 ± 44.5 vs. 899.7 ± 34.2 pg/mL, p<0.01) compared to control rats. In the porcine pulmonary vein banding model of pulmonary hypertension (PH-pigs) with elevated mean pulmonary artery pressure (15[13-15] vs. 35[27-43], p<0.01) and pulmonary vascular resistance (PVR) index (1.97[1.74-2.28] vs. 5.78[2.61-8.75], p <0.05), ALDO levels were also increased (27.1 ± 5.1 vs. 60.8 ± 10.6 pg/mL, p<0.03) in advance of right heart failure as compared to sham controls. PH-pigs demonstrated a 48.3 ± 9.9% (p<0.02) decrease in pulmonary vascular COMT expression and an increase in NE levels (114.6 ± 20.2 vs. 1,622.6 ± 489.2 pg/mL, p<0.02) that correlated positively with ALDO levels (R 2 =0.58, p<0.02). These findings were confirmed in patients with PAH. Together, these data indicate that there is crosstalk in the pulmonary vasculature between ALDO and the sympathetic nervous system to regulate NE levels in PAH, and thus, have implications for therapeutic interventions.

Download Full-text

Abstract 3570: A Critical and Novel Role of Nogo (Neurite Outgrowth Inhibitor) in Pulmonary Arterial Hypertension

Circulation ◽

10.1161/circ.118.suppl_18.s_446-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Gopinath Sutendra ◽

Sebastien Bonnet ◽

Paulette Wright ◽

Peter Dromparis ◽

Alois Haromy ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Nuclear Translocation ◽

Pulmonary Arteries ◽

Over Expression ◽

Nfat Activation ◽

Pulmonary Arterial ◽

Systemic Arteries

Nogo was first identified as an inhibitor of neuronal axonal regeneration. Recently, Nogo-B was implicated in the proliferative and anti-apoptotic remodeling in systemic arteries; reduced Nogo-B expression was seen in remodeled mouse femoral arteries following injury. Pulmonary arterial hypertension (PAH) is also characterized by proliferative/anti-apoptotic remodeling in pulmonary arteries (PA), sparing systemic vessels. PAH PA smooth muscle cells (PASMC) are characterized by mitochondrial hyperpolarization (increased ΔΨm), decreased production of reactive oxygen species (ROS) (suppressing mitochondria-dependent apoptosis), down-regulation of Kv1.5 and activation of the transcription factor NFAT (promoting contraction and proliferation). We found that in contrast to systemic vessels, Nogo-B expression is significantly increased in vivo and in vitro in PAs and PASMCs from patients (n=6) and mice (n=42) with PAH, compared to normals. We hypothesized that Nogo is involved in the pathogenesis of PAH . Nogo −/− mice (n=7) had a normal phenotype and, in contrast to Nogo +/+ , did not develop chronic hypoxia (CH)-induced PAH assessed invasively (catheterization, RV/LV+Septum) and non-invasively (pulmonary artery acceleration time and treadmill performance) (n=7, Table ). CH- Nogo +/+ PASMC had the expected increase in ΔΨm (measured by TMRM), decreased ROS (MitoSOX), increased [Ca ++ ] i (FLUO3), decreased Kv1.5 (immunohistochemistry) and NFAT activation (nuclear translocation). None of these changes occurred in CH- Nogo −/− PASMC while all were induced in normoxic Nogo +/+ PASMC by adenoviral over-expression of Nogo-B . Heterozygote CH- Nogo +/− (n=7) values were between Nogo −/− and Nogo +/+ suggesting a gene dose-dependent effect. Nogo is over-expressed in human and rodent PAH and induces critical features of the PAH phenotype. Nogo targeting might represent a novel and selective therapeutic strategy for PAH. Table

Download Full-text

In Vivo Interactions With Serotonin And Bone Morphogenetic Protein Receptor 2 Deficiency In The Development Of Pulmonary Arterial Hypertension

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a6312 ◽

2010 ◽

Author(s):

Neil A. MacRitchie ◽

Yvonne Dempsie ◽

Margaret Nilsen ◽

Nicholas W. Morrell ◽

Margaret R. MacLean

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Bone Morphogenetic Protein ◽

Bone Morphogenetic Protein Receptor ◽

Protein Receptor ◽

Morphogenetic Protein ◽

Pulmonary Arterial

Download Full-text

Apple polyphenol relieves hypoxia-induced pulmonary arterial hypertension via pulmonary endothelium protection and smooth muscle relaxation: In vivo and in vitro studies

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2018.08.080 ◽

2018 ◽

Vol 107 ◽

pp. 937-944 ◽

Cited By ~ 8

Author(s):

Chunyan Hua ◽

Jie Zhao ◽

Heng Wang ◽

Fangzheng Chen ◽

Hanyan Meng ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Muscle Relaxation ◽

In Vitro Studies ◽

Smooth Muscle Relaxation ◽

Pulmonary Endothelium ◽

Pulmonary Arterial

Download Full-text

BMPR2‐expressing bone marrow‐derived endothelial‐like progenitor cells alleviate pulmonary arterial hypertension in vivo

Respirology ◽

10.1111/resp.13552 ◽

2019 ◽

Vol 24 (11) ◽

pp. 1095-1103 ◽

Cited By ~ 8

Author(s):

Rebecca L. Harper ◽

Suzanne Maiolo ◽

Rebekah J. Ward ◽

Jemma Seyfang ◽

Michaelia P. Cockshell ◽

...

Keyword(s):

Bone Marrow ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Progenitor Cells ◽

Pulmonary Arterial

Download Full-text

Function of Adipose-Derived Mesenchymal Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension through miR-191 via Regulation of BMPR2

BioMed Research International ◽

10.1155/2019/2858750 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Caixin Zhang ◽

Pengbo Wang ◽

Anaz Mohammed ◽

Zhewen Zhou ◽

Shuwen Zhang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Underlying Mechanism ◽

Treated Group ◽

Therapeutic Strategies ◽

Protective Effects ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a serious condition. However, prevailing therapeutic strategies are not effective enough to treat PAH. Therefore, finding an effective therapy is clearly warranted. Adipose-derived mesenchymal stem cells (ASCs) and ASCs-derived exosomes (ASCs-Exos) exert protective effects in PAH, but the underlying mechanism remains unclear. Using a coculture of ASCs and monocrotaline pyrrole (MCTP)-treated human pulmonary artery endothelial cells (HPAECs), we demonstrated that ASCs increased cell proliferation in MCTP-treated HPAECs. Results showed that ASCs-Exos improved proliferation of both control HPAECs and MCTP-treated HPAECs. In addition, by transfecting ASCs with antagomir we observed that low exosomal miR-191 expression inhibited HPAECs proliferation whereas the agomir improved. Similar results were observed in vivo using a monocrotaline (MCT)-induced PAH rat model following ASCs transplantation. And ASCs transplantation attenuated MCT-induced PAH albeit less than the antagomir treated group. Finally, we found that miR-191 repressed the expression of bone morphogenetic protein receptor 2 (BMPR2) in HPAECs and PAH rats. Thus, we conjectured that miR-191, in ASCs and ASCs-Exos, plays an important role in PAH via regulation of BMPR2. These findings are expected to contribute to promising therapeutic strategies for treating PAH in the future.

Download Full-text

LncRNA-SMILR modulates RhoA/ROCK signaling by targeting miR-141 to regulate vascular remodeling in pulmonary arterial hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00717.2019 ◽

2020 ◽

Vol 319 (2) ◽

pp. H377-H391 ◽

Cited By ~ 1

Author(s):

Si Lei ◽

Fei Peng ◽

Mei-Lei Li ◽

Wen-Bing Duan ◽

Cai-Qin Peng ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Long Noncoding Rna ◽

Vascular Remodeling ◽

Noncoding Rna ◽

In Vivo Models ◽

Pulmonary Arterial

Smooth muscle-enriched long noncoding RNA (SMILR), as a long noncoding RNA (lncRNA), was increased in pulmonary arterial hypertension (PAH) patients and in vitro and in vivo models. SMILR activated RhoA/ROCK signaling by targeting miR-141 to disinhibit its downstream target RhoA. SMILR knockdown or miR-141 overexpression inhibited hypoxia-induced cell proliferation and migration via repressing RhoA/ROCK signaling in pulmonary arterial smooth muscle cells (PASMCs), which was confirmed in vivo experiments that knockdown of SMILR inhibited vascular remodeling and alleviated PAH in rats. SMILR may be a promising and novel therapeutic target for the treatment and drug development of PAH.

Download Full-text