Abstract 12990: High Fat Diet Delays Reverse Remodeling of Pulmonary Artery in Hypoxia-induced Pulmonary Hypertension Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Koichi Sugimoto ◽  
Tetsuro Yokokawa ◽  
Tomofumi Misaka ◽  
Sayoko Yokokawa ◽  
Kazuhiko Nakazato ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
High Fat Diet ◽  
Metabolic Disorder ◽  
Density Lipoprotein ◽  
Reverse Remodeling ◽  
High Fat ◽  
Pulmonary Artery Smooth Muscle

Background: Previous studies suggest the association of metabolic disorder with pulmonary hypertension. Elevated pulmonary artery pressure induced by hypoxia in mice returns to normal when they are placed back in normoxia. In this study, we investigated the effect of high-fat diet (HFD) on pulmonary artery pressure and reverse remodeling of pulmonary artery in mouse model of hypoxia-induced pulmonary hypertension. Methods: We used the female C57/Bl6 mice at the age of 8 weeks. After exposed to hypoxia (10% oxygen for 4 weeks) for induction of pulmonary hypertension, mice were returned to normoxic condition and fed HFD or low-fat diet (LFD) for 12 weeks. Results: The body weight (BW), glucose, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C), but not triglyceride (TG) were significantly increased in HFD group (36.9±5.1 vs. 24.0±1.4 g [BW], P<0.05; 404.2±55.1 vs. 326.5±8.7 mg/dl [glucose], P<0.05; 10.2±3.6 vs. 7.5±0.9 mg/dl [LDL-C], P<0.05; 47.2±10.0 vs. 30.9±8.7 mg/dl [HDL-C], P<0.05 and 40.0±21.1 vs. 53.4±12.9 mg/dl [TG], P=0.09). The right ventricular systolic pressure (RVSP) measured by a micro-manometer catheter and the Fulton index in HFD group were significantly higher than those in LFD group (23.8±2.3 vs. 19.3±2.9 mmHg [RVSP], P<0.05; 0.30±0.06 vs. 0.25±0.04 [Fulton index], P<0.05, respectively). The medial smooth muscle area (expressed as a percentage of the external area of the vessel) was larger in HFD group (40.1±5.3 vs. 34.5±3.1%, P<0.05). In addition, the levels of active caspase-3 detected by Western blotting was lower in HFD group than in LFD group. TUNEL staining revealed that the apoptosis of pulmonary artery smooth muscle cells was suppressed in HFD group. Conclusion: Our results suggest that metabolic disorder attenuates pulmonary artery reverse remodeling, at least in part, by suppressing apoptosis of pulmonary artery smooth muscle cells when hypoxia-induced pulmonary hypertension mice were returned to normoxia.

High-Fat Diet Attenuates the Improvement of Hypoxia-induced Pulmonary Artery Hypertension in Mice During Reoxygenation.

2021 ◽  
Author(s):  
Koichi Sugimoto ◽  
Tetsuro Yokokawa ◽  
Tomofumi Misaka ◽  
Takashi Kaneshiro ◽  
Akiomi Yoshihisa ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Pulmonary Artery Pressure ◽  
High Fat Diet ◽  
Metabolic Disorder ◽  
Pulmonary Arteries ◽  
Reverse Remodeling ◽  
High Fat ◽  
Artery Pressure

Abstract Background: It has been widely recognized that metabolic disorder is associated with pulmonary hypertension. It is known that elevated pulmonary artery pressure induced by hypoxia in mice returns to normal pressure under reoxygenation. However, it is still unclear how metabolic disorder affects the reverse remodeling of pulmonary arteries. In this study, we investigated the effects of a high-fat diet (HFD) on the decrease of pulmonary artery pressure and reverse remodeling of pulmonary arteries in mice with hypoxia-induced pulmonary hypertension.Methods: We used female C57/Bl6 mice aged 8 weeks. After the mice were exposed to hypoxia (10% oxygen for 4 weeks) for induction of pulmonary hypertension. Then, they were returned to normoxic conditions and randomized into a normal diet (ND) group and a HFD group. Both groups were fed their respective diets for 12 weeks.Results: The right ventricular systolic pressure measured by a micro-manometer catheter and the Fulton index were significantly higher in the HFD group than in the ND group at 12 weeks after reoxygenation. The medial smooth muscle area was larger in the HFD group. Caspase 3 activity in lung tissue of the HFD group was decreased, and an apoptosis of pulmonary smooth muscle cells was suppressed after reoxygenation. Moreover, the expression levels of peroxisome proliferator-activated receptor-γ and apelin were lower in the HFD group than in the LFD group.Conclusion: Our results suggest the metabolic disorder may suppress pulmonary artery reverse remodeling in mice with hypoxia-induced pulmonary hypertension under reoxygenation.

scholarly journals High-fat diet attenuates the improvement of hypoxia-induced pulmonary hypertension in mice during reoxygenation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Koichi Sugimoto ◽  
Tetsuro Yokokawa ◽  
Tomofumi Misaka ◽  
Takashi Kaneshiro ◽  
Akiomi Yoshihisa ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Pulmonary Artery Pressure ◽  
High Fat Diet ◽  
Metabolic Disorder ◽  
Pulmonary Arteries ◽  
Reverse Remodeling ◽  
High Fat ◽  
Artery Pressure

Abstract Background It is widely recognized that metabolic disorder is associated with pulmonary hypertension (PH). It is known that hypoxia-induced elevated pulmonary artery pressure in mice returns to normal pressure during reoxygenation. However, it is still unclear how metabolic disorder affects the reverse remodeling of pulmonary arteries. In this study, we investigated the effects of high-fat diet (HFD) on the decrease in pulmonary artery pressure and reverse remodeling of pulmonary arteries in mice with hypoxia-induced PH. Methods We used female C57BL/6 mice aged 8 weeks. After being exposed to hypoxia (10% oxygen for four weeks) to induce PH, the mice were returned to normoxic conditions and randomized into a normal diet (ND) group and HFD group. Both groups were fed with their respective diets for 12 weeks. Results The Fulton index and right ventricular systolic pressure measured by a micro-manometer catheter were significantly higher in the HFD group than in the ND group at 12 weeks after reoxygenation. The medial smooth muscle area was larger in the HFD group. Caspase-3 activity in the lung tissue of the HFD group was decreased, and the apoptosis of pulmonary smooth muscle cells was suppressed after reoxygenation. Moreover, the expression levels of peroxisome proliferator-activated receptor-γ and apelin were lower in the HFD group than in the ND group. Conclusions The results suggest that metabolic disorder may suppress pulmonary artery reverse remodeling in mice with hypoxia-induced PH during reoxygenation.

scholarly journals Untargeted Metabolic Profiling Cell-Based Approach of Pulmonary Artery Smooth Muscle Cells in Response to High Glucose and the Effect of the Antioxidant Vitamins D and E

Metabolites ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 87 ◽  
Author(s):  
Abdulwahab Alamri ◽  
Abdulhadi Burzangi ◽  
Paul Coats ◽  
David Watson
Keyword(s):  
Reactive Oxygen Species ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
High Glucose ◽  
Muscle Cells ◽  
Oxygen Species ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

Pulmonary arterial hypertension (PAH) is a multi-factorial disease characterized by the hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Excessive reactive oxygen species (ROS) formation resulted in alterations of the structure and function of pulmonary arterial walls, leading to right ventricular failure and death. Diabetes mellitus has not yet been implicated in pulmonary hypertension. However, recently, variable studies have shown that diabetes is correlated with pulmonary hypertension pathobiology, which could participate in the modification of pulmonary artery muscles. The metabolomic changes in PASMCs were studied in response to 25 mM of D-glucose (high glucose, or HG) in order to establish a diabetic-like condition in an in vitro setting, and compared to five mM of D-glucose (normal glucose, or LG). The effect of co-culturing these cells with an ideal blood serum concentration of cholecalciferol-D3 and tocopherol was also examined. The current study aimed to examine the role of hyperglycemia in pulmonary arterial hypertension by the quantification and detection of the metabolomic alteration of smooth muscle cells in high-glucose conditions. Untargeted metabolomics was carried out using hydrophilic interaction liquid chromatography and high-resolution mass spectrometry. Cell proliferation was assessed by cell viability and the [3H] thymidine incorporation assay, and the redox state within the cells was examined by measuring reactive oxygen species (ROS) generation. The results demonstrated that PASMCs in high glucose (HG) grew, proliferated faster, and generated higher levels of superoxide anion (O2·−) and hydrogen peroxide (H2O2). The metabolomics of cells cultured in HG showed that the carbohydrate pathway, especially that of the upper glycolytic pathway metabolites, was influenced by the activation of the oxidation pathway: the pentose phosphate pathway (PPP). The amount of amino acids such as aspartate and glutathione reduced via HG, while glutathione disulfide, N6-Acetyl-L-lysine, glutamate, and 5-aminopentanoate increased. Lipids either as fatty acids or glycerophospholipids were downregulated in most of the metabolites, with the exception of docosatetraenoic acid and PG (16:0/16:1(9Z)). Purine and pyrimidine were influenced by hyperglycaemia following PPP oxidation. The results in addition showed that cells exposed to 25 mM of glucose were oxidatively stressed comparing to those cultured in five mM of glucose. Cholecalciferol (D3, or vitamin D) and tocopherol (vitamin E) were shown to restore the redox status of many metabolic pathways.

scholarly journals LRP1 promotes synthetic phenotype of pulmonary artery smooth muscle cells in pulmonary hypertension

2019 ◽  
Vol 1865 (6) ◽  
pp. 1604-1616 ◽  
Author(s):  
Marius M. Zucker ◽  
Lukasz Wujak ◽  
Anna Gungl ◽  
Miroslava Didiasova ◽  
Djuro Kosanovic ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Pulmonary Artery Smooth Muscle ◽  
Synthetic Phenotype

scholarly journals Regulation of soluble guanylyl cyclase-α1 expression in chronic hypoxia-induced pulmonary hypertension: role of NFATc3 and HuR

2009 ◽  
Vol 297 (3) ◽  
pp. L475-L486 ◽  
Author(s):  
Sergio de Frutos ◽  
Carlos H. Nitta ◽  
Elizabeth Caldwell ◽  
Jessica Friedman ◽  
Laura V. González Bosc
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Guanylyl Cyclase ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Soluble Guanylyl Cyclase ◽  
Muscle Cells ◽  
Pulmonary Artery Smooth Muscle

The nitric oxide/soluble guanylyl cyclase (sGC) signal transduction pathway plays an important role in smooth muscle relaxation and phenotypic regulation. However, the transcriptional regulation of sGC gene expression is largely unknown. It has been shown that sGC expression increases in pulmonary arteries from chronic hypoxia-induced pulmonary hypertensive animals. Since the transcription factor NFATc3 is required for the upregulation of the smooth muscle hypertrophic/differentiation marker α-actin in pulmonary artery smooth muscle cells from chronically hypoxic mice, we hypothesized that NFATc3 is required for the regulation of sGC-α1 expression during chronic hypoxia. Exposure to chronic hypoxia for 2 days induced a decrease in sGC-α1 expression in mouse pulmonary arteries. This reduction was independent of NFATc3 but mediated by nuclear accumulation of the mRNA-stabilizing protein human antigen R (HuR). Consistent with our hypothesis, chronic hypoxia (21 days) upregulated pulmonary artery sGC-α1 expression, bringing it back to the level of the normoxic controls. This response was prevented in NFATc3 knockout and cyclosporin (calcineurin/NFATc inhibitor)-treated mice. Furthermore, we identified effective binding sites for NFATc in the mouse sGC-α1 promoter. Activation of NFATc3 increased sGC-α1 promoter activity in human embryonic derived kidney cells, rat aortic-derived smooth muscle cells, and human pulmonary artery smooth muscle cells. Our results suggest that NFATc3 and HuR are important regulators of sGC-α1 expression in pulmonary vascular smooth muscle cells during chronic hypoxia-induced pulmonary hypertension.

scholarly journals PPARγ regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-κB

2010 ◽  
Vol 299 (4) ◽  
pp. L559-L566 ◽  
Author(s):  
Xianghuai Lu ◽  
Tamara C. Murphy ◽  
Mark S. Nanes ◽  
C. Michael Hart
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Promoter Activity ◽  
Vascular Wall ◽  
Pulmonary Artery Smooth Muscle ◽  
Human Pulmonary Artery ◽  
Stimulation Of

NADPH oxidases are a major source of superoxide production in the vasculature. The constitutively active Nox4 subunit, which is selectively upregulated in the lungs of human subjects and experimental animals with pulmonary hypertension, is highly expressed in vascular wall cells. We demonstrated that rosiglitazone, a synthetic agonist of the peroxisome proliferator-activated receptor-γ (PPARγ), attenuated hypoxia-induced pulmonary hypertension, vascular remodeling, Nox4 induction, and reactive oxygen species generation in the mouse lung. The current study examined the molecular mechanisms involved in PPARγ-regulated, hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells (HPASMC). Exposing HPASMC to 1% oxygen for 72 h increased Nox4 gene expression and H2O2 production, both of which were reduced by treatment with rosiglitazone during the last 24 h of hypoxia exposure or by treatment with small interfering RNA (siRNA) to Nox4. Hypoxia also increased HPASMC proliferation as well as the activity of a Nox4 promoter luciferase reporter, and these increases were attenuated by rosiglitazone. Chromatin immunoprecipitation assays demonstrated that hypoxia increased binding of the NF-κB subunit, p65, to the Nox4 promoter and that binding was attenuated by rosiglitazone treatment. The role of NF-κB in Nox4 regulation was further supported by demonstrating that overexpression of p65 stimulated Nox4 promoter activity, whereas siRNA to p50 or p65 attenuated hypoxic stimulation of Nox4 promoter activity. These results provide novel evidence for NF-κB-mediated stimulation of Nox4 expression in HPASMC that can be negatively regulated by PPARγ. These data provide new insights into potential mechanisms by which PPARγ activation inhibits Nox4 upregulation and the proliferation of cells in the pulmonary vascular wall to ameliorate pulmonary hypertension and vascular remodeling in response to hypoxia.

scholarly journals Analysis of hypoxia-induced noncoding RNAs reveals metastasis-associated lung adenocarcinoma transcript 1 as an important regulator of vascular smooth muscle cell proliferation

2017 ◽  
Vol 242 (5) ◽  
pp. 487-496 ◽  
Author(s):  
Matthias Brock ◽  
Claudio Schuoler ◽  
Caroline Leuenberger ◽  
Carlo Bühlmann ◽  
Thomas J Haider ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Lung Adenocarcinoma ◽  
Noncoding Rnas ◽  
Muscle Cells ◽  
Heart Hypertrophy ◽  
Pulmonary Artery Smooth Muscle ◽  
Human Pulmonary Artery

Vascular remodeling, a pathogenic hallmark in pulmonary hypertension, is mainly driven by a dysbalance between proliferation and apoptosis of human pulmonary artery smooth muscle cells. It has previously been shown that microRNAs are involved in the pathogenesis of pulmonary hypertension. However, the role of long noncoding RNAs has not been evaluated. long noncoding RNA expression was quantified in human pulmonary artery smooth muscle cells using PCR arrays and quantitative PCR. Knockdown of genes was performed by transfection of siRNA or GapmeR. Proliferation and migration were measured using BrdU incorporation and wound healing assays. The mouse model of hypoxia-induced PH was used to determine the physiological meaning of identified long noncoding RNAs. The expression of 84 selected long noncoding RNAs was assessed in hypoxic human pulmonary artery smooth muscle cells and the levels of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were significantly increased. Depletion of hypoxia-inducible factor 1α abolished the hypoxia-induced upregulation of metastasis-associated lung adenocarcinoma transcript 1 expression. Silencing of MALAT1 significantly decreased proliferation and migration of human pulmonary artery smooth muscle cells. In vivo, MALAT1 expression was significantly increased in lungs of hypoxic mice. Of note, targeting of MALAT1 by GapmeR ameliorated heart hypertrophy in mice with pulmonary hypertension. This is the first report on functional characterization of MALAT1 in the pulmonary vasculature. Our data provide evidence that MALAT1 expression is significantly increased by hypoxia, probably by hypoxia-inducible factor 1α. Intervention experiments confirmed that MALAT1 regulates the proliferative phenotype of smooth muscle cells and silencing of MALAT1 reduced heart hypertrophy in mice with pulmonary hypertension. These data indicate a potential role of MALAT1 in the pathogenesis of pulmonary hypertension. Impact statement Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA that mediates several biological processes. In the context of vascular biology, MALAT1 has been shown to be inducible by hypoxia and to control cell proliferation. These processes are of major importance for the pathophysiology of hypoxia-induced pulmonary hypertension (PH). Until now, the physiological role of MALAT1 in PH remains unclear. By using smooth muscle cells and by employing an established PH mouse model, we provide evidence that hypoxia induces MALAT1 expression. Moreover, depletion of MALAT1 inhibited migration and proliferation of smooth muscle cells, probably by the induction of cyclin-dependent kinase inhibitors. Of note, MALAT1 was significantly increased in mice exposed to hypoxia and silencing of MALAT1 ameliorated heart hypertrophy in mice with hypoxia-induced PH. Since vascular remodeling and right heart failure as a consequence of pulmonary pressure overload is a major problem in PH, these data have implications for our pathogenetic understanding.

Sign in / Sign up

Export Citation Format

Share Document