scholarly journals Peroxisome proliferator activated receptor-γ-Rho-kinase interactions contribute to vascular remodeling after chronic intrauterine pulmonary hypertension

2014 ◽  
Vol 306 (3) ◽  
pp. L299-L308 ◽  
Author(s):  
Jason Gien ◽  
Nancy Tseng ◽  
Gregory Seedorf ◽  
Gates Roe ◽  
Steven H. Abman
Keyword(s):  
Pulmonary Hypertension ◽  
Protein Expression ◽  
Vascular Remodeling ◽  
Rho Kinase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Counts ◽  
Expression Activity ◽  
Rock Inhibition ◽  
Rock Activity

Peroxisome proliferator-activated receptor-γ (PPARγ) and Rho-kinase (ROCK) regulate smooth muscle cell (SMC) proliferation and contribute to vascular remodeling in adult pulmonary hypertension. Whether these pathways interact to contribute to the development of vascular remodeling in persistent pulmonary hypertension of the newborn (PPHN) remains unknown. We hypothesized that ROCK-PPARγ interactions increase SMC proliferation resulting in vascular remodeling in experimental PPHN. Pulmonary artery SMCs (PASMCs) were harvested from fetal sheep after partial ligation of the ductus arteriosus in utero (PPHN) and controls. Cell counts were performed daily for 5 days with or without PPARγ agonists and ROCK inhibition. PPARγ and ROCK protein expression/activity were measured by Western blot in normal and PPHN PASMCs. We assessed PPARγ-ROCK interactions by studying the effect of ROCK activation on PPARγ activity and PPARγ inhibition (siRNA) on ROCK activity and PASMC proliferation. At baseline, PPHN PASMC cell number was increased by 38% above controls on day 5. ROCK protein expression/activity were increased by 25 and 34% and PPARγ protein/activity decreased by 40 and 50% in PPHN PASMC. ROCK inhibition and PPARγ activation restored PPHN PASMC growth to normal values. ROCK inhibition increased PPARγ activity by 50% in PPHN PASMC, restoring PPARγ activity to normal. In normal PASMCs, ROCK activation decreased PPARγ activity and PPARγ inhibition increased ROCK activity and cell proliferation, resulting in a PPHN hyperproliferative PASMC phenotype. PPARγ-ROCK interactions regulate SMC proliferation and contribute to increased PPHN PASMC proliferation and vascular remodeling in PPHN. Restoring normal PPARγ-ROCK signaling may prevent vascular remodeling and improve outcomes in PPHN.

scholarly journals Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs

2016 ◽  
Vol 311 (3) ◽  
pp. C482-C497 ◽  
Author(s):  
Jun Zhang ◽  
Wenju Lu ◽  
Yuqin Chen ◽  
Qian Jiang ◽  
Kai Yang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Transient Receptor Potential ◽  
Hypoxia Inducible Factor ◽  
Pulmonary Arteries ◽  
Receptor Potential ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Canonical Transient Receptor Potential ◽  
Transient Receptor

The ubiquitin-proteasome system is considered to be the key regulator of protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor approved by the US Food and Drug Administration for treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ treatment was reported to inhibit right ventricular hypertrophy and vascular remodeling in hypoxia-exposed and monocrotaline-injected rats. However, the underlying mechanisms remain poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca2+ concentration ([Ca2+]i) and store-operated Ca2+ entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) are involved in pulmonary vascular remodeling. In this study we aim to determine whether BTZ attenuates the hypoxia-induced elevation of [Ca2+] in PASMCs and the signaling pathway involved in this mechanism. Our results showed that 1) in hypoxia- and monocrotaline-induced rat pulmonary hypertension (PH) models, BTZ markedly attenuated the development and progression of PH, 2) BTZ inhibited the hypoxia-induced increase in cell proliferation, basal [Ca2+]i, and SOCE in PASMCs, and 3) BTZ significantly normalized the hypoxia-upregulated expression of hypoxia-inducible factor-1α, bone morphogenetic protein 4, canonical transient receptor potential isoforms 1 and 6, and the hypoxia-downregulated expression of peroxisome proliferator-activated receptor-γ in rat distal pulmonary arteries and PASMCs. These results indicate that BTZ exerts its protective role in the development of PH potentially by inhibiting the canonical transient receptor potential-SOCE-[Ca2+]i signaling axis in PASMCs.

scholarly journals Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone

2008 ◽  
Vol 295 (1) ◽  
pp. L71-L78 ◽  
Author(s):  
Noriyuki Homma ◽  
Tetsutaro Nagaoka ◽  
Vijaya Karoor ◽  
Masatoshi Imamura ◽  
Laimute Taraseviciene-Stewart ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Protein Expression ◽  
Vascular Remodeling ◽  
Rho Kinase ◽  
Related Protein ◽  
Pulmonary Vascular Remodeling ◽  
Naturally Occurring ◽  
Dhea Treatment ◽  
Induced Changes

RhoA/Rho kinase (ROCK) signaling plays a key role in the pathogenesis of experimental pulmonary hypertension (PH). Dehydroepiandrosterone (DHEA), a naturally occurring steroid hormone, effectively inhibits chronic hypoxic PH, but the responsible mechanisms are unclear. This study tested whether DHEA was also effective in treating monocrotaline (MCT)-induced PH in left pneumonectomized rats and whether inhibition of RhoA/ROCK signaling was involved in the protective effect of DHEA. Three weeks after MCT injection, pneumonectomized rats developed PH with severe vascular remodeling, including occlusive neointimal lesions in pulmonary arterioles. In lungs from these animals, we detected cleaved (constitutively active) ROCK I as well as increases in activities of RhoA and ROCK and increases in ROCK II protein expression. Chronic DHEA treatment (1%, by food for 3 wk) markedly inhibited the MCT-induced PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 33 ± 5 and 16 ± 1 mmHg, respectively) and severe pulmonary vascular remodeling in pneumonectomized rats. The MCT-induced changes in RhoA/ROCK-related protein expression were nearly normalized by DHEA. A 3-wk DHEA treatment (1%) started 3 wk after MCT injection completely inhibited the progression of PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 47 ± 3 and 30 ± 3 mmHg, respectively), and this treatment also resulted in 100% survival in contrast to 30% in DHEA-untreated rats. These results suggest that inhibition of RhoA/ROCK signaling, including the cleavage and constitutive activation of ROCK I, is an important component of the impressive protection of DHEA against MCT-induced PH in pneumonectomized rats.

Abstract P091: New Rho-kinase Inhibitors Reduce Cardiac Dysfunction And Vascular Remodeling In Pulmonary Hypertension In Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Tadeu L Montagnoli ◽  
Jaqueline S Da Silva ◽  
Bruna S Rocha ◽  
Marina Silva ◽  
Bianca Santos-Carlos ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Kinase Inhibitors ◽  
Rho Kinase ◽  
Cardiomyocyte Hypertrophy ◽  
Ejection Time ◽  
Arterial Elastance ◽  
Morphological Alterations ◽  
Male Wistar Rats ◽  
Rock Inhibition

Pulmonary hypertension (PH) is characterized by extensive pulmonary vascular remodeling, leading to right ventricle (RV) hypertrophy and dysfunction. Since Rho kinases (ROCK) play a key role in smooth muscle proliferation and cardiomyocyte hypertrophy, this work evaluated the effects of ROCK inhibition by LASSBio-2020 and LASSBio-2065 on monocrotaline (MCT)-induced PH. After single injection of MCT (60 mg/kg i.p.), male Wistar rats were randomly divided in groups and treated with vehicle, LASSBio-2020 or LASSBio-2065 (60 μmol/kg/day, i.p.). Table 1 shows summarized data. After 14 days, ROCK inhibitors reduced pulmonary vascular resistance, indicated by the ratio of pulmonary acceleration time and ejection time (PAT/TET; p< 0.05) and medial wall thickness of distal pulmonary arterioles (p< 0.05). LASSBio-2020 and LASSBio-2065 also reduced Fulton index of RV hypertrophy (p< 0.05) and RV afterload, as shown by recovery of RV cardiac output (p< 0.05) and arterial elastance (p< 0.05). ROCK inhibitors improved diastolic function since both compounds reduced RV end-diastolic pressures (RVEDP) and Tau, measured through catheterization. Therefore, ROCK inhibition by LASSBio-2020 and LASSBio-2065 reverted functional and morphological alterations in PH rats and may represent a useful alternative for management of PH-associated RV dysfunction.

scholarly journals Correlation between PPAR Gene Polymorphisms and Primary Nephrotic Syndrome in Children

PPAR Research ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Jiaping Jin ◽  
Guixia Ding ◽  
Huaying Bao ◽  
Ying Chen ◽  
Yuan Han ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Serum Insulin ◽  
Complement C3 ◽  
Peroxisome Proliferator ◽  
Nucleotide Polymorphisms ◽  
Peroxisome Proliferator Activated Receptor ◽  
Primary Nephrotic Syndrome ◽  
Cell Counts ◽  
Steroid Responsiveness ◽  
Immune Dysfunctions

Pediatric primary nephrotic syndrome (PNS) is a chronic disease promoted by metabolic and immune dysfunctions. Peroxisome proliferator-activated receptor (PPAR) polymorphisms have been associated with a variety of metabolic and kidney disorders. We therefore hypothesized that PPAR polymorphisms might be involved in the pathophysiology of PNS. We compared the distributions of the PPAR-γPro12Ala and Val290Met, PPAR-γcoactivator-α(PGC-1α) Gly482Ser, and PPAR-αLeu162Val single nucleotide polymorphisms (SNPs) between children with PNS and normal controls and analyzed their correlations with clinical and metabolic indicators and steroid responsiveness. There were no significant differences in distributions of any of the polymorphisms between PNS cases and controls. However, PNS patients with the PPAR-γ(Pro12Ala) PP genotype had significantly higher fasting serum insulin, IgA, and HOMA-IR levels and lower insulin sensitivity than did patients with PA and AA genotypes. Additionally, the PGC-1α(Gly482Ser) A allele was associated with lower CD8+ T-cell counts and higher triglyceride and complement C3 levels compared with the G allele. No polymorphisms were related to hormone sensitivity. These results suggest that the PPAR-γ(Pro12Ala) and PGC-1α(Gly482Ser) SNPs may influence insulin and triglyceride metabolism in children with PNS and may thus be relevant to the prognosis of this chronic condition.

Abstract 981: Hypoxia Results in Exacerbation of Pulmonary Arterial Hypertension (PAH) in Male Mice with Deletion of PPARγin Smooth Muscle Cells (SMC) but Females are Protected by Adiponectin Mediated Induction of PPARα

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Laura H Rubinos ◽  
Georg Hansmann ◽  
Nesrine El-Bizri ◽  
Christophe Guignabert ◽  
Vinicio A De Jesus Perez ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Right Ventricular ◽  
Chronic Hypoxia ◽  
Systolic Pressure ◽  
Peroxisome Proliferator ◽  
Male Mice ◽  
Relative Level ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ventricular Systolic Pressure ◽  
Cell Counts

Lung tissues of patients with PAH have reduced levels of the peroxisome proliferator activated receptor gamma (PPARγ) and we previously reported that transgenic male mice with deletion of PPARγ in arterial smooth muscle (SM22CrePPARγ flox/flox ) develop spontaneous PAH. Moreover, PPARγ is necessary in mediating bone morphogenetic protein (BMP-2) inhibition of PDGF-BB induced SMC proliferation. We therefore hypothesized that PAH would be exacerbated in SM22CrePPARγ flox/flox mice under conditions like chronic hypoxia (3 weeks, FiO 2 =0.10) that induce PDGF-BB mediated SMC proliferation. Results: Consistent with this hypothesis, we report a more severe PAH phenotype only in the male SM22CrePPARγ flox/flox mice, as measured by greater right ventricular systolic pressure (RVSP: 38.6 vs. 30.9 mmHg), right ventricular hypertrophy (RVH=right ventricle/left ventricle+septum: 0.58 vs 0.35), and arterial muscularization (90.6 vs 60.3 %), when compared to littermate controls (p<0.05, n=6 – 8 per group, for all comparisons). Interestingly, female SM22CrePPARγ flox/flox mice were resistant to spontaneous or chronic hypoxia-induced PAH (RVSP: 18.5mmHg). We investigated the acute hypoxic vasoconstrictive response and found it exaggerated in the male but suppressed in the female (RVSP: 43.12 vs 20.42mmHg) SM22CrePPARγ flox/flox mice. We found no reduction in endothelin-1 (P<0.05) in the female vs. male SM22CrePPARγ flox/flox mice but serum levels of adiponectin were twofold higher (14.5 vs 6.9 μg/ml; p<0. 001) in females under normoxia and hypoxia. We further show through cell counts, that in pulmonary artery (PA) SMC from male SM22CrePPARγ flox/flox mice, BMP2 fails to suppress PA SMC proliferation in response to PDGF-BB (p<0.01; n=3) but exogenous adiponectin can ‘rescue’ this phenotype (p<0.01, n=3). The mechanism appears to be related to adiponectin mediated induction of PPAR alpha (PPARγ mRNA relative level: 0.37 vs 0.42 after adiponectin pretreatment, p<0.01), which we report for the first time in PA SMC. Conclusion : These findings strengthen the potential efficacy of PPAR-α/ γ agonists in the treatment of PAH patients with low endogenous levels of PPAR-γ and/or adiponectin, such as those with BMP-RII dysfunction or insulin resistance.

The dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma–associated adverse cardiac effects

2014 ◽  
Vol 11 (6) ◽  
pp. 440-447 ◽  
Author(s):  
Rémy Hanf ◽  
Lesley J Millatt ◽  
Bertrand Cariou ◽  
Benoit Noel ◽  
Géraldine Rigou ◽  
...  
Keyword(s):  
Heart Weight ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cardiac Effects ◽  
Cardiac Side Effects ◽  
Receptor Alpha ◽  
Cell Counts ◽  
Pparγ Agonist ◽  
Fasting Glycaemia ◽  
Glucose Lowering Effect

We report here the efficacy and safety of GFT505, a novel liver-targeted peroxisome proliferator-activated receptor alpha/delta (PPARα/δ) agonist, in the db/ db mouse model of diabetes. Mice were treated with vehicle, GFT505, PPARγ agonist rosiglitazone or dual-PPARα/γ agonist aleglitazar for up to 8 weeks. All compounds comparably reduced fasting glycaemia and HbA1c and improved insulin sensitivity. The glucose-lowering effect of GFT505 was associated with decreased hepatic gluconeogenesis, correlating with reduced expression of gluconeogenic genes. In contrast with the PPARγ-activating drugs, treatment with GFT505 did not affect heart weight and did not increase plasma adiponectin concentrations. This absence of cardiac effects of GFT505 was confirmed after 12 months of administration in cynomolgus monkeys, by the absence of echocardiographic and histological findings. Moreover, long-term GFT505 administration to monkeys induced no change in haematological parameters or in bone marrow differential cell counts. Compared to PPARγ-activating drugs, the dual-PPARα/δ agonist GFT505 therefore shows an improved benefit/risk ratio, treating multiple features of type 2 diabetes without inducing the cardiac side-effects associated with PPARγ activation.

Anti-adipogenesis and antioxidative defense status of a crude extract of ‘Kalasin 2’ peanut sprouts in 3T3-L1 mouse adipocytes

2019 ◽  
Vol 97 (6) ◽  
pp. 740-749
Author(s):  
Tantip Boonsong ◽  
Siriporn Pakwan ◽  
Wanida Chawnawa
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
Oxidative Status ◽  
Peroxisome Proliferator ◽  
Antioxidative Defense ◽  
Peroxisome Proliferator Activated Receptor ◽  
Defense Systems ◽  
Treatment Of Obesity ◽  
Mouse Adipocytes ◽  
And Oxidative Stress

The aim of this study was to investigate the effects of extracts from germinated (GPE) and non-germinated peanuts (NGPE) on adipogenesis and oxidative status in normal and oxidative-stress-induced 3T3-L1 mouse adipocytes. The treated cells were analysed for cell growth, lipid accumulation, levels of intracellular reactive oxygen species (ROS), and the expression levels of mRNAs and proteins related to adipogenesis and antioxidative defense systems. The results indicated that an extract from peanuts made 9 days after germination (9GPE) reduced lipid contents and mRNA expression of adipogenesis-related genes to a greater extent than an extract from peanuts made 1-day after germination (1GPE) or from NGPE, respectively. In oxidative-stress-induced adipocytes, 9GPE decreased ROS levels, lipid content, and the protein expression of peroxisome-proliferator-activated receptor gamma, and also increased the protein expression of antioxidants. These results illustrate the anti-adipogenic capacity and oxidative status improvement achievable with GPE, and that it could be used as a putative therapeutic agent in the prevention of and (or) treatment of obesity and diseases associated with oxidative stress.

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