Inhibition of gut- and lung-derived serotonin attenuates pulmonary hypertension in mice

2012 ◽  
Vol 303 (6) ◽  
pp. L500-L508 ◽  
Author(s):  
Shariq Abid ◽  
Amal Houssaini ◽  
Caroline Chevarin ◽  
Elisabeth Marcos ◽  
Claire-Marie Tissot ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Therapeutic Strategy ◽  
Tryptophan Hydroxylase ◽  
Combined Treatment ◽  
Systolic Pressure ◽  
Adjunctive Treatment ◽  
Proof Of Concept ◽  
Wild Type ◽  
Rate Limiting ◽  
The Brain

Decreasing the bioavailability of serotonin (5-HT) by inhibiting its biosynthesis may represent a useful adjunctive treatment of pulmonary hypertension (PH). We assessed this hypothesis using LP533401, which inhibits the rate-limiting enzyme tryptophan hydroxylase 1 (Tph1) expressed in the gut and lung, without inhibiting Tph2 expressed in neurons. Mice treated repeatedly with LP533401 (30–250 mg/kg per day) exhibited marked 5-HT content reductions in the gut, lungs, and blood, but not in the brain. After a single LP533401 dose (250 mg/kg), lung and gut 5-HT contents decreased by 50%, whereas blood 5-HT levels remained unchanged, suggesting gut and lung 5-HT synthesis. Treatment with the 5-HT transporter (5-HTT) inhibitor citalopram decreased 5-HT contents in the blood and lungs but not in the gut. In transgenic SM22-5-HTT+ mice, which overexpress 5-HTT in smooth muscle cells and spontaneously develop PH, 250 mg/kg per day LP533401 or 10 mg/kg per day citalopram for 21 days markedly reduced lung and blood 5-HT levels, right ventricular (RV) systolic pressure, RV hypertrophy, distal pulmonary artery muscularization, and vascular Ki67-positive cells ( P < 0.001). Combined treatment with both drugs was more effective in improving PH-related hemodynamic parameters than either drug alone. LP533401 or citalopram treatment partially prevented PH development in wild-type mice exposed to chronic hypoxia. Lung and blood 5-HT levels were lower in hypoxic than in normoxic mice and decreased further after LP533401 or citalopram treatment. These results provide proof of concept that inhibiting Tph1 may represent a new therapeutic strategy for human PH.

Tryptophan hydroxylase 1 knockout and tryptophan hydroxylase 2 polymorphism: effects on hypoxic pulmonary hypertension in mice

2007 ◽  
Vol 293 (4) ◽  
pp. L1045-L1052 ◽  
Author(s):  
M. Izikki ◽  
N. Hanoun ◽  
E. Marcos ◽  
L. Savale ◽  
A. M. Barlier-Mur ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Ventricular Hypertrophy ◽  
Tryptophan Hydroxylase ◽  
Mouse Strains ◽  
Wild Type ◽  
Tryptophan Hydroxylase 2 ◽  
Tph2 Gene ◽  
C1473g Polymorphism ◽  
The Difference ◽  
Rate Limiting

Serotonin [5-hydroxytryptamine (5-HT)] biosynthesis depends on two rate-limiting tryptophan hydroxylases (Tph): Tph1, which is expressed in peripheral organs, and Tph2, which is expressed in neurons. Because 5-HT is involved in pulmonary hypertension (PH), we investigated whether genetic variations in Tph1 and/or Tph2 affected PH development in mice. To examine the functional impact of peripheral Tph1 deficiency on hypoxic PH, we used Tph1−/− mice characterized by very low 5-HT synthesis rates and contents in the gut and lung and increased 5-HT synthesis in the forebrain. With chronic hypoxia, 5-HT synthesis in the forebrain increased further. Hypoxic PH, right ventricular hypertrophy, and distal pulmonary artery muscularization were less severe ( P < 0.001) than in wild-type controls. The Tph inhibitor p-chlorophenylalanine (100 mg·kg−1·day−1) further improved these parameters. We then investigated whether mouse strains harboring the C1473G polymorphism of the Tph2 gene showed different PH phenotypes during hypoxia. Forebrain Tph activity was greater and hypoxic PH was more severe in C57Bl/6 and 129X1/SvJ mice homozygous for the 1473C allele than in DBA/2 and BALB/cJ mice homozygous for the 1473G allele. p-Chlorophenylalanine reduced PH in all groups and abolished the difference in PH severity across mouse strains. Hypoxia increased 5-hydroxytryptophan accumulation but decreased 5-HT contents in the forebrain and lung, suggesting accelerated 5-HT turnover during hypoxia. These results provide evidence that dysregulation of 5-HT synthesis is closely linked to the hypoxic PH phenotype in mice and that Tph1 and Tph2 may contribute to PH development.

scholarly journals Effects of pyridoxine deficiency and dl-p-chlorophenylalanine administration to rats on 5-hydroxytryptamine and noradrenaline concentrations in brain and 5-hydroxytryptamine concentration in blood

1973 ◽  
Vol 134 (3) ◽  
pp. 763-767 ◽  
Author(s):  
Hemmige N. Bhagavan ◽  
David B. Coursin
Keyword(s):  
Body Weight ◽  
Gastrointestinal Tract ◽  
Tryptophan Hydroxylase ◽  
Marked Decrease ◽  
Brain Weight ◽  
Pyridoxine Deficiency ◽  
Weanling Rats ◽  
And Control ◽  
Rate Limiting ◽  
The Brain

Pyridoxine deficiency in post-weanling rats caused a marked decrease in body weight and a small but significant decrease in brain weight. Although the concentration of circulating 5-hydroxytryptamine was markedly decreased, the concentrations of 5-hydroxytryptamine and noradrenaline in the brain were not affected. p-Chlorophenylalanine, an inhibitor of 5-hydroxytryptamine synthesis, decreased the 5-hydroxytryptamine content of brain to very low values in both the deficient and control animals, whereas the noradrenaline contents were not appreciably affected. The concentration of 5-hydroxytryptamine in blood, the origin of which is primarily gastrointestinal, was decreased only in the controls but not in the deficient animals after p-chlorophenylalanine treatment. These results suggest that whereas l-tryptophan hydroxylase (EC 1.14.3.2) is rate-limiting in the brain as has been reported by others, the pyridoxal 5′-phosphate-dependent enzyme 5-hydroxytryptophan decarboxylase (EC 4.1.1.28) may be more important in the gastrointestinal tract in the regulation of 5-hydroxytryptamine synthesis.

Deficiency of ST2 signaling ameliorates RSV-associated pulmonary hypertension

2021 ◽  
Author(s):  
Luan D. Vu ◽  
Jordy Saravia ◽  
Sridhar Jaligama ◽  
Rajshri V. Baboeram Panday ◽  
Ryan D. Sullivan ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Congenital Heart ◽  
Systolic Pressure ◽  
Pathophysiological Mechanism ◽  
Wild Type ◽  
Ejection Time ◽  
Acceleration Time ◽  
Arginase 1 ◽  
Syncytial Virus ◽  
Oxide Synthase

Pulmonary hypertension (PH) observed during respiratory syncytial virus (RSV) bronchiolitis is associated with morbidity and mortality, especially in children with congenital heart disease. Yet, the pathophysiological mechanisms of RSV-associated PH remain unclear. Therefore, this study aimed to investigate the pathophysiological mechanism of RSV-associated PH. We employed a translational mouse model of RSV-associated PH, in which wild-type (WT) and ST2 knockout neonatal mice were infected with RSV at 5-days old and reinfected 4-weeks later. The development of PH in WT mice following RSV reinfection was evidenced by elevated right ventricle systolic pressure, shortenedpulmonary artery acceleration time (PAT) and decreased PAT/ejection time (ET) ratio. It coincided with the augmentation of periostin and IL-13 expression, and increased arginase bioactivity by both arginase 1 and 2 as well as induction of nitric oxide synthase (NOS) uncoupling. The absence of ST2 signaling prevented RSV reinfected mice from developing PH by suppressing NOS uncoupling. In summary, ST2 signaling was involved in the development of RSV-associated PH. ST2 signaling inhibition may be a novel therapeutic target for RSV-associated PH.

scholarly journals Smooth Muscle Cytochrome b5 Reductase 3 Deficiency Accelerates Pulmonary Hypertension Development in Sickle Cell Mice

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3619-3619
Author(s):  
Katherine Wood ◽  
Brittany Durgin ◽  
Heidi M Schmidt ◽  
Scott Hahn ◽  
Jeffrey Baust ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Right Ventricular ◽  
Sickle Cell ◽  
Cytochrome B5 ◽  
Systolic Pressure ◽  
Significant Risk ◽  
Tamoxifen Treatment ◽  
Wild Type ◽  
Cytochrome B5 Reductase

Pulmonary and systemic vasculopathy are significant risk factors for early morbidity and death in patients with sickle cell disease (SCD). An underlying mechanism of SCD vasculopathy is vascular smooth muscle (VSM) nitric oxide (NO) resistance, which is mediated by NO scavenging reactions with plasma hemoglobin and reactive oxygen species that can oxidize soluble guanylyl cyclase (sGC), the NO receptor. Prior studies show that cytochrome b5 reductase 3 (CYB5R3), known as methemoglobin reductase in erythrocytes, functions in VSM as an sGC heme iron reductase critical for reducing and sensitizing sGC to NO and generating cGMP for vasodilation. Therefore, we hypothesized that VSM CYB5R3 deficiency accelerates development of pulmonary hypertension (PH) in SCD. Bone marrow transplant was used to create SCD chimeric mice with background smooth muscle cell (SMC) specific tamoxifen-inducible Cyb5r3 knockout (SMC R3 KO) and wild-type (WT) control.Three weeks after completing tamoxifen treatment, we observed 60% knockdown of pulmonary arterial SMC CYB5R3, 5-6 mmHg elevated right ventricular maximum systolic pressure (RVmaxSP) and biventricular hypertrophy in SS chimeras with SMC R3 KO (SS/R3KD) relative to wild-type (SS/R3WT). Right ventricular (RV) contractility, heart rate, hematological parameters and cell-free hemoglobin were similar between groups. When identically generated SS/R3 chimeras were studied 12-weeks after completing tamoxifen treatment, RVmaxSP in SS/R3KD had not increased further, but RV hypertrophy relative to SS/R3WT persisted. These are the first studies to establish involvement of SMC CYB5R3 in SCD-associated development of PH, which can exist in mice by 5 weeks of SMC CYB5R3 protein deficiency. Disclosures Vitturi: Complexa Inc: Consultancy. Ofori-Acquah:Shire Human Genetic Therapies Inc: Other: Financial Relationship. Gladwin:Globin Solutions, Inc: Patents & Royalties: Provisional patents for the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning; Bayer Pharmaceuticals: Other: Co-investigator; United Therapeutics: Patents & Royalties: Co-inventor on an NIH government patent for the use of nitrite salts in cardiovascular diseases . Straub:Bayer Pharmaceuticals: Research Funding.

Tryptophan hydroxylase 2 in seasonal affective disorder: underestimated perspectives?

2015 ◽  
Vol 26 (6) ◽  
Author(s):  
Alexander V. Kulikov ◽  
Nina K. Popova
Keyword(s):  
Affective Disorder ◽  
Tryptophan Hydroxylase ◽  
Seasonal Affective Disorder ◽  
Recurrent Depression ◽  
Tryptophan Hydroxylase 2 ◽  
System Functioning ◽  
Brain Neurotransmitter ◽  
The Relationship ◽  
Rate Limiting ◽  
The Brain

AbstractSeasonal affective disorder (SAD) is characterized by recurrent depression occurring generally in fall/winter. Numerous pieces of evidence indicate the association of SAD with decreased brain neurotransmitter serotonin (5-HT) system functioning. Tryptophan hydroxylase 2 (TPH2) is the key and rate-limiting enzyme in 5-HT synthesis in the brain. This paper concentrates on the relationship between TPH2 activity and mood disturbances, the association between human

scholarly journals Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice

2008 ◽  
Vol 295 (2) ◽  
pp. H677-H690 ◽  
Author(s):  
Yanli Song ◽  
Laura Coleman ◽  
Jianru Shi ◽  
Hideyuki Beppu ◽  
Kaori Sato ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Transforming Growth Factor ◽  
Systolic Pressure ◽  
Receptor Expression ◽  
Endothelial Injury ◽  
Persistent Pulmonary Hypertension ◽  
Pcr Analysis ◽  
Type I ◽  
Wild Type ◽  
Bmp Receptors

Heterozygous bone morphogenetic protein receptor-II-knockout (BMPR2+/−) mice have a similar genetic trait like that in some idiopathic pulmonary arterial hypertension patients. To examine the effect of pulmonary endothelial injury in BMPR2+/− mice, we challenged the mice with two injections of monocrotaline combined with intratracheal instillation of replication-deficient adenovirus expressing 5-lipoxygenase (MCT+Ad5LO). After the challenge (1 wk), BMPR2+/− mice exhibited a doubling of right ventricular systolic pressure that was greater than that of wild-type mice and remained elevated for 3 wk before heart failure developed. Muscularization and thickening of small pulmonary arterioles was evident in the BMPR2+/− lungs at 2 wk after the challenge and became severe at 3 wk. Marked perivascular infiltration of T cells, B cells, and macrophages was associated with the remodeled vessels. Real-time PCR analysis showed that the expression of six endothelial cell markers in lung tissue was decreased to 20–40% of original levels at 1 wk after the challenge in both BMPR2+/− and wild-type mice and largely recovered in wild-type (50–80%) but not BMPR2+/− lungs (30–50%) at 3 wk after the challenge. Macrophage inflammatory protein-1α and fractalkine receptor expression doubled in BMPR2+/− compared with wild-type lungs. Expression of type I and type II BMP receptors, but not transforming growth factor-β receptors, in the challenged BMPR2+/− and wild-type lungs showed a similar pattern of expression as that of endothelial markers. Apoptotic responses at 1 wk after MCT and Ad5LO challenge were also significantly greater in the BMPR2+/− lungs than the wild-type lungs. These data show that BMPR2+/− mice are more sensitive to MCT+Ad5LO-induced pulmonary hypertension than wild-type mice. Greater endothelial injury and an enhanced inflammatory response could be the underlying causes of the sensitivity and may work in concert with BMPR2 heterozygosity to promote the development of persistent pulmonary hypertension.

scholarly journals Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice

2021 ◽  
Author(s):  
Ken’ichiro Nogami ◽  
Yusuke Maruyama ◽  
Fusako Sakai-Takemura ◽  
Norio Motohashi ◽  
Ahmed Elhussieny ◽  
...  
Keyword(s):  
Muscular Strength ◽  
Therapeutic Strategy ◽  
Genetic Disorder ◽  
Mdx Mice ◽  
Proof Of Concept ◽  
Wild Type ◽  
Dystrophic Muscle ◽  
Muscular Dysfunction ◽  
Exercise Induced ◽  
Muscular Damage

Abstract Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness due to the loss of dystrophin. Extracellular Ca2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) takes up cytosolic Ca2+ into the sarcoplasmic reticulum (SR), but its activity is decreased in dystrophic muscle. Here, we show that an allosteric SERCA activator, CDN1163, ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. Administration of CDN1163 prevented exercise-induced muscular damage and restored mitochondrial function. In addition, treatment with CDN1163 for seven weeks enhanced muscular strength and reduced muscular degeneration and fibrosis in mdx mice. Our findings provide preclinical proof-of-concept evidence that pharmacological activation of SERCA could be a promising therapeutic strategy for DMD. Moreover, CDN1163 improved muscular strength surprisingly in wild-type mice, which may pave the new way for the treatment of muscular dysfunction.

Abstract 216: Causal Role of Oxidized Lipids in Pulmonary Hypertension Development

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Gregoire Ruffenach ◽  
Soban Umar ◽  
Mylene Vaillancourt ◽  
Victor Grijalva ◽  
Ellen I O’Connor ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Methyl Ester ◽  
Systolic Pressure ◽  
Oxidized Lipids ◽  
Heart Catheterization ◽  
Chow Diet ◽  
Stable Form ◽  
Wild Type ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a deadly disease characterized by increased pulmonary arterial pressure and pulmonary vascular occlusion. Recently, we and others demonstrated a robust increase in oxidized lipids, including 15-hydroxyeicosatetraenoic acids (15-HETE), in the lungs and plasma of PAH patients and animal models of pulmonary hypertension (PH). We hypothesized that diets rich in 15-HETE are sufficient to cause PH in wild type mice. We also examined whether 15-HETE or its metabolites are required to cause PH by comparing the effect of 15-HETE with 15-HETE methyl ester, which is a stable form of 15HETE that is not easily metabolized. C57BL/6 male mice were fed for 3 weeks with 15-HETE diet (5μg/day), 15-HETE methyl ester (15-HETE-ME, 5μg/day), or regular chow diet (n=8-21 mice/group). PH development was followed via weekly serial echocardiography. Right ventricular systolic pressure (RVSP) was measured via direct heart catheterization. RV hypertrophy index (RV/[IVS+LV]) was measured. Lung morphology and lipid accumulation were assessed using H&E and Oil red O staining. Echocardiography revealed the first sign of PH in mice on 15HETE diet as early as one week and a significant decrease in the pulmonary arterial acceleration time after 2 weeks of treatment (16.6±1.9 vs. 21.2±1.4 msec, p<0.05). Mice on 15HETE diet also had significantly higher RVSP (31.3±1.1 vs. 38.4±2.3 mmHg, p<0.05). Increase in RVSP was concomitant with significantly higher RV hypertrophy index (0.26 ± 0.02 vs. 0.33 ±0.02, p<0.05). Pulmonary arteriolar thickness was also significantly increased in mice on 15-HETE diet compared to regular diet (35.1±0.8 vs 53.4±1, p<0.05). Our new model of PH is not a model of atherosclerosis as there was no detectable plaque in aorta of the mice on 15-HETE diet. Finally, mice on 15-HETE-ME diet also developed PH as RVSP was significantly higher compared to control (31.3±1.1 vs. 39±3 mmHg, p<0.05). The severity of PH was similar in 15HETE-ME and 15HETE, confirming 15HETE itself and not its metabolites is sufficient to cause PH in wild type mice. We have developed a new and physiologically relevant animal model to study PH as a consequence of oxidized lipids overload as it occurs in humans with PAH.

scholarly journals Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation

2020 ◽  
Author(s):  
Inmaculada Sanjuan-Ruiz ◽  
Noé Govea-Perez ◽  
Melissa Mcalonis-Downes ◽  
Stéphane Dieterle ◽  
Salim Megat ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Motor Deficit ◽  
Proof Of Concept ◽  
Wild Type ◽  
Age Dependent ◽  
Early Lethality ◽  
Lateral Sclerosis ◽  
Fus Protein

AbstractMutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a wild-type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein (FusΔNLS) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-type FUS completely rescued the early lethality caused by the two FusΔNLS alleles, and improved age-dependent motor deficit and reduced lifespan associated with the heterozygous expression of FusΔNLS. Mechanistically, wild-type FUS decreased the load of cytoplasmic FUS, increased exon 7 skipping and retention of introns 6 and 7 in the endogenous mouse Fus mRNA, leading to decreased expression of the mutant mRNA. Thus, the wild-type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent wild-type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease.

scholarly journals Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension

2017 ◽  
Vol 312 (5) ◽  
pp. L609-L624 ◽  
Author(s):  
Levi D. Maston ◽  
David T. Jones ◽  
Wieslawa Giermakowska ◽  
Tamara A. Howard ◽  
Judy L. Cannon ◽  
...  
Keyword(s):  
T Cells ◽  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Systolic Pressure ◽  
T Cell Subsets ◽  
Pathological Feature ◽  
Wild Type ◽  
T Helper ◽  
T Helper 17 ◽  
T Helper 17 Cells

Inflammation is a prominent pathological feature in pulmonary arterial hypertension, as demonstrated by pulmonary vascular infiltration of inflammatory cells, including T and B lymphocytes. However, the contribution of the adaptive immune system is not well characterized in pulmonary hypertension caused by chronic hypoxia. CD4+ T cells are required for initiating and maintaining inflammation, suggesting that these cells could play an important role in the pathogenesis of hypoxic pulmonary hypertension. Our objective was to test the hypothesis that CD4+ T cells, specifically the T helper 17 subset, contribute to chronic hypoxia-induced pulmonary hypertension. We compared indices of pulmonary hypertension resulting from chronic hypoxia (3 wk) in wild-type mice and recombination–activating gene 1 knockout mice (RAG1−/−, lacking mature T and B cells). Separate sets of mice were adoptively transferred with CD4+, CD8+, or T helper 17 cells before normoxic or chronic hypoxic exposure to evaluate the involvement of specific T cell subsets. RAG1−/− mice had diminished right ventricular systolic pressure and arterial remodeling compared with wild-type mice exposed to chronic hypoxia. Adoptive transfer of CD4+ but not CD8+ T cells restored the hypertensive phenotype in RAG1−/− mice. Interestingly, RAG1−/− mice receiving T helper 17 cells displayed evidence of pulmonary hypertension independent of chronic hypoxia. Supporting our hypothesis, depletion of CD4+ cells or treatment with SR1001, an inhibitor of T helper 17 cell development, prevented increased pressure and remodeling responses to chronic hypoxia. We conclude that T helper 17 cells play a key role in the development of chronic hypoxia-induced pulmonary hypertension.

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