scholarly journals Periostin Mediates Right Ventricular Failure through Induction of Inducible Nitric Oxide Synthase Expression in Right Ventricular Fibroblasts from Monocrotaline-Induced Pulmonary Arterial Hypertensive Rats

2018 ◽  
Vol 20 (1) ◽  
pp. 62 ◽  
Author(s):  
Keisuke Imoto ◽  
Muneyoshi Okada ◽  
Hideyuki Yamawaki
Keyword(s):  
Nitric Oxide ◽  
Right Ventricular ◽  
Inos Expression ◽  
Right Ventricular Failure ◽  
No Production ◽  
Ventricular Failure ◽  
Extracellular Signal ◽  
Male Wistar Rats ◽  
Pulmonary Arterial ◽  
Inducible Nitric Oxide

Pulmonary arterial hypertension (PAH) leads to lethal right ventricular failure (RVF). Periostin (POSTN) mRNA expression is increased in right ventricles (RVs) of monocrotaline (MCT)-induced PAH model rats. However, the pathophysiological role of POSTN in RVF has not been clarified. We investigated the effects of POSTN on inducible nitric oxide (NO) synthase (iNOS) expression and NO production, which causes cardiac dysfunction, in right ventricular fibroblasts (RVFbs). Male Wistar rats were intraperitoneally injected with MCT (60 mg/kg) or saline. Three weeks after injection, RVFbs were isolated from RVs of MCT- or saline-injected rats (MCT-RVFb or CONT-RVFb). In MCT-RVFb, iNOS expression and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) were higher than those in CONT-RVFb. Recombinant POSTN increased iNOS expression and NO production, which were prevented by a pharmacological inhibition of ERK1/2, JNK or NF-κB in RVFbs isolated from normal rats. Culture medium of POSTN-stimulated RVFbs suppressed Ca2+ inflow through l-type Ca2+ channel (LTCC) in H9c2 cardiomyoblasts. We demonstrated that POSTN enhances iNOS expression and subsequent NO production via ERK1/2, JNK, and NF-κB signaling pathways in RVFbs. POSTN might mediate RVF through the suppression of LTCC activity of cardiomyocytes by producing NO from RVFbs in PAH model rats.

scholarly journals Role of Mitogen-Activated Protein Kinases in Peptidoglycan-Induced Expression of Inducible Nitric Oxide Synthase and Nitric Oxide in Mouse Peritoneal Macrophages: Extracellular Signal-Related Kinase, a Negative Regulator

2011 ◽  
Vol 18 (6) ◽  
pp. 994-1001 ◽  
Author(s):  
Kunal H. Bhatt ◽  
Ajit Sodhi ◽  
Rituparna Chakraborty
Keyword(s):  
Nitric Oxide ◽  
Transcription Factors ◽  
Inos Expression ◽  
No Production ◽  
Erk Pathway ◽  
Mitogen Activated Protein Kinases ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACTThe expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) are important host defense mechanisms against pathogens in mononuclear phagocytes. The objectives of this study were to examine the roles of mitogen-activated protein kinases (MAPKs) and transcription factors (nuclear factor-κB [NF-κB] and activating protein 1 [AP-1]) in peptidoglycan (PGN)-induced iNOS expression and NO production in macrophages. PGN is a cell wall component of Gram-positive bacteria that stimulates inflammatory responses bothex vivoandin vivo. PGN stimulates the activation of all three classes of MAPKs, extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38mapkin macrophages, albeit with differential activation kinetics. Using a selective inhibitor of JNK (SP600125) and JNK1/2 small interfering RNA (siRNA) knocked-down macrophages, it was observed that PGN-induced iNOS and NO expression is significantly inhibited. This suggested that JNK MAPK plays an essential role in PGN-induced iNOS expression and NO production. In contrast, inhibition of the ERK pathway using PD98059 dose dependently enhanced PGN-induced iNOS expression and NO production. PGN-induced ERK activation was attenuated in ERK1/2 siRNA knocked-down macrophages; however, NO and iNOS expression were significantly enhanced. An electrophoretic mobility shift assay showed that SP600125 inhibited PGN-induced NF-κB and AP-1 activation, whereas inhibition of the ERK pathway enhanced NF-κB activation, but with no effect on AP-1. These results indicate that the JNK MAPK positively regulate PGN-induced iNOS and NO expression by activating NF-κB and AP-1 transcription factors, whereas the ERK pathway plays a negative regulatory role via affecting NF-κB activity.

Mechanisms of right ventricular failure

ESC CardioMed ◽  
2018 ◽  
pp. 2493-2495
Author(s):  
Joanne A. Groeneveldt ◽  
Anton Vonk Noordegraaf ◽  
Frances S. de Man
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Right Ventricular Dysfunction ◽  
Right Ventricular Failure ◽  
Ventricular Failure ◽  
Adaptive Mechanisms ◽  
Patient Will ◽  
Pulmonary Arterial ◽  
The Right

In pulmonary arterial hypertension, afterload on the right ventricle is increased. Due to several adaptive mechanisms, the right ventricle is able to cope with a three- to fivefold increase in afterload. However, when adaptive mechanisms are no longer sufficient to compensate for this increase, the patient will develop right ventricular dysfunction and failure. This chapter provides an overview of mechanisms currently considered as having important roles in right ventricular adaptation and right ventricular failure.

scholarly journals Hot topics in the mechanisms of pulmonary arterial hypertension disease: cancer-like pathobiology, the role of the adventitia, systemic involvement, and right ventricular failure

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401988977 ◽  
Author(s):  
Edda Spiekerkoetter ◽  
Elena A. Goncharova ◽  
Christophe Guignabert ◽  
Kurt Stenmark ◽  
Grazyna Kwapiszewska ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systemic Disease ◽  
Right Ventricular Failure ◽  
Lung Pathology ◽  
Ventricular Failure ◽  
Disease Pathogenesis ◽  
Pulmonary Arterial

In order to intervene appropriately and develop disease-modifying therapeutics for pulmonary arterial hypertension, it is crucial to understand the mechanisms of disease pathogenesis and progression. We herein discuss four topics of disease mechanisms that are currently highly debated, yet still unsolved, in the field of pulmonary arterial hypertension. Is pulmonary arterial hypertension a cancer-like disease? Does the adventitia play an important role in the initiation of pulmonary vascular remodeling? Is pulmonary arterial hypertension a systemic disease? Does capillary loss drive right ventricular failure? While pulmonary arterial hypertension does not replicate all features of cancer, anti-proliferative cancer therapeutics might still be beneficial in pulmonary arterial hypertension if monitored for safety and tolerability. It was recognized that the adventitia as a cell-rich compartment is important in the disease pathogenesis of pulmonary arterial hypertension and should be a therapeutic target, albeit the data are inconclusive as to whether the adventitia is involved in the initiation of neointima formation. There was agreement that systemic diseases can lead to pulmonary arterial hypertension and that pulmonary arterial hypertension can have systemic effects related to the advanced lung pathology, yet there was less agreement on whether idiopathic pulmonary arterial hypertension is a systemic disease per se. Despite acknowledging the limitations of exactly assessing vascular density in the right ventricle, it was recognized that the failing right ventricle may show inadequate vascular adaptation resulting in inadequate delivery of oxygen and other metabolites. Although the debate was not meant to result in a definite resolution of the specific arguments, it sparked ideas about how we might resolve the discrepancies by improving our disease modeling (rodent models, large-animal studies, studies of human cells, tissues, and organs) as well as standardization of the models. Novel experimental approaches, such as lineage tracing and better three-dimensional imaging of experimental as well as human lung and heart tissues, might unravel how different cells contribute to the disease pathology.

scholarly journals Transcriptomic Signature of Right Ventricular Failure in Experimental Pulmonary Arterial Hypertension: Deep Sequencing Demonstrates Mitochondrial, Fibrotic, Inflammatory and Angiogenic Abnormalities

2018 ◽  
Vol 19 (9) ◽  
pp. 2730 ◽  
Author(s):  
Francois Potus ◽  
Charles Hindmarch ◽  
Kimberly Dunham-Snary ◽  
Jeff Stafford ◽  
Stephen Archer
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Transforming Growth Factor ◽  
Expression Profiles ◽  
Right Ventricular Failure ◽  
Matricellular Protein ◽  
Ventricular Failure ◽  
Transcriptomic Signature ◽  
Pulmonary Arterial

Right ventricular failure (RVF) remains the leading cause of death in pulmonary arterial hypertension (PAH). We investigated the transcriptomic signature of RVF in hemodynamically well-phenotyped monocrotaline (MCT)-treated, male, Sprague-Dawley rats with severe PAH and decompensated RVF (increased right ventricular (RV) end diastolic volume (EDV), decreased cardiac output (CO), tricuspid annular plane systolic excursion (TAPSE) and ventricular-arterial decoupling). RNA sequencing revealed 2547 differentially regulated transcripts in MCT-RVF RVs. Multiple enriched gene ontology (GO) terms converged on mitochondria/metabolism, fibrosis, inflammation, and angiogenesis. The mitochondrial transcriptomic pathway is the most affected in RVF, with 413 dysregulated genes. Downregulated genes included TFAM (−0.45-fold), suggesting impaired mitochondrial biogenesis, CYP2E1 (−3.8-fold), a monooxygenase which when downregulated increases oxidative stress, dehydrogenase/reductase 7C (DHRS7C) (−2.8-fold), consistent with excessive autonomic activation, and polypeptide N-acetyl-galactose-aminyl-transferase 13 (GALNT13), a known pulmonary hypertension (PH) biomarker (−2.7-fold). The most up-regulated gene encodes Periostin (POSTN; 4.5-fold), a matricellular protein relevant to fibrosis. Other dysregulated genes relevant to fibrosis include latent-transforming growth factor beta-binding protein 2 (LTBP2), thrombospondin4 (THBS4). We also identified one dysregulated gene relevant to all disordered transcriptomic pathways, ANNEXIN A1. This anti-inflammatory, phospholipid-binding mediator, is a putative target for therapy in RVF-PAH. Comparison of expression profiles in the MCT-RV with published microarray data from the RV of pulmonary artery-banded mice and humans with bone morphogenetic protein receptor type 2 (BMPR2)-mutations PAH reveals substantial conservation of gene dysregulation, which may facilitate clinical translation of preclinical therapeutic and biomarkers studies. Transcriptomics reveals the molecular fingerprint of RVF to be heavily characterized by mitochondrial dysfunction, fibrosis and inflammation.

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