scholarly journals Role of PKM2-PARP1/Inflammation/Oxidative DNA Damage Axis in the Pathogenesis of Right Ventricular Failure Associated with Pulmonary Arterial Hypertension

2020 ◽  
Author(s):  
T. Shimauchi ◽  
J. Omura ◽  
S.B. Bonnet ◽  
V. Nadeau ◽  
R. Paulin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Oxidative Dna Damage ◽  
Right Ventricular Failure ◽  
Ventricular Failure ◽  
Pulmonary Arterial

Abstract 13700: Role of Parp1-pkm2 Axis in the Pathogenesis of Right Ventricular Failure Associated With Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Tsukasa Shimauchi ◽  
Junichi Omura ◽  
Sandra Breuils Bonnet ◽  
Valerie Nadeau ◽  
Eve Tremblay ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Oxidative Dna Damage ◽  
Right Ventricular Failure ◽  
Ventricular Failure ◽  
Rat Models ◽  
Pulmonary Arterial

Background: Right ventricular failure (RVF) is a poor prognostic factor for pulmonary arterial hypertension (PAH) patients. Inflammation, oxidative stress-induced DNA damage, and glycolysis are key RVF-driven pathways triggering cardiomyocytes (CM) dysfunction. Persistent DNA damage-dependent Poly (ADP ribose) Polymerase 1 (PARP1) activation was documented to promote glycolysis and pro-inflammatory responses through nuclear retention of Pyruvate Kinase Muscle isozyme 2 (PKM2). Despite the tremendous attention to PARP1/PKM2 axis in many pathologies, their implication in RVF remains unexplored. We hypothesized sustained PARP1 activation accounts for nuclear PKM2 localization, contributing to CM dysfunction and transition from compensated (cRVH) to decompensated RVH(dRVH). Methods and Results: We found by WB and IF that PARP1/PKM2 expression/activity is increased in dRVH (patients died from RVF, n=9) compared to cRVH (Cardiac index >2.2, n=14) and control donors (n=14) and correlates with RV hypertrophy and fibrosis. Similar findings were found in two rat models of RVF (monocrotaline; MCT, pulmonary artery banding; PAB). In addition, cardiac inflammation (NF-kB, HMGB1, IL-8, CCL-2, SOCS3, CD68), oxidative DNA damage (MTH1, 8-oxodG), and apoptosis (TUNEL) were significantly increased in dRVH compared to cRVH (human and rat models). In vitro , we confirmed by WB and IF that oxidative DNA damage (H 2 O 2 ) induce nuclear expression of PARP1/PKM2 in CM leading to the release of inflammatory mediators (NFkB, HMGB1) and cell death. These effects were prevented by pharmacological inhibition of PARP1 (ABT888) and enforced cytosolic retention of PKM2 (TEPP46 and DASA58). In vivo , PARP1 inhibition (Olaparib; 10mg/kg) as well as TEPP46 (25mg/kg) delayed progression of RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis) in PAB rats (n=8 per groups). Preliminary data indicate CM-specific inactivation of PARP1 induces resistance to RVF in PAB mice (All p<0.05). Conclusions: We demonstrated for the first time that PARP1/PKM2 axis is a critical integrator of oxidative stress, inflammation, and metabolic dysfunction during pathological RVF. Modulating PARP1/PKM2 axis may represent a promising avenue for ameliorating RVF in PAH.

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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