Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

<p>Abstract</p> <p>Background</p> <p>Involvement of inflammation in pulmonary hypertension (PH) has previously been demonstrated and recently, immune-modulating dendritic cells (DCs) infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH) and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS), as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation.</p> <p>Methods</p> <p>We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT), monocrotaline-exposure/pneumonectomy (MCT/PE).</p> <p>Results</p> <p>Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine) in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature. Immunolabeling for OX62, CD68 and actin revealed adventitial and medial DC- and monocyte-infiltration; in MCT/PE, medial smooth muscle cells were admixed with CD68⁺/vimentin⁺cells.</p> <p>Conclusion</p> <p>Our experimental findings support a new concept of immunologic responses to increased OS in MCT/PE-induced PAH, possibly linking recruitment of dendritic cells and OS-producing mast-cells to characteristic vasculopathy.</p

The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload

BackgroundPulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A2 receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction.MethodsThe effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM).ResultsIn the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM.ConclusionThis study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4, and its potential to be a disease-modifying therapy in PAH and other cardiac conditions

Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice.

The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old Tnfaip3DNGR1-KO mice develop pulmonary hypertension (PH) symptoms. These mice harbor a targeted deletion of the TNFα-induced protein-3 (Tnfaip3) gene, encoding the NF-κB regulatory protein A20, specifically in type I conventional dendritic cells (cDC1s). Here, we studied the involvement of dendritic cells (DCs) in PH in more detail. We found various immune cells, including DCs, in the hearts of Tnfaip3DNGR1-KO mice, particularly in the right ventricle (RV). Secondly, in young Tnfaip3DNGR1-KO mice, innate immune activation through airway exposure to toll-like receptor ligands essentially did not result in elevated RV pressures, although we did observe significant RV hypertrophy. Thirdly, PH symptoms in Tnfaip3DNGR1-KO mice were not enhanced by concomitant mutation of bone morphogenetic protein receptor type 2 (Bmpr2), which is the most affected gene in PAH patients. Finally, in human IPAH lung tissue we found co-localization of DCs and CD8+ T cells, representing the main cell type activated by cDC1s. Taken together, these findings support a unique role of cDC1s in PAH pathogenesis, independent of general immune activation or a mutation in the Bmpr2 gene

Author Correction: Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2.

Abstract: Pulmonary arterial hypertension (PAH), is a fatal disease characterized by a pseudo-malignant phenotype. We investigated the expression and the role of the receptor tyrosine kinase Axl in experimental (i.e., monocrotaline and Su5416/hypoxia treated rats) and clinical PAH. In vitro Axl inhibition by R428 and Axl knock-down inhibited growth factor-driven proliferation and migration of non-PAH and PAH PASMCs. Conversely, Axl overexpression conferred a growth advantage. Axl declined in PAECs of PAH patients. Axl blockage inhibited BMP9 signaling and increased PAEC apoptosis, while BMP9 induced Axl phosphorylation. Gas6 induced SMAD1/5/8 phosphorylation and ID1/ID2 increase were blunted by BMP signaling obstruction. Axl association with BMPR2 was facilitated by Gas6/BMP9 stimulation and diminished by R428. In vivo R428 aggravated right ventricular hypertrophy and dysfunction, abrogated BMPR2 signaling, elevated pulmonary endothelial cell apoptosis and loss. Together, Axl is a key regulator of endothelial BMPR2 signaling and potential determinant of PAH

BET Bromodomain Inhibitors and Pulmonary Arterial Hypertension: Take Care of the Heart

Comment inReply to Piquereau and Perros and to Pullamsetti and de Jesus Perez. [Am J Respir Crit Care Med. 2019]Comment onMulticenter Preclinical Validation of BET Inhibition for the Treatment of Pulmonary Arterial Hypertension. [Am J Respir Crit Care Med. 2019]International audienceno abstrac

Hypertension artérielle pulmonaire

Il est admis que l’auto-immunité résulte d’une combinaison de risques, tels qu’un terrain génétique, des facteurs environnementaux déclenchants et des événements stochastiques inconnus. L’hypertension artérielle pulmonaire (HTAP) partage avec les maladies auto-immunes prototypiques les facteurs de risque génétiques, la prédominance féminine et son corollaire d’influence des hormones sexuelles, l’association à d’autres maladies inflammatoires ou auto-immunes, le déficit des fonctions immunorégulatrices et la présence d’auto-anticorps. Quelques cas indiquant l’effet bénéfique de thérapies immunosuppressives ou anti-inflammatoires dans l’HTAP sont rapportés, ce qui permet de recentrer les mécanismes immunitaires dans la physiopathologie de la maladie. Nous discutons dans cette revue des connaissances actuelles sur les mécanismes auto-immuns mis en œuvre dans l’HTAP, notamment l’élaboration d’une réponse immunitaire locale au sein du tissu pulmonaire, à savoir une néogenèse lymphoïde pulmonaire. Une meilleure compréhension du rôle de l’auto-immunité dans le remodelage vasculaire pourrait permettre de développer des stratégies d’immunomodulation ciblées dans l’HTAP

Response by Mendes-Ferreira et al to Letter Regarding Article, “Bmpr2 Mutant Rats Develop Pulmonary and Cardiac Characteristics of Pulmonary Arterial Hypertension”

Comment onBmpr2 Mutant Rats Develop Pulmonary and Cardiac Characteristics of Pulmonary Arterial Hypertension. [Circulation. 2019]Letter by Nadeau et al Regarding Article, "Bmpr2 Mutant Rats Develop Pulmonary and Cardiac Characteristics of Pulmonary Arterial Hypertension". [Circulation. 2019]International audienceno abstrac

Iron deficiency in pulmonary arterial hypertension: perspectives

In left heart failure, iron supplementation (IS) is a first-line treatment option, regardless of anemia. Pulmonary arterial hypertension (PAH), a rare disease leading to right heart failure, is also associated with iron deficiency. While it is a much debated topic, recent evidence demonstrate that restoration of iron stores results in improved right ventricular function and exercise tolerance. Hence, IS may also be considered as an option in the treatment of PAH