The Need to Recognize the Pulmonary Circulation and the Right Ventricle as an Integrated Functional Unit: Facts and Hypotheses (2013 Grover Conference series)

Voelkel, Norbert F.; Bogaard, Harm Jan; Gomez-Arroyo, José

doi:10.1086/679702

Cited by 23 publications

(21 citation statements)

References 46 publications

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“…Considering that autophagy may play a different role during different phases, [20] we sought to determine the autophagy signatures during the switch from compensatory hypertrophy to failing in the RV within the MCT model, as it progresses to PH. To reduce the variation of rats included, the rats at each time point were also carefully phenotyped (e.g., with hemodynamic, clinical, and echocardiography characteristics).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the MCT model is characterized by RV failure similar to humans, and is characterized by decreased activity, ascites, overall weight loss, and increased mortality [2, 3, 7]. Although the impact of autophagy has been extensively studied in the pulmonary vasculature in the MCT model, [18, 19] there is a paucity of data concerning the impact of autophagy in the RV in the model [20]. …”

Section: Introductionmentioning

confidence: 99%

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Altered mTOR and Beclin-1 mediated autophagic activation during right ventricular remodeling in monocrotaline-induced pulmonary hypertension

et al. 2017

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BackgroundRight ventricular structure and function is a major predictor of outcomes in pulmonary hypertension (PH), yet the underlying mechanisms remain poorly understood. Growing evidence suggests the importance of autophagy in cardiac remodeling; however, its dynamics in the process of right ventricle(RV) remodeling in PH has not been fully explored. We sought to study the time course of cardiomyocyte autophagy in the RV in PH and determine whether mammalian target of rapamycin (mTOR) and Beclin-1 hypoxia-related pro-autophagic pathways are underlying mechanisms.MethodsRats were studied at 2, 4, and 6 weeks after subcutaneous injection of 60 mg/kg monocrotaline (MCT) (MCT-2 W, 4 W, 6 W) or vehicle (CON-2 W, 4 W, 6 W). Cardiac hemodynamics and RV function were assessed in rats. Autophagy structures and markers were assessed using transmission electron microscope, RT-qPCR, immunohistochemistry staining, and western blot analyses. Western blot was also used to quantify the expression of mTOR and Beclin-1 mediated pro-autophagy signalings in the RV.ResultsTwo weeks after MCT injection, pulmonary artery systolic pressure increased and mild RV hypertrophy without RV dilation was observed. RV enlargement presented at 4 weeks with moderately decreased function, whereas typical characteristics of RV decompensation and failure occurred at 6 weeks thus demonstrating the progression of RV remodeling in the MCT model. A higher LC3 (microtubule- associated protein light chain 3) II/I ratio, upregulated LC3 mRNA and protein levels, as well as accumulation of autophagosomes in RV of MCT rats indicated autophagy induction. Autophagy activation was coincident with increased pulmonary artery systolic pressure. Pro-autophagy signaling pathways were activated in a RV remodeling stage-dependent manner since phospho-AMPK (adenosine monophosphate-activated protein kinase)-α were primarily upregulated and phospho-mTOR suppressed in the RV at 2 and 4 weeks post-MCT injection, whearas, BNIP3 (Bcl2-interacting protein 3) and beclin-1 expression were relatively low during these stages, they were significantly upregulated after 6 weeks in this model.ConclusionsOur findings provide evidence of sustained activation of autophagy in RV remodeling of MCT induced PH model, while pro-autophagic signaling pathways varied depending on the phase.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Altered mTOR and Beclin-1 mediated autophagic activation during right ventricular remodeling in monocrotaline-induced pulmonary hypertension

et al. 2017

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“…In many experimental studies in the literature, data interpretation is hampered by the lack of RV pressure-volume analysis (Borgdorff et al, 2015a) which remains the gold standard to assess the RV response to pressure overload (Vogel, 2008;Chesler et al, 2009;Spruijt et al, 2014;Voelkel et al, 2015). Indeed, the use of pressurevolume analysis as means of load-independent contractility measurements has long time been restricted to the LV since RV anatomy aggravates accurate conductance signal acquisition.…”

Section: Discussionmentioning

confidence: 99%

Maintained right ventricular pressure overload induces ventricular–arterial decoupling in mice

Böehm

Lawrie

Wilhelm

et al. 2017

Experimental Physiology

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This is the peer reviewed version of the following article: Boehm, M. et al (2016), Maintained right ventricular pressure overload induces ventricular-arterial decoupling in mice. Exp Physiol., which has been published in final form at https://doi.org/10.1113/EP085963. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request.This is an Accepted Article that has been peer-reviewed and approved for publication in the Experimental Physiology, but has yet to undergo copy-editing and proof correction. Please cite this article as an Accepted Article; doi: 10.1113/EP085963. This article is protected by copyright. All rights reserved. AbstractNew Findings: What is the central question of this study?The aim is to investigate whether complementary assessment of non-invasive ultrasound imaging along with closed chest-derived intra-cardiac pressure-volume catheterization is applicable to mice for an in-depth characterization of right ventricular (RV) function even upon maintained pressure overload. What is the main finding and its importance?Characterization

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“…Right ventricular dysfunction has now been recognized as a rate-limiting factor in patients with severe PAH; in fact, the quality of life and the outcome depend on the right ventricular functional reserve (156, 157). Experimentally, over-expression of various cytokines has been demonstrated in heart failure models.…”

Section: Right Heart Failure and Inflammationmentioning

confidence: 99%

Challenges and opportunities in treating inflammation associated with pulmonary hypertension

Voelkel

Tamošiūnienė

Nicolls

2016

Expert Review of Cardiovascular Therapy

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Inflammatory cells are present in the lungs from patients with many, if not all, forms of severe pulmonary hypertension. Historically the first inflammatory cell identified in the pulmonary vascular lesions was the mast cell. T and B lymphocytes, as well as macrophages, are present in and around the pulmonary arterioles and many patients have elevated blood levels of interleukin 1 and 6; some patients show elevated levels of leukotriene B4. An overlap between collagen-vascular disease-associated pulmonary arterial hypertension (PAH) and idiopathic PAH exists, yet only a few studies have been designed that evaluate the effect of anti-inflammatory treatments. Here we review the pertinent data that connect PAH and inflammation/immune dysregulation and evaluate experimental models of severe PAH with an emphasis on the Sugen/athymic rat model of severe PAH. We postulate that there are more than one inflammatory phenotype and predict that there will be several anti-inflammatory treatment strategies for severe PAH.

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The Need to Recognize the Pulmonary Circulation and the Right Ventricle as an Integrated Functional Unit: Facts and Hypotheses (2013 Grover Conference series)

Cited by 23 publications

References 46 publications

Altered mTOR and Beclin-1 mediated autophagic activation during right ventricular remodeling in monocrotaline-induced pulmonary hypertension

Altered mTOR and Beclin-1 mediated autophagic activation during right ventricular remodeling in monocrotaline-induced pulmonary hypertension

Maintained right ventricular pressure overload induces ventricular–arterial decoupling in mice

Challenges and opportunities in treating inflammation associated with pulmonary hypertension

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