Emerging Concepts and Translational Priorities in Pulmonary Arterial Hypertension

Michelakis, Evangelos D.; Wilkins, Martin R.; Rabinovitch, Marlene

doi:10.1161/circulationaha.106.673988

Cited by 131 publications

(117 citation statements)

References 100 publications

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“…PH has similarities to cancer as it is marked by a hyperproliferative diathesis and apoptosis-resistance in lung vascular cells (Michelakis et al, 2008). Our study showed apoptosis resistance as evident by lower number of TUNEL positive cells and decreased procaspase-3 expression in lungs of MCT-treated rats.…”

Section: Discussionsupporting

confidence: 52%

Withania somniferashows a protective effect in monocrotaline-induced pulmonary hypertension

Kaur¹,

Singh²,

Samuel³

et al. 2014

Pharmaceutical Biology

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Context: Withania somnifera (Linn.) Dunal (Solanaceae), a clinically used herbal drug in Ayurveda, shows potent antioxidant, anti-inflammatory, pro-apoptotic, and cardioprotective effects. However, the efficacy of W. somnifera in pulmonary hypertension (PH), a cardiopulmonary disorder, remains unexplored. Objective: The present study investigates the effect of W. somnifera root powder on monocrotaline (MCT)-induced PH in rats. Materials and methods: In preventive studies, W. somnifera root powder (50 and 100 mg/kg/d, p.o.) was administered from day 1 following single administration of MCT (60 mg/kg, s.c.) in Sprague-Dawley (SD) rats. After 35 d, right ventricular pressure (RVP) was measured in anesthetized rats. Various physical markers of right ventricular hypertrophy (RVH) were measured in isolated hearts. Markers of endothelial function, inflammation, and oxidative stress were estimated in lung homogenate. Vasoreactivity of pulmonary arteries was also studied. In therapeutic treatment, W. somnifera (50 and 100 mg/kg/d, p.o.) was administered from day 21 to 35 post-MCT administration. Results: Preventive treatment with 50 and 100 mg/kg W. somnifera significantly reduced the RVP (32.18 ± 1.273 mm Hg and 29.98 ± 1.119 mm Hg, respectively, versus 42.96 ± 1.789 mm Hg of MCT) and all markers of RVH in MCT-challenged rats. There was an improvement in inflammation, oxidative stress and endothelial dysfunction, and attenuation of proliferative marker and apoptotic resistance in lungs. Therapeutic treatment with W. somnifera (100 mg/kg) also reduced RVP and RVH. Discussion: This study demonstrated that W. somnifera significantly protected against MCTinduced PH due to its antioxidant, anti-inflammatory, pro-apoptotic, and cardioprotective properties.

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Section: Discussionsupporting

confidence: 52%

Withania somniferashows a protective effect in monocrotaline-induced pulmonary hypertension

Kaur¹,

Singh²,

Samuel³

et al. 2014

Pharmaceutical Biology

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“…This review, compiled by a search strategy of PubMed, using the terms pulmonary arterial hypertension with specification for articles published in English, seeks to provide contemporary and concise answers to the specific questions posed and concentrates specifically on category 1 (see later) pulmonary hypertension (PH) under the rubric of pulmonary arterial hypertension (PAH). For a more general overview, the reader is referred to several excellent recently published documents on guidelines, classification and therapy of PH 2-5…”

Section: Discussionmentioning

confidence: 99%

Contemporary insights into the pathogenesis, diagnosis and therapy of pulmonary arterial hypertension

Essop¹

2010

CardioVascular Journal of Africa

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SummaryCurrent data challenge the concept that pulmonary arterial hypertension (PAH) is purely a disorder of impaired vasomotor tone. Instead, we recognise today that the phenotype of PAH represents the complex and disordered regulation of expression of key signalling molecules and abnormal molecular trafficking. Discovery of mutations of the ubiquitous receptors of the transforming growth factor beta (TGF-β) superfamily in many patients with PAH has been instrumental in unravelling the pathobiology of this otherwise fatal disorder. Much still needs to be learnt before we are able to substantially alter the natural history of PAH. Until such time, therapies that fundamentally attempt to restore vasomotor tone continue to be developed and tested.Current clinical research in the therapeutic arena is focused on defining the best permutation of the three major groups of drugs – prostacyclin analogues, phosphodiesterase type-five inhibitors and the endothelin receptor antagonists. However, if we are to make any significant impact on the otherwise dismal outcome of PAH, we have to recognise that even more important than the challenge of new therapies, is the challenge in diagnosing the condition early in the course of its relentless progression to right heart failure and eventual death.

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“…Limitations of these models include the following: 1) monocrotaline and hypoxia models lack plexogenic lesions seen in human PAH; 2) hypoxia may induce only modest increases in right ventricular pressure and vascular remodeling; 3) hypoxia may not induce significant endothelial cell proliferation; and 4) in contrast to human PAH, the hypoxia-induced muscularization of the precapillary pulmonary arterioles and vasoconstriction are slowly reversible when normal oxygen levels are restored (106). There has been recent interest in VEGFR-2 blockade with SU5416 (Sugen) combined with hypoxia as a model of PAH, since studies in rats have demonstrated formation of plexiform lesions that have been lacking in the other models described (1).…”

Section: L491mentioning

confidence: 99%

Genetically manipulated mouse models of lung disease: potential and pitfalls

Baron

Choi

Owen

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Gene targeting in mice (transgenic and knockout) has provided investigators with an unparalleled armamentarium in recent decades to dissect the cellular and molecular basis of critical pathophysiological states. Fruitful information has been derived from studies using these genetically engineered mice with significant impact on our understanding, not only of specific biological processes spanning cell proliferation to cell death, but also of critical molecular events involved in the pathogenesis of human disease. This review will focus on the use of gene-targeted mice to study various models of lung disease including airways diseases such as asthma and chronic obstructive pulmonary disease, and parenchymal lung diseases including idiopathic pulmonary fibrosis, pulmonary hypertension, pneumonia, and acute lung injury. We will attempt to review the current technological approaches of generating gene-targeted mice and the enormous dataset derived from these studies, providing a template for lung investigators.

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Emerging Concepts and Translational Priorities in Pulmonary Arterial Hypertension

Cited by 131 publications

References 100 publications

Withania somniferashows a protective effect in monocrotaline-induced pulmonary hypertension

Withania somniferashows a protective effect in monocrotaline-induced pulmonary hypertension

Contemporary insights into the pathogenesis, diagnosis and therapy of pulmonary arterial hypertension

Genetically manipulated mouse models of lung disease: potential and pitfalls

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