Persistence of complex vascular lesions despite prolonged prostacyclin therapy of pulmonary arterial hypertension

Pogoriler, Jennifer; Rich, Stuart; Archer, Stephen L.; Husain, Aliya N.

doi:10.1111/j.1365-2559.2012.04246.x

Cited by 39 publications

(31 citation statements)

References 35 publications

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“…However, autopsy studies have demonstrated that prostacyclin treatment does not reverse lung vascular remodelling in patients with PAH [13,14]. Similarly, we found that inhaled iloprost treatment did not reverse lung vascular remodelling in the SuHx rat model of PAH.…”

Section: Discussionsupporting

confidence: 45%

“…Because multiple studies have shown that prostacyclin treatment significantly increases cardiac output [6,7], improves functional capacity [8] and has been associated with improved survival [9], prostanoids have become the recommended treatment for patients with severe PAH, particularly for those with severe right ventricle (RV) dysfunction [10]. Whereas it has been generally assumed that the therapeutic effect of prostacyclins is explained by pulmonary vasodilation and modulation of vascular remodelling [5,11], many clinical trials have demonstrated a limited effect in reducing mean pulmonary arterial pressure [12], and there is recent evidence showing that lung vascular remodelling is not reduced even after long-term treatment [13,14]. Because the mechanisms whereby prostacyclin treatment improves cardiac performance and functional capacity remain largely undetermined, we hypothesised that prostanoids have direct cardiac effects that improve RV function without necessarily affecting lung vascular remodelling.…”

Section: Introductionmentioning

confidence: 99%

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Iloprost reverses established fibrosis in experimental right ventricular failure

et al. 2014

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Prostacyclin and its analogues improve cardiac output and functional capacity in patients with pulmonary arterial hypertension (PAH); however, the underlying mechanism is not fully understood. We hypothesised that prostanoids have load-independent beneficial effects on the right ventricle (RV).Angio-obliterative PAH and RV failure were induced in rats with a single injection of SU5416 followed by 4 weeks of exposure to hypoxia. Upon confirmation of RV dysfunction and PAH, rats were randomised to 0.1 μg·kg −1 nebulised iloprost or drug-free vehicle, three times daily for 2 weeks. RV function and treadmill running time were evaluated pre-and post-iloprost/vehicle treatment. Pulmonary artery banded rats were treated 8 weeks after surgery to allow for significant RV hypertrophy.Inhaled iloprost significantly improved tricuspid annulus plane systolic excursion and increased exercise capacity, while mean pulmonary artery pressure and the percentage of occluded pulmonary vessels remained unchanged. Rats treated with iloprost had a striking reduction in RV collagen deposition, procollagen mRNA levels and connective tissue growth factor expression in both SU5416/hypoxia and pulmonary artery banded rats. In vitro, cardiac fibroblasts treated with iloprost showed a reduction in transforming growth factor (TGF)-β1-induced connective tissue growth factor expression, in a protein kinase A-dependent manner. Iloprost decreased TGF-β1-induced procollagen mRNA expression as well as cardiac fibroblast activation and migration. Iloprost significantly induced metalloproteinase-9 gene expression and activity and increased the expression of autophagy genes associated with collagen degradation.Inhaled iloprost improves RV function and reverses established RV fibrosis partially by preventing collagen synthesis and by increasing collagen turnover. @ERSpublications Prostanoids have load-independent effects on the right ventricle that could contribute to improvement in #PAH http://ow.ly/Ae5Om

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Section: Discussionsupporting

confidence: 45%

Section: Introductionmentioning

confidence: 99%

Iloprost reverses established fibrosis in experimental right ventricular failure

et al. 2014

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“…In a recent series of 354 patients with PAH on therapy, the 3-year survival rate was reported to be 58% (52). Furthermore, the patients on prostacyclin therapy for a longer duration exhibit worse pulmonary vascular pathology compared with the ones on a shorter duration (103), underscoring the progressive nature of the disease despite modern therapy. Group 2: PH secondary to left heart diseases; group 3: PH secondary to chronic lung diseases and associated hypoxia; group 4: PH associated with chronic thrombo-embolism; group 5 includes PH associated with a variety of unrelated diseases such as sarcoidosis, metabolic and hematologic disorders, myeloproliferative diseases, chronic renal failure on dialysis and thyroid diseases.…”

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confidence: 97%

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Mathew

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Mathew R. Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. Am J Physiol Heart Circ Physiol 306: H15-H25, 2014. First published October 25, 2013 doi:10.1152/ajpheart.00266.2013.-Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality rate. Despite important advances in the field, the precise mechanisms leading to PH are not yet understood. Main features of PH are loss of vasodilatory response, the activation of proliferative and antiapoptotic pathways leading to pulmonary vascular remodeling and obstruction, elevated pressure and right ventricular hypertrophy, resulting in right ventricular failure and death. Experimental studies suggest that endothelial dysfunction may be the key underlying feature in PH. Caveolin-1, a major protein constituent of caveolae, interacts with several signaling molecules including the ones implicated in PH and modulates them. Disruption and progressive loss of endothelial caveolin-1 with reciprocal activation of proliferative pathways occur before the onset of PH, and the rescue of caveolin-1 inhibits proliferative pathways and attenuates PH. Extensive endothelial damage/loss occurs during the progression of the disease with subsequent enhanced expression of caveolin-1 in smooth muscle cells. This caveolin-1 in smooth muscle cells switches from being an antiproliferative factor to a proproliferative one and participates in cell proliferation and cell migration, possibly leading to irreversible PH. In contrast, the disruption of endothelial caveolin-1 is not observed in the hypoxia-induced PH, a reversible form of PH. However, proliferative pathways are activated in this model, indicating caveolin-1 dysfunction. Thus disruption or dysfunction of endothelial caveolin-1 leads to PH, and the status of caveolin-1 may determine the reversibility versus irreversibility of PH. This article reviews the role of caveolin-1 and cell membrane integrity in the pathogenesis and progression of PH.caveolin-1; endothelial cells; pulmonary hypertension; smooth muscle cells THIS ARTICLE is part of a collection on Pathophysiology of Hypertension. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.In 1891, Ernst von Romberg, a German physician, described histological changes in pulmonary hypertension (PH) as pulmonary vascular sclerosis (30). Since then remarkable advances have been made in the understanding of PH, but the pathogenesis of PH still remains elusive, partly because a number of diseases can lead to PH and multiple signaling pathways are implicated in PH. Furthermore, not all signaling pathways are activated in a given patient, and their activation may depend on the stage of the disease. Experimental data suggest that the vascular changes occur before the onset of PH (47,48). Therefore, it is not surprising that by the time the diagnosis of PH is made, most patients have significant pathological changes in pulmonary vasculatu...

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“…A limitation in the current treatment of patients with PAH is the inability of prostanoids, endothelin receptor blockers, phosphodiesterase inhibitors, or their various combinations to reverse the pulmonary arteriopathy. 2,3 An effective strategy in the development of more efficacious therapy would be to identify the molecular determinants of the arterial wall remodeling.…”

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confidence: 99%

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

et al. 2016

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Despite several advances in the pathobiology of pulmonary arterial hypertension (PAH), its pathogenesis is not completely understood. Current therapy improves symptoms but has disappointing effects on survival. Sphingosine-1-phosphate (S1P) is a lysophospholipid synthesized by sphingosine kinase 1 (SphK1) and SphK2. Considering the regulatory roles of S1P in several tissues leading to vasoconstriction, inflammation, proliferation, and fibrosis, we investigated whether S1P plays a role in the pathogenesis of PAH. To test this hypothesis, we used plasma samples and lung tissue from patients with idiopathic PAH (IPAH) and the Sugen5416/hypoxia/normoxia rat model of occlusive PAH. Our study revealed an increase in the plasma concentration of S1P in patients with IPAH and in early and late stages of PAH in rats. We observed increased expression of both SphK1 and SphK2 in the remodeled pulmonary arteries of patients with IPAH and PAH rats. Exogenous S1P stimulated the proliferation of cultured rat pulmonary arterial endothelial and smooth-muscle cells. We also found that 3 weeks of treatment of late-stage PAH rats with an SphK1 inhibitor reduced the increased plasma levels of S1P and the occlusive pulmonary arteriopathy. Although inhibition of SphK1 improved cardiac index and the total pulmonary artery resistance index, it did not reduce right ventricular systolic pressure or right ventricular hypertrophy. Our study supports that S1P is involved in the pathogenesis of occlusive arteriopathy in PAH and provides further evidence that S1P signaling may be a novel therapeutic target.Keywords: occlusive lesions, S1P, pulmonary, cardiac. Pulmonary arterial hypertension (PAH) remains debilitating and deadly despite advanced and expensive medical treatment. 1 Its pathogenic mechanisms have not been fully identified and therapeutically targeted. A limitation in the current treatment of patients with PAH is the inability of prostanoids, endothelin receptor blockers, phosphodiesterase inhibitors, or their various combinations to reverse the pulmonary arteriopathy. 2,3 An effective strategy in the development of more efficacious therapy would be to identify the molecular determinants of the arterial wall remodeling.Sphingosine-1-phosphate (S1P) is a biologically active lipid synthesized intracellularly by sphingosine kinase 1 (SphK1) and SphK2 and degraded by S1P lyase and various phosphatases. It is released by endothelial cells, red blood cells, activated platelets, and monocytes and has regulatory roles in several physiological and pathological processes. 4,5 Physiological levels of circulating S1P are vasculoprotective, whereas abnormal activation of SphK/S1P signaling is associated with diseases such as cancer, fibrosis, diabetes, and hypertension. [6][7][8][9][10] At high cellular or tissue levels, S1P is a proproliferative, antiapoptotic, promigratory, profibrotic, and proinflammatory signaling molecule. 11 SphK activity and S1P production are stimulated by numerous signals, including growth factors, cytokines, m...

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Persistence of complex vascular lesions despite prolonged prostacyclin therapy of pulmonary arterial hypertension

Cited by 39 publications

References 35 publications

Iloprost reverses established fibrosis in experimental right ventricular failure

Iloprost reverses established fibrosis in experimental right ventricular failure

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

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