2-Methoxyestradiol mediates the protective effects of estradiol in monocrotaline-induced pulmonary hypertension

Tofovic, Stevan P.; Zhang, Xichen; Jackson, Edwin K.; Đačić, Sanja; Petruševska, Gordana

doi:10.1016/j.vph.2006.05.007

Cited by 76 publications

(88 citation statements)

References 43 publications

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“…MCT-induced PH, similar to the human form of disease, is characterized by infiltration of inflammatory cells and significant remodeling of small-size pulmonary arteries as well as right ventricular hypertrophy and failure (46,55). The present data reveal that, in animals developing drug-induced PH, MAG-DPA treatment markedly inhibits the growth of cells involved in pulmonary vascular remodeling and results in a reduction in right ventricular hypertrophy and vascular remodeling of pulmonary arteries.…”

Section: Discussionsupporting

confidence: 56%

“…There were several limitations in the present study. The MCT model of PH has been thoroughly described and validated in the rat (55,57), and thus we have not performed intrapulmonary artery tension measurements. This study attests of the ability of MAG-DPA to prevent MCT-induced PH, in which inflammatory mechanisms related to pulmonary vascular endothelial dysfunction may contribute to the development and progression of pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

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Docosapentaenoic acid monoacylglyceride reduces inflammation and vascular remodeling in experimental pulmonary hypertension

Morin

Hiram

Rousseau

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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S. Docosapentaenoic acid monoacylglyceride reduces inflammation and vascular remodeling in experimental pulmonary hypertension. Am J Physiol Heart Circ Physiol 307: H574 -H586, 2014. First published June 14, 2014 doi:10.1152/ajpheart.00814.2013 Polyunsaturated fatty acids (n-3 PUFA) have been shown to reduce inflammation and proliferation of pulmonary artery smooth muscle cells under pathophysiological conditions. However, the anti-inflammatory effect of the newly synthesized docosapentaenoic acid monoacylglyceride (MAG-DPA) on key signaling pathways in pulmonary hypertension (PH) pathogenesis has yet to be assessed. The aim of the present study was to determine the effects of MAG-DPA on pulmonary inflammation and remodeling occurring in a rat model of PH, induced by a single injection of monocrotaline (MCT: 60 mg/kg). Our results demonstrate that MAG-DPA treatment for 3 wk following MCT injection resulted in a significant improvement of right ventricular hypertrophy (RVH) and a reduction in Fulton's Index (FI). Morphometric analyses revealed that the wall thickness of pulmonary arterioles was significantly lower in MCT ϩ MAG-DPA-treated rats compared with controls. This result was further correlated with a decrease in Ki-67 immunostaining. Following MAG-DPA treatments, lipid analysis showed a consistent increase in DPA together with lower levels of arachidonic acid (AA), as measured in blood and tissue samples. Furthermore, in MCT-treated rats, oral administration of MAG-DPA decreased NF-B and p38 MAPK activation, leading to a reduction in MMP-2, MMP-9, and VEGF expression levels in lung tissue homogenates. Altogether, these data provide new evidence regarding the mode of action of MAG-DPA in the prevention of pulmonary hypertension induced by MCT. docosapentaenoic acid; inflammation; pulmonary hypertension; nuclear factor-B; tumor necrosis factor-␣

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Docosapentaenoic acid monoacylglyceride reduces inflammation and vascular remodeling in experimental pulmonary hypertension

Morin

Hiram

Rousseau

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Chronic exposure of BMPR2 mutant mice to 16αOHE was associated with increased PH penetrance and severity compared with mutant mice not exposed to 16αOHE [68]. Conversely, studies have demonstrated that 2-OHE2 and 2-ME2 may exert protective effects in monocrotaline-induced PH in rats [69,70]. Due to their potentially opposing actions, it has been hypothesised that an imbalance in the production of E2 metabolites may play a role in human PAH pathogenesis.…”

Section: Oestrogen Signallingmentioning

confidence: 99%

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Hemnes

Humbert

2017

Eur Respir Rev

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The pathobiology of pulmonary arterial hypertension (PAH) is complex and incompletely understood. Although three pathogenic pathways have been relatively well characterised, it is widely accepted that dysfunction in a multitude of other cellular processes is likely to play a critical role in driving the development of PAH. Currently available therapies, which all target one of the three well-characterised pathways, provide significant benefits for patients; however, PAH remains a progressive and ultimately fatal disease. The development of drugs to target alternative pathogenic pathways is, therefore, an attractive proposition and one that may complement existing treatment regimens to improve outcomes for patients. Considerable research has been undertaken to identify the role of the less well-understood pathways and in this review we will highlight some of the key discoveries and the potential for utility as therapeutic targets.

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“…Although the incidence of PH remains higher in female patients (7), in various animal models females have been shown to be protected against PH (8)(9)(10), a phenomenon known as the "estrogen paradox" of PH. This sex difference in susceptibility to experimental PH has been suggested to be in part due to the action of estrogen (E2), as ovariectomy exacerbates PH and pretreatment with E2 and its metabolites attenuates the progression of different animal models of PH (4,9,11).…”

mentioning

confidence: 99%

“…This sex difference in susceptibility to experimental PH has been suggested to be in part due to the action of estrogen (E2), as ovariectomy exacerbates PH and pretreatment with E2 and its metabolites attenuates the progression of different animal models of PH (4,9,11).…”

mentioning

confidence: 99%

Estrogen Rescues Preexisting Severe Pulmonary Hypertension in Rats

Umar

Iorga²,

Matori³

et al. 2011

Am J Respir Crit Care Med

126

155

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Rationale: Pulmonary hypertension (PH) is characterized by progressive increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure, and death. Current treatments only temporarily reduce severity of the disease, and an ideal therapy is still lacking. Objectives: Estrogen pretreatment has been shown to attenuate development of PH. Because PH is not often diagnosed early, we examined if estrogen can rescue preexisting advanced PH. Methods: PH was induced in male rats with monocrotaline (60 mg/kg). At Day 21, rats were either treated with 17-b estradiol or estrogen (E2, 42.5 mg/kg/d), estrogen receptor-b agonist (diarylpropionitrile, 850 mg/kg/d), or estrogen receptor a-agonist (4,4',4"-[4-Propyl-(1H)-pyrazole-1,3,5-triyl] trisphenol, 850 mg/kg/d) for 10 days or left untreated to develop RV failure. Serial echocardiography, cardiac catheterization, immunohistochemistry, Western blot, and real-time polymerase chain reaction were performed. Measurements and Main Results: Estrogen therapy prevented progression of PH to RV failure and restored lung and RV structure and function. This restoration was maintained even after removal of estrogen at Day 30, resulting in 100% survival at Day 42. Estradiol treatment restored the loss of blood vessels in the lungs and RV. In the presence of angiogenesis inhibitor TNP-470 (30 mg/kg) or estrogen receptor-b antagonist (PHTPP, 850 mg/kg/d), estrogen failed to rescue PH. Estrogen receptor-b selective agonist was as effective as estrogen in rescuing PH. Conclusions: Estrogen rescues preexisting severe PH in rats by restoring lung and RV structure and function that are maintained even after removal of estrogen. Estrogen-induced rescue of PH is associated with stimulation of cardiopulmonary neoangiogenesis, suppression of inflammation, fibrosis, and RV hypertrophy. Furthermore, estrogen rescue is likely mediated through estrogen receptor-b.Keywords: pulmonary hypertension; estrogen; neoangiogenesis; estrogen receptors; inflammation Pulmonary hypertension (PH) is a chronic lung disease characterized by pulmonary vascular remodeling and progressive increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy and RV failure (RVF). End-stage RVF has long been regarded as a terminal state of pathological cardiopulmonary remodeling, including fibrosis and chamber dilation, being unresponsive to available therapies. Advanced PH is most often treated with aggressive nonpharmacological therapies, such as lung transplantation, but this approach is only feasible for a fraction of patients. In the past decade, cell and gene therapies have shown great potential for treatment of PH in animal models (1, 2) and humans (3). However, effective pharmacological therapy for treatment of patients with advanced PH would be much more practical and much more cost effective. Several agents have been identified to attenuate the development of PH when the therapy is started before the initiating stimuli (4-6). Unfortunately, up to now, there has been no id...

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2-Methoxyestradiol mediates the protective effects of estradiol in monocrotaline-induced pulmonary hypertension

Cited by 76 publications

References 43 publications

Docosapentaenoic acid monoacylglyceride reduces inflammation and vascular remodeling in experimental pulmonary hypertension

Docosapentaenoic acid monoacylglyceride reduces inflammation and vascular remodeling in experimental pulmonary hypertension

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Estrogen Rescues Preexisting Severe Pulmonary Hypertension in Rats

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