Pathogenic mechanisms of pulmonary arterial hypertension

Chan, Stephen Y.; Loscalzo, Joseph

doi:10.1016/j.yjmcc.2007.09.006

Cited by 229 publications

(191 citation statements)

References 236 publications

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“…Sildenafil decreases the activity of myosin light chain kinase and reduces the speed of myosin phosphorylation, so that the smooth muscle cell is contractility reduced, and pulmonary vascular smooth muscle can dilate (Ignarro, 1990). Secondly, sildenafil reduces pulmonary arterial pressure, decreasing the shearing forces on endothelial cells and the mRNA expression of vascular endothelial growth factor (VEGF) (Chan and Loscalzo, 2008;Rondelet et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Sildenafil up-regulates Kv1.5 mRNA expression in rats with pulmonary hypertension

Hu¹

2011

Afr. J. Pharm. Pharmacol.

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The effects of sildenafil on pulmonary vascular remodeling as well as potassium channels (Kv1.5) activity of pulmonary vasculature has not been clearly addressed in pulmonary hypertension secondary to left-to-right shunt. A rat model with pulmonary hypertension secondary to left-to-right shunt was established by performing an abdominal aorta to inferior vena cava fistula. Twenty-seven male Sprague-Dawley (SD) rats were randomly assigned into sham group (n = 9), shunt group (n = 9) and shunt + sildenafil group (n = 9). Rats in shunt + sildenafil group were fed with sildenafil 10 mg/kg/day instantly after shunt was established, whereas the rats in the sham group and the shunt group were fed with normal saline of the same volume. Eleven weeks later, the mean pulmonary artery pressure (mPAP), the ratio of right ventricular mass to left ventricular plus septal mass [RV/(LV +S)], the relative medial thickness (RMT) of middle and small pulmonary muscularized arteries, as well as the expression of voltage-gated potassium channel Kv1.5 mRNA in pulmonary vasculature were detected. The rats in shunt group developed pulmonary hypertension as evidenced by significant increase in mPAP, RV/(LV +S) and RMT (all P < 0.01), meanwhile, the Kv1.5 mRNA expression in pulmonary vasculature decreased (P < 0.01). Compared with the shunt group, the rats in shunt + sildenafil group had a significant decrease in mPAP, RV/(LV+S) and RMT and a significant increase in the expression of Kv1.5 mRNA (all P < 0.01). Interestingly, there were no statistically significant differences between sham group and shunt + sildenafil group in mPAP, RV/(LV +S), RMT and expression of Kv1.5 mRNA (all P > 0.01). Sildenafil attenuates pulmonary vascular remodeling and up-regulates Kv1.5 mRNA expression in rats with pulmonary hypertension secondary to left-to-right shunt.

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Section: Discussionmentioning

confidence: 99%

Sildenafil up-regulates Kv1.5 mRNA expression in rats with pulmonary hypertension

Hu¹

2011

Afr. J. Pharm. Pharmacol.

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“…Both might contribute to vascular remodeling in end-stage disease in PAH patients. [3][4][5] In hypoxia, Egr-1 has been shown to be up-regulated in lungs 22,23 and isolated fibroblasts 24 subjected to chronic hypoxia. Focusing on the pulmonary vessels, Yan and colleagues 22 have shown that in lungs of mice subjected to hypoxia, Egr-1 is specifically produced in pulmonary vessel smooth muscle cell.…”

Section: Egr-1 Transcription During Pulmonary Vascular Remodelingmentioning

confidence: 99%

“…NAB2 may have its Egr-1 in PAH Development 2207 AJP November 2011, Vol. 179,No. 5 direct effect on preventing a permanent transcription of Egr-1, as seen at early-stage PAH (MϩF 14).…”

Section: Egr-1 Transcription During Pulmonary Vascular Remodelingmentioning

confidence: 99%

“…This finding shows that inflammatory processes, in this case macrophage infiltration, may contribute to neointimal development as seen in end-stage vascular remodeling in human PAH. 29,30 -31 Egr-1 is also located upstream of numerous other genes, such as platelet-derived growth factor 3,5,32 and tissue factor, 9 that participate in PAH. 9 Egr-1 could thus be an important early factor in PAH by regulating different genes involved in neointimal development.…”

Section: Egr-1 Transcription During Pulmonary Vascular Remodelingmentioning

confidence: 99%

“…2,3 These neointimal lesions cause intraluminal obstruction arising from proliferation of endothelial and smooth muscle cells, fibrosis, and inflammation. 2,4,5 In congenital heart disease, increased pulmonary blood flow is an essential trigger for neointimal formation and disease development. Although neointimal development is well-described histopathologically, the pathogenesis of PAH and its typical vascular lesions is largely unknown.…”

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Egr-1 Expression During Neointimal Development in Flow-Associated Pulmonary Hypertension

Dickinson

Bartelds

Molema

et al. 2011

The American Journal of Pathology

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In flow-associated pulmonary arterial hypertension (PAH), increased pulmonary blood flow is an essential trigger for neointimal formation. Using microarray analysis, we recently found that the early growth response protein 1 (Egr-1) transcription factor is increased in experimental flow-associated end-stage PAH. Its role in PAH development is unknown. Here, we assessed the spatiotemporal expression of Egr-1 during neointimal development in flow-associated PAH. Flow-associated PAH was produced in rats by combining monocrotaline administration with an aortocaval shunt. Animals were sacrificed 1 day before or 1 day, 1 week, or 4 to 5 weeks after flow addition. Egr-1 expression was spatiotemporally assessed using laser microdissection, quantitative realtime PCR and immunohistochemistry. In addition, Egr-1 expression was assessed in a non-neointimal pulmonary hypertension model and in human PAH associated with congenital shunt. In 4 to 5 weeks, rats subjected to increased flow developed PAH with neointimal lesions. Egr-1 mRNA was increased 1 day after flow addition and in end-stage PAH, whereas monocrotaline only did not result in increased Egr-1 mRNA. Directly after flow addition, Egr-1 was expressed in endothelial cells. During disease development, Egr-1 protein expression increased and migrated throughout the vessel wall. In PAH patients, Egr-1 was expressed in vessels with media hypertrophy and neo- Pulmonary arterial hypertension (PAH) is a vasoproliferative disorder in which vascular obstruction of the small pulmonary arteries leads to an increased pulmonary vascular resistance and eventually death. 1 PAH is considered irreversible when pulmonary vascular remodeling is characterized by the development of unique neointimal lesions, including concentric laminar intima fibrosis and plexiform lesions. 2,3 These neointimal lesions cause intraluminal obstruction arising from proliferation of endothelial and smooth muscle cells, fibrosis, and inflammation. 2,4,5 In congenital heart disease, increased pulmonary blood flow is an essential trigger for neointimal formation and disease development. Although neointimal development is well-described histopathologically, the pathogenesis of PAH and its typical vascular lesions is largely unknown. Several animal models have been described to investigate the pathogenesis of PAH. 6 The toxic alkaloid monocrotaline model is a commonly used experimental model of pulmonary hypertension. However, in this model neointimal lesions, typical for irreversible PAH, 3 are not seen. We and other investigators have shown that combining monocrotaline with an increased pulmonary blood flow results in pulmonary neointimal lesions in end-stage disease. [7][8][9][10] Little is known about the development of these lesions during disease progression.In a rat model of flow-associated PAH, we recently identified the early growth response protein 1 (Egr-1) transcription factor, by microarray analysis, to be upregulated in end-stage PAH only when increased pulmonary blood flow was added to monocrotalin...

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Prevention and treatment of radiotherapy‐induced side effects

2020

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Radiotherapy remains a mainstay of cancer treatment, being used in roughly 50% of patients. The precision with which the radiation dose can be delivered is rapidly improving. This precision allows the more accurate targeting of radiation dose to the tumor and reduces the amount of surrounding normal tissue exposed. Although this often reduces the unwanted side effects of radiotherapy, we still need to further improve patients' quality of life and to escalate radiation doses to tumors when necessary. Highprecision radiotherapy forces one to choose which organ or functional organ substructures should be spared. To be able to make such choices, we urgently need to better understand the molecular and physiological mechanisms of normal tissue responses to radiotherapy. Currently, oversimplified approaches using constraints on mean doses, and irradiated volumes of normal tissues are used to plan treatments with minimized risk of radiation side effects. In this review, we discuss the responses of three different normal tissues to radiotherapy: the salivary glands, cardiopulmonary system, and brain. We show that although they may share very similar local cellular processes, they respond very differently through organ-specific, nonlocal mechanisms. We also discuss how a better knowledge of these mechanisms can be used to treat or to prevent the effects of radiotherapy on normal tissue and to optimize radiotherapy delivery.

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Pathogenic mechanisms of pulmonary arterial hypertension

Cited by 229 publications

References 236 publications

Sildenafil up-regulates Kv1.5 mRNA expression in rats with pulmonary hypertension

Sildenafil up-regulates Kv1.5 mRNA expression in rats with pulmonary hypertension

Egr-1 Expression During Neointimal Development in Flow-Associated Pulmonary Hypertension

Prevention and treatment of radiotherapy‐induced side effects

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