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Jane A. Mitchell - One of the best experts on this subject based on the ideXlab platform.
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kidney transplantation in a patient lacking cytosolic phospholipase a2 proves renal origins of urinary pgi m and tx m
Circulation Research, 2018Co-Authors: Jane A. Mitchell, Nicholas S. Kirkby, Daniel M. Reed, Rebecca Knowles, Matthew L Edin, William White, Melissa V Chan, Hilary Longhurst, Magdi Yaqoob, Ginger L MilneAbstract:Rationale: The balance between vascular Prostacyclin which is anti-thrombotic and platelet thromboxane A 2 which is pro-thrombotic is fundamental to cardiovascular health. Prostacyclin and thromboxane A 2 are formed following the concerted actions of cytosolic phospholipase A 2 (cPLA 2α ) and cyclooxygenase. Urinary 2,3-dinor-6-keto PGF1 α (PGI-M) and 11-dehydro-TXB2 (TX-M) have been taken as biomarkers of Prostacyclin and thromboxane A 2 formation with the circulation and used to explain cyclooxygenase biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. Objective: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA 2α , causing almost complete loss of Prostacyclin and thromboxane A 2 , who was transplanted with a normal kidney resulting in an experimental scenario of 9whole body cPLA2α knockout, kidney specific knock-in9. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of Prostacyclin and thromboxane A 2 in the circulation. Methods and Results: Metabolites were measured using LC-MS/MS. Endothelial cells were grown from blood progenitors. Before kidney transplantation the patient9s endothelial cells and platelets released negligible levels of Prostacyclin (measured as 6-ketoPGF 1α ) and thromboxane A 2 (measured as TXB 2 ), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. Following transplantation and the establishment of normal renal function the levels of PGI-M and TX-M in the patient9s urine rose to within normal ranges while endothelial production of Prostacyclin and platelet production of thromboxane A 2 remained negligible. Conclusions: This data shows that PGI-M and TX-M can be derived exclusively from the kidney without contribution from Prostacyclin made by endothelial cells or thromboxane A 2 by platelets in the general circulation. Previous work relying upon urinary metabolites of Prostacyclin and thromboxane A 2 as markers of whole body endothelial and platelet function now requires re-evaluation.
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abstract 20347 kidney transplantation in a patient lacking cytosolic phospholipase a2 leads to urinary Prostacyclin and thromboxane a2 metabolites within normal ranges
Circulation, 2016Co-Authors: Jane A. Mitchell, Nicholas S. Kirkby, Daniel M. Reed, Ginger L Milne, Rebecca Knowles, Matthew L Edin, William White, Hilary Longhurst, Magdi Yaqoob, Darryl C ZeldinAbstract:Measurements of metabolites of Prostacyclin and thromboxane A 2 (TXA 2 ) in the urine have been held as the best estimates of eicosanoid production in the circulation. As such, measurement of these urinary markers has been used to inform (i) drug action in clinical studies, (ii) personal risk of cardiovascular disease in patient groups and (iii) a plethora of basic science relating to eicosanoids, particularly in regard to cyclooxygenase biology and the general idea that Prostacyclin in the circulation is formed by cyclooxygenase-2. However, urinary markers are not universally accepted as reflective of the circulation, with some studies indicating that they originate in the kidney. We have previously reported a patient with genetic cytosolic phospholipase A 2 (cPLA 2 α) deficiency, who lacks the capacity to generate Prostacyclin in endothelial cells and TXA 2 in platelets. This patient has now undergone a kidney transplant receiving a genetically normal organ and creating a truly unique experimental model akin to a human ‘whole body cPLA2α knockout, kidney specific knock-in’, for the determination of sites of eicosanoid production. Here we have used samples from this individual including endothelial cells grown from blood progenitors, before and after kidney transplant, to allow us to definitively establish the role of the kidney versus the circulation in generation of urinary Prostacyclin and TXA 2 metabolites. Before transplant, endothelial Prostacyclin, platelet TXA 2 and urinary metabolites of both PGI-M and TX-M were very greatly below the normal range. After transplantation, endothelial Prostacyclin and platelet TXA 2 production remained negligible whereas the urinary metabolites PGI-M and TX-M were brought into the normal range. These results not only describe a unique clinical case but also demonstrate that the kidney alone can produce urinary metabolites of Prostacyclin and TXA 2 within the normal range. Consequently, urinary metabolites cannot be relied upon as surrogates for production in the systemic circulation. We must now revisit and reinterpret studies in which PGI-M and TX-M have been used as indicators of cardiovascular health, function and risk.
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Role of Prostacyclin in pulmonary hypertension
Global cardiology science & practice, 2014Co-Authors: Jane A. Mitchell, Blerina Ahmetaj-shala, Nicholas S. Kirkby, William R. Wright, Louise Mackenzie, Daniel M. Reed, Nura A. MohamedAbstract:Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it's discovery in the 1970s concerted efforts have been made to make the best therapeutic utility of Prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of Prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of Prostacyclin but that target the receptors that Prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of Prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of Prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to Prostacyclin and its use in pulmonary arterial hypertension.
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role of nitric oxide and Prostacyclin as vasoactive hormones released by the endothelium
Experimental Physiology, 2008Co-Authors: Jane A. Mitchell, Ferhana Y Ali, Lucy Bailey, Laura Moreno, Louise S HarringtonAbstract:The endothelium lines the luminal surface of every blood vessel, allowing it contact with circulating blood elements, as well as the underlying vascular smooth muscle layer. In healthy vessels, the endothelium expresses constitutive forms of nitric oxide synthase (NOSIII) and cyclo-oxygenase (COX-1), which produce the vasoactive hormones NO and Prostacyclin, respectively. Both NO and Prostacyclin relax blood vessels and inhibit platelet activation. The actions of Prostacyclin are mediated by cell surface Prostacyclin (IP) receptors and/or intracellular peroxisome proliferator-activated receptors (PPAR) beta. The actions of NO are mediated predominately by activation of intracellular guanylyl cyclase, leading to the formation of cGMP. In platelets, the actions of NO and Prostacyclin are synergistic, but in vessels their actions are additive. In diseased vessels, inducible forms of NOS (NOSII) and cyclo-oxygeanse (COX-2) are expressed in vascular smooth muscle, resulting in the release of large amounts of NO, Prostacyclin and prostaglandin E2. The relative contribution of NOSII and COX-2 to vascular inflammation is still debated, but is likely to result in both protective and damaging responses. The relative contribution of constitutive forms of NOS and COX, as well as interactions between IP, PPAR beta and guanylyl cyclase pathways in vessels and platelets, is discussed.
Ginger L Milne - One of the best experts on this subject based on the ideXlab platform.
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kidney transplantation in a patient lacking cytosolic phospholipase a2 proves renal origins of urinary pgi m and tx m
Circulation Research, 2018Co-Authors: Jane A. Mitchell, Nicholas S. Kirkby, Daniel M. Reed, Rebecca Knowles, Matthew L Edin, William White, Melissa V Chan, Hilary Longhurst, Magdi Yaqoob, Ginger L MilneAbstract:Rationale: The balance between vascular Prostacyclin which is anti-thrombotic and platelet thromboxane A 2 which is pro-thrombotic is fundamental to cardiovascular health. Prostacyclin and thromboxane A 2 are formed following the concerted actions of cytosolic phospholipase A 2 (cPLA 2α ) and cyclooxygenase. Urinary 2,3-dinor-6-keto PGF1 α (PGI-M) and 11-dehydro-TXB2 (TX-M) have been taken as biomarkers of Prostacyclin and thromboxane A 2 formation with the circulation and used to explain cyclooxygenase biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. Objective: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA 2α , causing almost complete loss of Prostacyclin and thromboxane A 2 , who was transplanted with a normal kidney resulting in an experimental scenario of 9whole body cPLA2α knockout, kidney specific knock-in9. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of Prostacyclin and thromboxane A 2 in the circulation. Methods and Results: Metabolites were measured using LC-MS/MS. Endothelial cells were grown from blood progenitors. Before kidney transplantation the patient9s endothelial cells and platelets released negligible levels of Prostacyclin (measured as 6-ketoPGF 1α ) and thromboxane A 2 (measured as TXB 2 ), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. Following transplantation and the establishment of normal renal function the levels of PGI-M and TX-M in the patient9s urine rose to within normal ranges while endothelial production of Prostacyclin and platelet production of thromboxane A 2 remained negligible. Conclusions: This data shows that PGI-M and TX-M can be derived exclusively from the kidney without contribution from Prostacyclin made by endothelial cells or thromboxane A 2 by platelets in the general circulation. Previous work relying upon urinary metabolites of Prostacyclin and thromboxane A 2 as markers of whole body endothelial and platelet function now requires re-evaluation.
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abstract 20347 kidney transplantation in a patient lacking cytosolic phospholipase a2 leads to urinary Prostacyclin and thromboxane a2 metabolites within normal ranges
Circulation, 2016Co-Authors: Jane A. Mitchell, Nicholas S. Kirkby, Daniel M. Reed, Ginger L Milne, Rebecca Knowles, Matthew L Edin, William White, Hilary Longhurst, Magdi Yaqoob, Darryl C ZeldinAbstract:Measurements of metabolites of Prostacyclin and thromboxane A 2 (TXA 2 ) in the urine have been held as the best estimates of eicosanoid production in the circulation. As such, measurement of these urinary markers has been used to inform (i) drug action in clinical studies, (ii) personal risk of cardiovascular disease in patient groups and (iii) a plethora of basic science relating to eicosanoids, particularly in regard to cyclooxygenase biology and the general idea that Prostacyclin in the circulation is formed by cyclooxygenase-2. However, urinary markers are not universally accepted as reflective of the circulation, with some studies indicating that they originate in the kidney. We have previously reported a patient with genetic cytosolic phospholipase A 2 (cPLA 2 α) deficiency, who lacks the capacity to generate Prostacyclin in endothelial cells and TXA 2 in platelets. This patient has now undergone a kidney transplant receiving a genetically normal organ and creating a truly unique experimental model akin to a human ‘whole body cPLA2α knockout, kidney specific knock-in’, for the determination of sites of eicosanoid production. Here we have used samples from this individual including endothelial cells grown from blood progenitors, before and after kidney transplant, to allow us to definitively establish the role of the kidney versus the circulation in generation of urinary Prostacyclin and TXA 2 metabolites. Before transplant, endothelial Prostacyclin, platelet TXA 2 and urinary metabolites of both PGI-M and TX-M were very greatly below the normal range. After transplantation, endothelial Prostacyclin and platelet TXA 2 production remained negligible whereas the urinary metabolites PGI-M and TX-M were brought into the normal range. These results not only describe a unique clinical case but also demonstrate that the kidney alone can produce urinary metabolites of Prostacyclin and TXA 2 within the normal range. Consequently, urinary metabolites cannot be relied upon as surrogates for production in the systemic circulation. We must now revisit and reinterpret studies in which PGI-M and TX-M have been used as indicators of cardiovascular health, function and risk.
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cyclooxygenase 1 not cyclooxygenase 2 is responsible for physiological production of Prostacyclin in the cardiovascular system
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Nicholas S. Kirkby, Martina H Lundberg, Louise S Harrington, P D M Leadbeater, Ginger L Milne, Claire M F Potter, Malak AlyamaniAbstract:Prostacyclin is an antithrombotic hormone produced by the endothelium, whose production is dependent on cyclooxygenase (COX) enzymes of which two isoforms exist. It is widely believed that COX-2 drives Prostacyclin production and that this explains the cardiovascular toxicity associated with COX-2 inhibition, yet the evidence for this relies on indirect evidence from urinary metabolites. Here we have used a range of experimental approaches to explore which isoform drives the production of Prostacyclin in vitro and in vivo. Our data show unequivocally that under physiological conditions it is COX-1 and not COX-2 that drives Prostacyclin production in the cardiovascular system, and that urinary metabolites do not reflect Prostacyclin production in the systemic circulation. With the idea that COX-2 in endothelium drives Prostacyclin production in healthy individuals removed, we must seek new answers to why COX-2 inhibitors increase the risk of cardiovascular events to move forward with drug discovery and to enable more informed prescribing advice.
Nicholas S. Kirkby - One of the best experts on this subject based on the ideXlab platform.
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kidney transplantation in a patient lacking cytosolic phospholipase a2 proves renal origins of urinary pgi m and tx m
Circulation Research, 2018Co-Authors: Jane A. Mitchell, Nicholas S. Kirkby, Daniel M. Reed, Rebecca Knowles, Matthew L Edin, William White, Melissa V Chan, Hilary Longhurst, Magdi Yaqoob, Ginger L MilneAbstract:Rationale: The balance between vascular Prostacyclin which is anti-thrombotic and platelet thromboxane A 2 which is pro-thrombotic is fundamental to cardiovascular health. Prostacyclin and thromboxane A 2 are formed following the concerted actions of cytosolic phospholipase A 2 (cPLA 2α ) and cyclooxygenase. Urinary 2,3-dinor-6-keto PGF1 α (PGI-M) and 11-dehydro-TXB2 (TX-M) have been taken as biomarkers of Prostacyclin and thromboxane A 2 formation with the circulation and used to explain cyclooxygenase biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. Objective: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA 2α , causing almost complete loss of Prostacyclin and thromboxane A 2 , who was transplanted with a normal kidney resulting in an experimental scenario of 9whole body cPLA2α knockout, kidney specific knock-in9. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of Prostacyclin and thromboxane A 2 in the circulation. Methods and Results: Metabolites were measured using LC-MS/MS. Endothelial cells were grown from blood progenitors. Before kidney transplantation the patient9s endothelial cells and platelets released negligible levels of Prostacyclin (measured as 6-ketoPGF 1α ) and thromboxane A 2 (measured as TXB 2 ), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. Following transplantation and the establishment of normal renal function the levels of PGI-M and TX-M in the patient9s urine rose to within normal ranges while endothelial production of Prostacyclin and platelet production of thromboxane A 2 remained negligible. Conclusions: This data shows that PGI-M and TX-M can be derived exclusively from the kidney without contribution from Prostacyclin made by endothelial cells or thromboxane A 2 by platelets in the general circulation. Previous work relying upon urinary metabolites of Prostacyclin and thromboxane A 2 as markers of whole body endothelial and platelet function now requires re-evaluation.
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abstract 20347 kidney transplantation in a patient lacking cytosolic phospholipase a2 leads to urinary Prostacyclin and thromboxane a2 metabolites within normal ranges
Circulation, 2016Co-Authors: Jane A. Mitchell, Nicholas S. Kirkby, Daniel M. Reed, Ginger L Milne, Rebecca Knowles, Matthew L Edin, William White, Hilary Longhurst, Magdi Yaqoob, Darryl C ZeldinAbstract:Measurements of metabolites of Prostacyclin and thromboxane A 2 (TXA 2 ) in the urine have been held as the best estimates of eicosanoid production in the circulation. As such, measurement of these urinary markers has been used to inform (i) drug action in clinical studies, (ii) personal risk of cardiovascular disease in patient groups and (iii) a plethora of basic science relating to eicosanoids, particularly in regard to cyclooxygenase biology and the general idea that Prostacyclin in the circulation is formed by cyclooxygenase-2. However, urinary markers are not universally accepted as reflective of the circulation, with some studies indicating that they originate in the kidney. We have previously reported a patient with genetic cytosolic phospholipase A 2 (cPLA 2 α) deficiency, who lacks the capacity to generate Prostacyclin in endothelial cells and TXA 2 in platelets. This patient has now undergone a kidney transplant receiving a genetically normal organ and creating a truly unique experimental model akin to a human ‘whole body cPLA2α knockout, kidney specific knock-in’, for the determination of sites of eicosanoid production. Here we have used samples from this individual including endothelial cells grown from blood progenitors, before and after kidney transplant, to allow us to definitively establish the role of the kidney versus the circulation in generation of urinary Prostacyclin and TXA 2 metabolites. Before transplant, endothelial Prostacyclin, platelet TXA 2 and urinary metabolites of both PGI-M and TX-M were very greatly below the normal range. After transplantation, endothelial Prostacyclin and platelet TXA 2 production remained negligible whereas the urinary metabolites PGI-M and TX-M were brought into the normal range. These results not only describe a unique clinical case but also demonstrate that the kidney alone can produce urinary metabolites of Prostacyclin and TXA 2 within the normal range. Consequently, urinary metabolites cannot be relied upon as surrogates for production in the systemic circulation. We must now revisit and reinterpret studies in which PGI-M and TX-M have been used as indicators of cardiovascular health, function and risk.
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Role of Prostacyclin in pulmonary hypertension
Global cardiology science & practice, 2014Co-Authors: Jane A. Mitchell, Blerina Ahmetaj-shala, Nicholas S. Kirkby, William R. Wright, Louise Mackenzie, Daniel M. Reed, Nura A. MohamedAbstract:Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it's discovery in the 1970s concerted efforts have been made to make the best therapeutic utility of Prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of Prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of Prostacyclin but that target the receptors that Prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of Prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of Prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to Prostacyclin and its use in pulmonary arterial hypertension.
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cyclooxygenase 1 not cyclooxygenase 2 is responsible for physiological production of Prostacyclin in the cardiovascular system
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Nicholas S. Kirkby, Martina H Lundberg, Louise S Harrington, P D M Leadbeater, Ginger L Milne, Claire M F Potter, Malak AlyamaniAbstract:Prostacyclin is an antithrombotic hormone produced by the endothelium, whose production is dependent on cyclooxygenase (COX) enzymes of which two isoforms exist. It is widely believed that COX-2 drives Prostacyclin production and that this explains the cardiovascular toxicity associated with COX-2 inhibition, yet the evidence for this relies on indirect evidence from urinary metabolites. Here we have used a range of experimental approaches to explore which isoform drives the production of Prostacyclin in vitro and in vivo. Our data show unequivocally that under physiological conditions it is COX-1 and not COX-2 that drives Prostacyclin production in the cardiovascular system, and that urinary metabolites do not reflect Prostacyclin production in the systemic circulation. With the idea that COX-2 in endothelium drives Prostacyclin production in healthy individuals removed, we must seek new answers to why COX-2 inhibitors increase the risk of cardiovascular events to move forward with drug discovery and to enable more informed prescribing advice.
Wei Zhang - One of the best experts on this subject based on the ideXlab platform.
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Prostacyclin analogue beraprost inhibits cardiac fibroblast proliferation depending on Prostacyclin receptor activation through a tgf β smad signal pathway
PLOS ONE, 2014Co-Authors: Yun Chen, Xiaole Xu, Shengju Yang, Guoliang Meng, Wei ZhangAbstract:Previous studies showed that Prostacyclin inhibited fibrosis. However, both receptors of Prostacyclin, Prostacyclin receptor (IP) and peroxisome proliferator-activated receptor (PPAR), are abundant in cardiac fibroblasts. Here we investigated which receptor was vital in the anti-fibrosis effect of Prostacyclin. In addition, the possible mechanism involved in protective effects of Prostacyclin against cardiac fibrosis was also studied. We found that beraprost, a Prostacyclin analogue, inhibited angiotensin II (Ang II)-induced neonatal rat cardiac fibroblast proliferation in a concentration-dependent and time-dependent manner. Beraprost also suppressed Ang II-induced collagen I mRNA expression and protein synthesis in cardiac fibroblasts. After IP expression was knocked down by siRNA, Ang II-induced proliferation and collagen I synthesis could no longer be rescued by beraprost. However, treating cells with different specific inhibitors of PPAR subtypes prior to beraprost and Ang II stimulation, all of the above attenuating effects of beraprost were still available. Moreover, beraprost significantly blocked transforming growth factor β (TGF β) expression as well as Smad2 phosphorylation and reduced Smad-DNA binding activity. Beraprost also increased phosphorylation of cAMP response element binding protein (CREB) at Ser133 in the nucleus. Co-immunoprecipitation analysis revealed that beraprost increased CREB but decreased Smad2 binding to CREB-binding protein (CBP) in nucleus. In conclusion, beraprost inhibits cardiac fibroblast proliferation by activating IP and suppressing TGF β-Smad signal pathway.
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Prostacyclin Analogue Beraprost Inhibits Cardiac Fibroblast Proliferation Depending on Prostacyclin Receptor Activation through a TGF b-Smad Signal Pathway
2014Co-Authors: Yun Chen, Shengju Yang, Guoliang Meng, Wenjuan Yao, Hongyan Zhu, Wei ZhangAbstract:Previous studies showed that Prostacyclin inhibited fibrosis. However, both receptors of Prostacyclin, Prostacyclin receptor (IP) and peroxisome proliferator-activated receptor (PPAR), are abundant in cardiac fibroblasts. Here we investigated which receptor was vital in the anti-fibrosis effect of Prostacyclin. In addition, the possible mechanism involved in protective effects of Prostacyclin against cardiac fibrosis was also studied. We found that beraprost, a Prostacyclin analogue, inhibited angiotensin II (Ang II)-induced neonatal rat cardiac fibroblast proliferation in a concentration-dependent and time-dependent manner. Beraprost also suppressed Ang II-induced collagen I mRNA expression and protein synthesis in cardiac fibroblasts. After IP expression was knocked down by siRNA, Ang II-induced proliferation and collagen I synthesis could no longer be rescued by beraprost. However, treating cells with different specific inhibitors of PPAR subtypes prior to beraprost and Ang II stimulation, all of the above attenuating effects of beraprost were still available. Moreover, beraprost significantly blocked transforming growth factor b (TGF b) expression as well as Smad2 phosphorylation and reduced Smad-DNA binding activity. Beraprost also increased phosphorylation of cAMP response element binding protein (CREB) at Ser133 in the nucleus. Co-immunoprecipitation analysis revealed that beraprost increased CREB but decreased Smad2 binding to CREB-binding protein (CBP) in nucleus. In conclusion, beraprost inhibits cardiac fibroblast proliferation by activating IP an
Daniel M. Reed - One of the best experts on this subject based on the ideXlab platform.
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kidney transplantation in a patient lacking cytosolic phospholipase a2 proves renal origins of urinary pgi m and tx m
Circulation Research, 2018Co-Authors: Jane A. Mitchell, Nicholas S. Kirkby, Daniel M. Reed, Rebecca Knowles, Matthew L Edin, William White, Melissa V Chan, Hilary Longhurst, Magdi Yaqoob, Ginger L MilneAbstract:Rationale: The balance between vascular Prostacyclin which is anti-thrombotic and platelet thromboxane A 2 which is pro-thrombotic is fundamental to cardiovascular health. Prostacyclin and thromboxane A 2 are formed following the concerted actions of cytosolic phospholipase A 2 (cPLA 2α ) and cyclooxygenase. Urinary 2,3-dinor-6-keto PGF1 α (PGI-M) and 11-dehydro-TXB2 (TX-M) have been taken as biomarkers of Prostacyclin and thromboxane A 2 formation with the circulation and used to explain cyclooxygenase biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. Objective: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA 2α , causing almost complete loss of Prostacyclin and thromboxane A 2 , who was transplanted with a normal kidney resulting in an experimental scenario of 9whole body cPLA2α knockout, kidney specific knock-in9. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of Prostacyclin and thromboxane A 2 in the circulation. Methods and Results: Metabolites were measured using LC-MS/MS. Endothelial cells were grown from blood progenitors. Before kidney transplantation the patient9s endothelial cells and platelets released negligible levels of Prostacyclin (measured as 6-ketoPGF 1α ) and thromboxane A 2 (measured as TXB 2 ), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. Following transplantation and the establishment of normal renal function the levels of PGI-M and TX-M in the patient9s urine rose to within normal ranges while endothelial production of Prostacyclin and platelet production of thromboxane A 2 remained negligible. Conclusions: This data shows that PGI-M and TX-M can be derived exclusively from the kidney without contribution from Prostacyclin made by endothelial cells or thromboxane A 2 by platelets in the general circulation. Previous work relying upon urinary metabolites of Prostacyclin and thromboxane A 2 as markers of whole body endothelial and platelet function now requires re-evaluation.
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abstract 20347 kidney transplantation in a patient lacking cytosolic phospholipase a2 leads to urinary Prostacyclin and thromboxane a2 metabolites within normal ranges
Circulation, 2016Co-Authors: Jane A. Mitchell, Nicholas S. Kirkby, Daniel M. Reed, Ginger L Milne, Rebecca Knowles, Matthew L Edin, William White, Hilary Longhurst, Magdi Yaqoob, Darryl C ZeldinAbstract:Measurements of metabolites of Prostacyclin and thromboxane A 2 (TXA 2 ) in the urine have been held as the best estimates of eicosanoid production in the circulation. As such, measurement of these urinary markers has been used to inform (i) drug action in clinical studies, (ii) personal risk of cardiovascular disease in patient groups and (iii) a plethora of basic science relating to eicosanoids, particularly in regard to cyclooxygenase biology and the general idea that Prostacyclin in the circulation is formed by cyclooxygenase-2. However, urinary markers are not universally accepted as reflective of the circulation, with some studies indicating that they originate in the kidney. We have previously reported a patient with genetic cytosolic phospholipase A 2 (cPLA 2 α) deficiency, who lacks the capacity to generate Prostacyclin in endothelial cells and TXA 2 in platelets. This patient has now undergone a kidney transplant receiving a genetically normal organ and creating a truly unique experimental model akin to a human ‘whole body cPLA2α knockout, kidney specific knock-in’, for the determination of sites of eicosanoid production. Here we have used samples from this individual including endothelial cells grown from blood progenitors, before and after kidney transplant, to allow us to definitively establish the role of the kidney versus the circulation in generation of urinary Prostacyclin and TXA 2 metabolites. Before transplant, endothelial Prostacyclin, platelet TXA 2 and urinary metabolites of both PGI-M and TX-M were very greatly below the normal range. After transplantation, endothelial Prostacyclin and platelet TXA 2 production remained negligible whereas the urinary metabolites PGI-M and TX-M were brought into the normal range. These results not only describe a unique clinical case but also demonstrate that the kidney alone can produce urinary metabolites of Prostacyclin and TXA 2 within the normal range. Consequently, urinary metabolites cannot be relied upon as surrogates for production in the systemic circulation. We must now revisit and reinterpret studies in which PGI-M and TX-M have been used as indicators of cardiovascular health, function and risk.
-
Role of Prostacyclin in pulmonary hypertension
Global cardiology science & practice, 2014Co-Authors: Jane A. Mitchell, Blerina Ahmetaj-shala, Nicholas S. Kirkby, William R. Wright, Louise Mackenzie, Daniel M. Reed, Nura A. MohamedAbstract:Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it's discovery in the 1970s concerted efforts have been made to make the best therapeutic utility of Prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of Prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of Prostacyclin but that target the receptors that Prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of Prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of Prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to Prostacyclin and its use in pulmonary arterial hypertension.
