C.-M. Pilard , G. Cardouat , I. Gauthereau , P. Robillard , F. Sauvestre , F. Pelluard , S. Berenguer , L. Sentilhes , F. Coatleven , L. Renesme , E. Dumas-De-La-Roque , R. Marthan , P. Berger , V. Freund-Michel , C. Guibert
{"title":"雷公藤红素:支气管肺发育不良伴肺动脉高压的一种新的潜在治疗选择","authors":"C.-M. Pilard , G. Cardouat , I. Gauthereau , P. Robillard , F. Sauvestre , F. Pelluard , S. Berenguer , L. Sentilhes , F. Coatleven , L. Renesme , E. Dumas-De-La-Roque , R. Marthan , P. Berger , V. Freund-Michel , C. Guibert","doi":"10.1016/j.acvdsp.2023.07.040","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p><span>Bronchopulmonary dysplasia is a common pathology of premature newborns caused by oxygen and </span>mechanical ventilation<span>, resulting in hypoalveolarization and impaired angiogenesis<span>. It can be complicated by pulmonary hypertension (PH-BPD) with excess mortality. Celastrol has anti-inflammatory and antioxidant properties.</span></span></p></div><div><h3>Objective</h3><p>We addressed potential therapeutic interest of celastrol in PH-BPD.</p></div><div><h3>Methods</h3><p>Different concentrations of celastrol (0,1–0,5–1<!--> <!-->mg/kg/d) were tested in a murine model of hyperoxic PH-BPD (14 days with 90% O<sub>2</sub><span>–Hx). We evaluated hemodynamic<span> parameters with echocardiography, lung remodeling with histological methods and pulmonary arterial (PA) reactivity with myograph. Cytoplasmic calcium (Ca</span></span><sub>2</sub><span><span>+i) response to endothelin-1 (ET-1) was evaluated in human fetal PA smooth muscle cells (fPASMC) with </span>spectrophotometry in normoxic (21% O</span><sub>2</sub>) and Hx conditions (48<!--> <!-->h with 60% O<sub>2</sub><span>). Inflammation and oxidant stress were also addressed.</span></p></div><div><h3>Results/Expected results</h3><p>Celastrol reduces mortality at doses of 1 and 0,5<!--> <!-->mg/kg/d compared to Hx control. At 1<!--> <span><span><span>mg/kg/d, it normalizes PA acceleration time and reduces vascular hyperreactivity to ET-1 inversely to phenylephrine and 5-HT, with no effect on the altered response to </span>acetylcholine induced by Hx. At all doses, it decreases right </span>heart hypertrophy<span><span> and vascular remodeling<span> but has no effect on media cells proliferation observed in Hx condition. It has also no impact on </span></span>alveolarization and vascular density. Although celastrol (0.1 and 0.3</span></span> <!-->μM) decreases the increased Ca<sub>2</sub><span>+i response to ET-1 in Hx in fPASMC, expression of ET-1 receptors was unchanged. In fPASMC, celastrol 0.3</span> <span>μM decreases the increased concentration of IL6 observed in Hx but has no effect on IL8 and MIF. In both models, Hx-induced oxidant stress remains mild with absence of protein carbonylation<span> and lipid peroxidation and celastrol at 1</span></span> <span>mg/kg/d increases heme oxygenase 1 expression.</span></p></div><div><h3>Conclusion/Perspectives</h3><p>Celastrol has a preventive dose-dependent effect on major hallmarks of PH induced by Hx and could be considered as a new potential therapeutic option for PH-BPD.</p></div>","PeriodicalId":8140,"journal":{"name":"Archives of Cardiovascular Diseases Supplements","volume":null,"pages":null},"PeriodicalIF":18.0000,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Celastrol: A new potential therapeutic option in pulmonary hypertension associated with bronchopulmonary dysplasia\",\"authors\":\"C.-M. Pilard , G. Cardouat , I. Gauthereau , P. Robillard , F. Sauvestre , F. Pelluard , S. Berenguer , L. Sentilhes , F. Coatleven , L. Renesme , E. Dumas-De-La-Roque , R. Marthan , P. Berger , V. Freund-Michel , C. Guibert\",\"doi\":\"10.1016/j.acvdsp.2023.07.040\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Introduction</h3><p><span>Bronchopulmonary dysplasia is a common pathology of premature newborns caused by oxygen and </span>mechanical ventilation<span>, resulting in hypoalveolarization and impaired angiogenesis<span>. It can be complicated by pulmonary hypertension (PH-BPD) with excess mortality. Celastrol has anti-inflammatory and antioxidant properties.</span></span></p></div><div><h3>Objective</h3><p>We addressed potential therapeutic interest of celastrol in PH-BPD.</p></div><div><h3>Methods</h3><p>Different concentrations of celastrol (0,1–0,5–1<!--> <!-->mg/kg/d) were tested in a murine model of hyperoxic PH-BPD (14 days with 90% O<sub>2</sub><span>–Hx). We evaluated hemodynamic<span> parameters with echocardiography, lung remodeling with histological methods and pulmonary arterial (PA) reactivity with myograph. Cytoplasmic calcium (Ca</span></span><sub>2</sub><span><span>+i) response to endothelin-1 (ET-1) was evaluated in human fetal PA smooth muscle cells (fPASMC) with </span>spectrophotometry in normoxic (21% O</span><sub>2</sub>) and Hx conditions (48<!--> <!-->h with 60% O<sub>2</sub><span>). Inflammation and oxidant stress were also addressed.</span></p></div><div><h3>Results/Expected results</h3><p>Celastrol reduces mortality at doses of 1 and 0,5<!--> <!-->mg/kg/d compared to Hx control. At 1<!--> <span><span><span>mg/kg/d, it normalizes PA acceleration time and reduces vascular hyperreactivity to ET-1 inversely to phenylephrine and 5-HT, with no effect on the altered response to </span>acetylcholine induced by Hx. At all doses, it decreases right </span>heart hypertrophy<span><span> and vascular remodeling<span> but has no effect on media cells proliferation observed in Hx condition. It has also no impact on </span></span>alveolarization and vascular density. Although celastrol (0.1 and 0.3</span></span> <!-->μM) decreases the increased Ca<sub>2</sub><span>+i response to ET-1 in Hx in fPASMC, expression of ET-1 receptors was unchanged. In fPASMC, celastrol 0.3</span> <span>μM decreases the increased concentration of IL6 observed in Hx but has no effect on IL8 and MIF. In both models, Hx-induced oxidant stress remains mild with absence of protein carbonylation<span> and lipid peroxidation and celastrol at 1</span></span> <span>mg/kg/d increases heme oxygenase 1 expression.</span></p></div><div><h3>Conclusion/Perspectives</h3><p>Celastrol has a preventive dose-dependent effect on major hallmarks of PH induced by Hx and could be considered as a new potential therapeutic option for PH-BPD.</p></div>\",\"PeriodicalId\":8140,\"journal\":{\"name\":\"Archives of Cardiovascular Diseases Supplements\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":18.0000,\"publicationDate\":\"2023-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Archives of Cardiovascular Diseases Supplements\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1878648023002616\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of Cardiovascular Diseases Supplements","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1878648023002616","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"Medicine","Score":null,"Total":0}
Celastrol: A new potential therapeutic option in pulmonary hypertension associated with bronchopulmonary dysplasia
Introduction
Bronchopulmonary dysplasia is a common pathology of premature newborns caused by oxygen and mechanical ventilation, resulting in hypoalveolarization and impaired angiogenesis. It can be complicated by pulmonary hypertension (PH-BPD) with excess mortality. Celastrol has anti-inflammatory and antioxidant properties.
Objective
We addressed potential therapeutic interest of celastrol in PH-BPD.
Methods
Different concentrations of celastrol (0,1–0,5–1 mg/kg/d) were tested in a murine model of hyperoxic PH-BPD (14 days with 90% O2–Hx). We evaluated hemodynamic parameters with echocardiography, lung remodeling with histological methods and pulmonary arterial (PA) reactivity with myograph. Cytoplasmic calcium (Ca2+i) response to endothelin-1 (ET-1) was evaluated in human fetal PA smooth muscle cells (fPASMC) with spectrophotometry in normoxic (21% O2) and Hx conditions (48 h with 60% O2). Inflammation and oxidant stress were also addressed.
Results/Expected results
Celastrol reduces mortality at doses of 1 and 0,5 mg/kg/d compared to Hx control. At 1 mg/kg/d, it normalizes PA acceleration time and reduces vascular hyperreactivity to ET-1 inversely to phenylephrine and 5-HT, with no effect on the altered response to acetylcholine induced by Hx. At all doses, it decreases right heart hypertrophy and vascular remodeling but has no effect on media cells proliferation observed in Hx condition. It has also no impact on alveolarization and vascular density. Although celastrol (0.1 and 0.3 μM) decreases the increased Ca2+i response to ET-1 in Hx in fPASMC, expression of ET-1 receptors was unchanged. In fPASMC, celastrol 0.3μM decreases the increased concentration of IL6 observed in Hx but has no effect on IL8 and MIF. In both models, Hx-induced oxidant stress remains mild with absence of protein carbonylation and lipid peroxidation and celastrol at 1mg/kg/d increases heme oxygenase 1 expression.
Conclusion/Perspectives
Celastrol has a preventive dose-dependent effect on major hallmarks of PH induced by Hx and could be considered as a new potential therapeutic option for PH-BPD.
期刊介绍:
Archives of Cardiovascular Diseases Supplements is the official journal of the French Society of Cardiology. The journal publishes original peer-reviewed clinical and research articles, epidemiological studies, new methodological clinical approaches, review articles, editorials, and Images in cardiovascular medicine. The topics covered include coronary artery and valve diseases, interventional and pediatric cardiology, cardiovascular surgery, cardiomyopathy and heart failure, arrhythmias and stimulation, cardiovascular imaging, vascular medicine and hypertension, epidemiology and risk factors, and large multicenter studies. Additionally, Archives of Cardiovascular Diseases also publishes abstracts of papers presented at the annual sessions of the Journées Européennes de la Société Française de Cardiologie and the guidelines edited by the French Society of Cardiology.