A G-protein-biased S1P.sub.1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome
Heart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF...
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| Veröffentlicht in: | PloS one 2022-01, Vol.17 (1), p.e0257929 |
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| creator | Evaristi, Maria Francesca Poirier, Bruno Chénedé, Xavier Lefebvre, Anne-Marie Roccon, Alain Gillot, Florence Beeské, Sandra Corbier, Alain Pruniaux-Harnist, Marie-Pierre Janiak, Philip Parkar, Ashfaq A |
| description | Heart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P.sub.1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function. 31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing adult and aged animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799. Echocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in adult and aged animals: in adult animals E/e' was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p |
| doi_str_mv | 10.1371/journal.pone.0257929 |
| format | Article |
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Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P.sub.1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function. 31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing adult and aged animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799. Echocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in adult and aged animals: in adult animals E/e' was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 ± 2.3 for Le-ZSF1-CTRL (median ± IQR). In aged animals E/e' was evaluated at 23.15 ± 4.45 for Ob-ZSF1-CTRL, 19.5 ± 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 ± 1.7 for Le-ZSF1-CTRL, p<0.01 (median ± IQR). In aged animals, SAR247799 reduced cardiac hypertrophy (g/mm mean ± SEM of heart weight/tibia length 0.053 ± 0.001 for Ob-ZSF1-CTRL vs 0.046 ± 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 ± 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In adult animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean ± SEM 67.8 ± 3.41 for Ob-ZSF1-CTRL 55.8 ± 4.27 or Ob-ZSF1-SAR247799, p<0.05 and 57.3 ± 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In aged animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 ± 0.621 vs 8.17 ± 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 ± 0.029 for Le-ZSF1-CTRL, mean ± SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P.sub.1 desensitization. These experimental findings suggest that S1P.sub.1 activation with SAR247799 may be considered as a new therapeutic approach for LVH and diastolic dysfunction, major components of HFpEF.]]></description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0257929</identifier><language>eng</language><publisher>Public Library of Science</publisher><subject>Cardiovascular agents ; Complications and side effects ; Drug therapy ; Heart enlargement ; Heart failure ; Metabolic syndrome X ; Physiological aspects ; Prevention ; Risk factors</subject><ispartof>PloS one, 2022-01, Vol.17 (1), p.e0257929</ispartof><rights>COPYRIGHT 2022 Public Library of Science</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,864,27924,27925</link.rule.ids></links><search><creatorcontrib>Evaristi, Maria Francesca</creatorcontrib><creatorcontrib>Poirier, Bruno</creatorcontrib><creatorcontrib>Chénedé, Xavier</creatorcontrib><creatorcontrib>Lefebvre, Anne-Marie</creatorcontrib><creatorcontrib>Roccon, Alain</creatorcontrib><creatorcontrib>Gillot, Florence</creatorcontrib><creatorcontrib>Beeské, Sandra</creatorcontrib><creatorcontrib>Corbier, Alain</creatorcontrib><creatorcontrib>Pruniaux-Harnist, Marie-Pierre</creatorcontrib><creatorcontrib>Janiak, Philip</creatorcontrib><creatorcontrib>Parkar, Ashfaq A</creatorcontrib><title>A G-protein-biased S1P.sub.1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome</title><title>PloS one</title><description><![CDATA[Heart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P.sub.1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function. 31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing adult and aged animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799. Echocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in adult and aged animals: in adult animals E/e' was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 ± 2.3 for Le-ZSF1-CTRL (median ± IQR). In aged animals E/e' was evaluated at 23.15 ± 4.45 for Ob-ZSF1-CTRL, 19.5 ± 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 ± 1.7 for Le-ZSF1-CTRL, p<0.01 (median ± IQR). In aged animals, SAR247799 reduced cardiac hypertrophy (g/mm mean ± SEM of heart weight/tibia length 0.053 ± 0.001 for Ob-ZSF1-CTRL vs 0.046 ± 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 ± 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In adult animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean ± SEM 67.8 ± 3.41 for Ob-ZSF1-CTRL 55.8 ± 4.27 or Ob-ZSF1-SAR247799, p<0.05 and 57.3 ± 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In aged animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 ± 0.621 vs 8.17 ± 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 ± 0.029 for Le-ZSF1-CTRL, mean ± SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P.sub.1 desensitization. These experimental findings suggest that S1P.sub.1 activation with SAR247799 may be considered as a new therapeutic approach for LVH and diastolic dysfunction, major components of HFpEF.]]></description><subject>Cardiovascular agents</subject><subject>Complications and side effects</subject><subject>Drug therapy</subject><subject>Heart enlargement</subject><subject>Heart failure</subject><subject>Metabolic syndrome X</subject><subject>Physiological aspects</subject><subject>Prevention</subject><subject>Risk factors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNqN0E1LwzAYB_AgCs7pN_AQEARhrU3SJs2xiC-DwcTpriNtkhppE2lS0W9vfDls4EFyeELy-z-HPwCnKEsRYejyxY2DFV366qxKM1wwjvkemCBOcEJxRva37ofgyPuXLCtISekEfFTwNnkdXFDGJrURXkm4QvepH-sUQdE6a3yYwVX1gHPGOJ9B00f-FtlifQeFlVDGVHCdaaAebROMs9BYKOAgAuydVB10GvYqiPob-Q8rB9erY3CgRefVye-cgqeb68eru2SxvJ1fVYukRZTyBBdUIM6QzpmmQvKaE14ygjLOBKOkzFFGZPwrtSwV4Qwz3bAC14TmDSWYkik4-9nbik5tjNUuDKLpjW82FS15URQkljMF6R8qHql608RetYnvO4GLnUA0Qb2HVozeb-arh__b5XrXnm_ZZyW68OxdN3716rfhJ-JWlo8</recordid><startdate>20220114</startdate><enddate>20220114</enddate><creator>Evaristi, Maria Francesca</creator><creator>Poirier, Bruno</creator><creator>Chénedé, Xavier</creator><creator>Lefebvre, Anne-Marie</creator><creator>Roccon, Alain</creator><creator>Gillot, Florence</creator><creator>Beeské, Sandra</creator><creator>Corbier, Alain</creator><creator>Pruniaux-Harnist, Marie-Pierre</creator><creator>Janiak, Philip</creator><creator>Parkar, Ashfaq A</creator><general>Public Library of Science</general><scope>IOV</scope><scope>ISR</scope></search><sort><creationdate>20220114</creationdate><title>A G-protein-biased S1P.sub.1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome</title><author>Evaristi, Maria Francesca ; Poirier, Bruno ; Chénedé, Xavier ; Lefebvre, Anne-Marie ; Roccon, Alain ; Gillot, Florence ; Beeské, Sandra ; Corbier, Alain ; Pruniaux-Harnist, Marie-Pierre ; Janiak, Philip ; Parkar, Ashfaq A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g1669-256a1971f47f6ad9b9398731097a76384103d47f8fd8e39727fc752b364c63263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Cardiovascular agents</topic><topic>Complications and side effects</topic><topic>Drug therapy</topic><topic>Heart enlargement</topic><topic>Heart failure</topic><topic>Metabolic syndrome X</topic><topic>Physiological aspects</topic><topic>Prevention</topic><topic>Risk factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Evaristi, Maria Francesca</creatorcontrib><creatorcontrib>Poirier, Bruno</creatorcontrib><creatorcontrib>Chénedé, Xavier</creatorcontrib><creatorcontrib>Lefebvre, Anne-Marie</creatorcontrib><creatorcontrib>Roccon, Alain</creatorcontrib><creatorcontrib>Gillot, Florence</creatorcontrib><creatorcontrib>Beeské, Sandra</creatorcontrib><creatorcontrib>Corbier, Alain</creatorcontrib><creatorcontrib>Pruniaux-Harnist, Marie-Pierre</creatorcontrib><creatorcontrib>Janiak, Philip</creatorcontrib><creatorcontrib>Parkar, Ashfaq A</creatorcontrib><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Evaristi, Maria Francesca</au><au>Poirier, Bruno</au><au>Chénedé, Xavier</au><au>Lefebvre, Anne-Marie</au><au>Roccon, Alain</au><au>Gillot, Florence</au><au>Beeské, Sandra</au><au>Corbier, Alain</au><au>Pruniaux-Harnist, Marie-Pierre</au><au>Janiak, Philip</au><au>Parkar, Ashfaq A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A G-protein-biased S1P.sub.1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome</atitle><jtitle>PloS one</jtitle><date>2022-01-14</date><risdate>2022</risdate><volume>17</volume><issue>1</issue><spage>e0257929</spage><pages>e0257929-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract><![CDATA[Heart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P.sub.1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function. 31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing adult and aged animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799. Echocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in adult and aged animals: in adult animals E/e' was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 ± 2.3 for Le-ZSF1-CTRL (median ± IQR). In aged animals E/e' was evaluated at 23.15 ± 4.45 for Ob-ZSF1-CTRL, 19.5 ± 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 ± 1.7 for Le-ZSF1-CTRL, p<0.01 (median ± IQR). In aged animals, SAR247799 reduced cardiac hypertrophy (g/mm mean ± SEM of heart weight/tibia length 0.053 ± 0.001 for Ob-ZSF1-CTRL vs 0.046 ± 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 ± 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In adult animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean ± SEM 67.8 ± 3.41 for Ob-ZSF1-CTRL 55.8 ± 4.27 or Ob-ZSF1-SAR247799, p<0.05 and 57.3 ± 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In aged animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 ± 0.621 vs 8.17 ± 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 ± 0.029 for Le-ZSF1-CTRL, mean ± SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P.sub.1 desensitization. These experimental findings suggest that S1P.sub.1 activation with SAR247799 may be considered as a new therapeutic approach for LVH and diastolic dysfunction, major components of HFpEF.]]></abstract><pub>Public Library of Science</pub><doi>10.1371/journal.pone.0257929</doi><tpages>e0257929</tpages></addata></record> |
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| subjects | Cardiovascular agents Complications and side effects Drug therapy Heart enlargement Heart failure Metabolic syndrome X Physiological aspects Prevention Risk factors |
| title | A G-protein-biased S1P.sub.1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome |
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