Necroptosis and RhoA/ROCK pathways: molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia/reperfusion injury in a rat model
Nesfatin-1 as a new energy-regulating peptide has been known to display a pivotal role in modulation of cardiovascular functions and protection against ischemia/reperfusion injury. However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investiga...
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| Veröffentlicht in: | Molecular biology reports 2021-03, Vol.48 (3), p.2507-2518 |
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| creator | Sharifi, Masoomeh Nazarinia, Donya Ramezani, Fatemeh Azizi, Yaser Naderi, Nasim Aboutaleb, Nahid |
| description | Nesfatin-1 as a new energy-regulating peptide has been known to display a pivotal role in modulation of cardiovascular functions and protection against ischemia/reperfusion injury. However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which nesfatin-1 exert cardioprotection effects against myocardial ischemia–reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of nesfatin-1 (10, 15 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK1-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of nesfatin-1 markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK1, RIPK3, MLKL, ROCK1, and ROCK2 proteins. The lowest and middle tested concentrations of nesfatin-1 failed to exert protective effects against MI/R. These findings have shown that nesfatin-1 can exert cardioprotection against MI/R in a dose dependent manner by suppressing necroptosis via modulation of RIPK1-RIPK3-MLKL axis and RhoA/ROCK/RIP3 signaling pathway. |
| doi_str_mv | 10.1007/s11033-021-06289-x |
| format | Article |
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However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which nesfatin-1 exert cardioprotection effects against myocardial ischemia–reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of nesfatin-1 (10, 15 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK1-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of nesfatin-1 markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK1, RIPK3, MLKL, ROCK1, and ROCK2 proteins. The lowest and middle tested concentrations of nesfatin-1 failed to exert protective effects against MI/R. 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However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which nesfatin-1 exert cardioprotection effects against myocardial ischemia–reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of nesfatin-1 (10, 15 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK1-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of nesfatin-1 markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK1, RIPK3, MLKL, ROCK1, and ROCK2 proteins. The lowest and middle tested concentrations of nesfatin-1 failed to exert protective effects against MI/R. 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metabolism</topic><topic>Biomedical and Life Sciences</topic><topic>Cardiac function</topic><topic>Cardiotonic Agents - therapeutic use</topic><topic>Collagen</topic><topic>Coronary artery</topic><topic>Disease Models, Animal</topic><topic>Electrocardiography</topic><topic>Fibrosis</topic><topic>Glutathione - metabolism</topic><topic>Histology</topic><topic>Ischemia</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Malondialdehyde - metabolism</topic><topic>Molecular modelling</topic><topic>Morphology</topic><topic>Myocardial ischemia</topic><topic>Myocardial Reperfusion Injury - diagnostic imaging</topic><topic>Myocardial Reperfusion Injury - drug therapy</topic><topic>Myocardial Reperfusion Injury - pathology</topic><topic>Myocardial Reperfusion Injury - physiopathology</topic><topic>Myocardium - pathology</topic><topic>Necroptosis</topic><topic>Necroptosis - drug effects</topic><topic>Necrosis</topic><topic>Nucleobindins - pharmacology</topic><topic>Nucleobindins - therapeutic use</topic><topic>Original Article</topic><topic>Oxidative stress</topic><topic>Protein Serine-Threonine Kinases - 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Academic</collection><jtitle>Molecular biology reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sharifi, Masoomeh</au><au>Nazarinia, Donya</au><au>Ramezani, Fatemeh</au><au>Azizi, Yaser</au><au>Naderi, Nasim</au><au>Aboutaleb, Nahid</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Necroptosis and RhoA/ROCK pathways: molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia/reperfusion injury in a rat model</atitle><jtitle>Molecular biology reports</jtitle><stitle>Mol Biol Rep</stitle><addtitle>Mol Biol Rep</addtitle><date>2021-03-01</date><risdate>2021</risdate><volume>48</volume><issue>3</issue><spage>2507</spage><epage>2518</epage><pages>2507-2518</pages><issn>0301-4851</issn><eissn>1573-4978</eissn><abstract>Nesfatin-1 as a new energy-regulating peptide has been known to display a pivotal role in modulation of cardiovascular functions and protection against ischemia/reperfusion injury. However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which nesfatin-1 exert cardioprotection effects against myocardial ischemia–reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of nesfatin-1 (10, 15 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK1-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of nesfatin-1 markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK1, RIPK3, MLKL, ROCK1, and ROCK2 proteins. The lowest and middle tested concentrations of nesfatin-1 failed to exert protective effects against MI/R. These findings have shown that nesfatin-1 can exert cardioprotection against MI/R in a dose dependent manner by suppressing necroptosis via modulation of RIPK1-RIPK3-MLKL axis and RhoA/ROCK/RIP3 signaling pathway.</abstract><cop>Dordrecht</cop><pub>Springer Netherlands</pub><pmid>33755849</pmid><doi>10.1007/s11033-021-06289-x</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-7514-5939</orcidid></addata></record> |
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| ispartof | Molecular biology reports, 2021-03, Vol.48 (3), p.2507-2518 |
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| subjects | Animal Anatomy Animal Biochemistry Animals Biomarkers - metabolism Biomedical and Life Sciences Cardiac function Cardiotonic Agents - therapeutic use Collagen Coronary artery Disease Models, Animal Electrocardiography Fibrosis Glutathione - metabolism Histology Ischemia Life Sciences Male Malondialdehyde - metabolism Molecular modelling Morphology Myocardial ischemia Myocardial Reperfusion Injury - diagnostic imaging Myocardial Reperfusion Injury - drug therapy Myocardial Reperfusion Injury - pathology Myocardial Reperfusion Injury - physiopathology Myocardium - pathology Necroptosis Necroptosis - drug effects Necrosis Nucleobindins - pharmacology Nucleobindins - therapeutic use Original Article Oxidative stress Protein Serine-Threonine Kinases - metabolism Rats, Wistar Reactive Oxygen Species - metabolism Receptor-Interacting Protein Serine-Threonine Kinases - metabolism Reperfusion Rho-associated kinase rho-Associated Kinases - metabolism rhoA GTP-Binding Protein - metabolism RhoA protein Signal transduction Signal Transduction - drug effects Superoxide Dismutase - metabolism Western blotting |
| title | Necroptosis and RhoA/ROCK pathways: molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia/reperfusion injury in a rat model |
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