title: Resveratrol protects against lipopolysaccharide-induced cardiac dysfunction by enhancing SERCA2a activity through promoting the phospholamban oligomerization.
abstract: The bacterial endotoxin lipopolysaccharide (LPS) is a main culprit responsible for cardiac dysfunction in sepsis. This study examined whether resveratrol could protect against LPS-induced cardiac dysfunction by improving the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity. Echocardiographic parameters, cardiomyocyte contractile and Ca2+transient properties, markers for cardiac inflammation, cell death, and oxidative stress, SERCA2a activity, and the ratios of phospholamban (PLB) monomer to oligomer were measured. Cardiac function was decreased >50% after LPS challenge (6 mg/kg for 6 h), which was improved by resveratrol. There was neither difference in plasma tumor necrosis factor-α and troponin I levels nor in infiltration of CD45+cells in cardiac tissue between resveratrol-treated and untreated groups. In cardiomyocytes, LPS significantly decreased contractile amplitude, elongated relengthening time, diminished Ca2+transient, reduced SERCA2a activity, and increased superoxide generation. These pathological alterations were attenuated by resveratrol treatment. Immunoblot analysis showed that LPS-treated mice had increased levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and the monomer form of PLB, along with decreases in the levels of SERCA2a, the oligomer form of PLB and nuclear factor erythroid 2-related factor (Nrf-2). Resveratrol treatment upregulated SERCA2a, the oligomer form of PLB, and Nrf-2 expression and function, and downregulated MDA, 4-HNE, and the monomer form of PLB. Our data suggest that the activity of SERCA2a in endotoxemia is inhibited, possibly due to increases in the monomer form of PLB. Resveratrol protects the heart from LPS-induced injuries at least in part through promoting the oligomerization of PLB that leads to enhanced SERCA2a activity.
authors: Cardiovascular Center, First Hospital of Jilin University, Changchun, China; Departments of Pediatrics and Radiation Oncology, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, Kentucky.
authors: Tao
authors: T
authors: Bai
authors: Cardiovascular Center, First Hospital of Jilin University, Changchun, China; Departments of Pediatrics and Radiation Oncology, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, Kentucky.
authors: Xinyue
authors: X
authors: Hu
authors: Cardiovascular Center, First Hospital of Jilin University, Changchun, China.
authors: Yang
authors: Y
authors: Zheng
authors: Cardiovascular Center, First Hospital of Jilin University, Changchun, China; Departments of Pediatrics and Radiation Oncology, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, Kentucky.
authors: Shudong
authors: S
authors: Wang
authors: Department of Geriatric Medicine, First Hospital of Jilin University, Changchun, China; and kongjian_2015@163.com.
authors: Jian
authors: J
authors: Kong
authors: Departments of Pediatrics and Radiation Oncology, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, Kentucky.
authors: Lu
authors: L
authors: Cai
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation; D006321:Heart / Q000187:drug effects*; D015151:Immunoblotting; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011108:Polymers / Q000378:metabolism; D000077185:Resveratrol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects* / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D019210:Troponin I / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation; D000099211:Phospholamban
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D002118:Calcium; D002135:Calcium-Binding Proteins; D008070:Lipopolysaccharides; D008315:Malondialdehyde; D051267:NF-E2-Related Factor 2; D011108:Polymers; D000077185:Resveratrol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013267:Stilbenes; D013481:Superoxides; D019210:Troponin I; D014409:Tumor Necrosis Factor-alpha; D000099211:Phospholamban; C495636:Nfe2l2 protein, mouse; C027576:4-hydroxy-2-nonenal
keywords: heart failure; nuclear factor (erythroid-derived 2)-like 2; sarcoplasmic endoplasmic reticulum calcium ion-ATPase