Resveratrol protects against lipopolysaccharide-induced cardiac dysfunction by enhancing SERCA2a activity through promoting the phospholamban oligomerization

Resveratrol protects against lipopolysaccharide-induced cardiac dysfunction by enhancing SERCA2a activity through promoting the phospholamban oligomeriza- tion. Am J Physiol Heart Circ Physiol 311: H1051–H1062, 2016. First published September 2, 2016; doi:10.1152/ajpheart.00296.2016.—The bacterial endotoxin lipopolysaccharide (LPS) is a main culprit responsi- ble 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 con- tractile 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-? 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 am- plitude, elongated relengthening time, diminished Ca2? transient, re- duced SERCA2a activity, and increased superoxide generation. These pathological alterations were attenuated by resveratrol treatment. Immu- noblot 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.