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HSP60 in heart failure: abnormal distribution and role in cardiac myocyte apoptosis

¹Molecular and Cellular Cardiology, Cardiovascular Division, University of California, Davis, and ²Sacramento Veterans Affairs Medical Center, Sacramento, California; ³Department of Physiology, Second Military Medical University, Shanghai, People's Republic of China; ⁴Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Bonn, Germany; ⁵Ningxia Medical College, Yinchuan, People's Republic of China; ⁶Department of Biomedical Engineering, University of California, Davis, California; and ⁷Methodist Hospital, Houston, Texas

Submitted 26 June 2007 ; accepted in final form 3 August 2007

Heat shock protein (HSP) 60 is a mitochondrial and cytosolic protein. Previously, we reported that HSP60 doubled in end-stage heart failure, even though levels of the protective HSP72 were unchanged. Furthermore, we observed that acute injury in adult cardiac myocytes resulted in movement of HSP60 to the plasma membrane. We hypothesized that the inflammatory state of heart failure would cause translocation of HSP60 to the plasma membrane and that this would provide a pathway for cardiac injury. Two models were used to test this hypothesis: 1) a rat model of heart failure and 2) human explanted failing hearts. We found that HSP60 localized to the plasma membrane and was also found in the plasma early in heart failure. Plasma membrane HSP60 localized to lipid rafts and was detectable on the cell surface with the use of both flow cytometry and confocal microscopy. Localization of HSP60 to the cell surface correlated with increased apoptosis. In heart failure, HSP60 is in the plasma membrane fraction, on the cell surface, and in the plasma. Membrane HSP60 correlated with increased apoptosis. Release of HSP60 may activate the innate immune system, promoting a proinflammatory state, including an increase in TNF-. Thus abnormal trafficking of HSP60 to the cell surface may be an early trigger for myocyte loss and the progression of heart failure.

heat shock proteins; protein trafficking; plasma membrane; cytokines

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