HSP60 in heart failure: abnormal distribution and role in cardiac myocyte apoptosis.
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-alpha. Thus abnormal trafficking of HSP60 to the cell surface may be an early trigger for myocyte loss and the progression of heart failure.
Molecular and Cellular Cardiology, Cardiovascular Division, University of California, Davis, California 95616, USA.
Li
L
Lin
S C
SC
Kim
Yin
Y
Wang
S
S
Gupta
B
B
Davis
S I
SI
Simon
G
G
Torre-Amione
A A
AA
Knowlton
D000368:Aged; D000818:Animals; D017209:Apoptosis; D009320:Atrial Natriuretic Factor / Q000097:blood; D009202:Cardiomyopathies / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018834:Chaperonin 60 / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D020097:Natriuretic Peptide, Brain / Q000097:blood; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation
D018834:Chaperonin 60; D014409:Tumor Necrosis Factor-alpha; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor