Le. Lemke et al., Decreased p38 MAPK activity in end-stage failing human myocardium: p38 MAPK alpha is the predominant isoform expressed in human heart, J MOL CEL C, 33(8), 2001, pp. 1527-1540
Short duration exposure to cellular stresses have been shown to activate p3
8 mitogen-activated protein kinase (MAPK) in cultured rat ventricular cardi
omyocytes and isolated perfused hearts; however, effects of chronic stress
on p38 MAPK are not well understood. This study determined whether alterati
ons in the p38 MAPK pathway occurred prior to end-stage human heart failure
. The p38 MAPK alpha isoform was detectable in human cardiac tissue. Howeve
r, carefully controlled analysis of protein and message in this study demon
strated an absence of the p38 MAPK beta -isoforn, Low levels of message for
the non-SB203580 sensitive p3S MAPK gamma and delta isoforms were also det
ected in both normal and failing human myocardium. Ischemic and idiopathic
end-stage failing human hearts were compared to non-failing hearts for both
p3S alpha MAPK protein level and total p38 MAPK activity. Western blotting
techniques demonstrated no significant changes in total p38 alpha MAPK con
tent. However, approximately 75% decreases in active/phosphorylated p38 MAP
K (P <0.005) were observed in both ischemic and idiopathic failing hearts c
ompared to non-failing hearts, m-gel kinase assays confirmed that activated
p38 MAPK detected by Western blotting, phosphorylated its potential downst
ream targets. When compared to non-failing hearts, approximately 46% decrea
ses in p3S MAPK phosphorylation of mitogen-activated protein kinase-activat
ed protein kinase-2 (MAPKAPK-2) were observed in ischemic and idiopathic fa
iling hearts (P = 0.03 and P = 0.04 respectively). Active p38 MAPK was loca
lized to sarcomeric structures in the cytosol of myocytes by confocal immun
ofluoresence microscopy. The correlation between decreased MAPKAPK-2 phosph
orylation and loss of active p3S MAPK in failing human myocytes suggests th
at decreases in the activation of p3S MAPK alpha, the predominant cardiac i
soform, occur prior to end-stage heart failure. (C) 2001 Academic Press.