Background We recently demonstrated that G(h), which transfers the sig
nal from the alpha(1)-adrenergic receptor to the 69-kD phos pholipase
C, is the previously identified tissue-type transglutaminase (TGase II
). The alpha(1)-adrenergic receptor mediates actions of the sympatheti
c nervous system, including cardiac, arteriolar and smooth muscle cont
ractions. In human cardiac tissue, the expression of the alpha(1)-adre
nergic receptor is increased under pathophysiological conditions, but
changes in the physiological response are small. Therefore, it has bee
n suggested that the other components involved in the alpha(1)-adrener
gic receptor-mediated signaling pathway are probably altered. Methods
and Results Immunological and biochemical studies with nonfailing and
failing human heart tissues revealed that the GTP-binding and TGase ac
tivities of human heart TGase II (hhG alpha(h)) are downregulated in b
oth ischemic and dilated cardiomyopathic human heart. In ischemic card
iomyopathy, the alpha(1)-adrenergic receptor number increased twofold
(27.0 fmol/mg) compared with the nonfailing (12.8 fmol/mg) and the dil
ated cardiomyopathic (15.6 fmol/mg) heart tissues, but the coupling of
hhG alpha(h) with the alpha(1)-adrenergic receptor did not increase.
The intrinsic activity of hhG alpha(h) was greatly decreased in membra
ne fractions, whereas the cytosolic TGase activity was not changed. In
the dilated cardiomyopathic human heart, these intrinsic enzyme activ
ities of hhG alpha(h) were also downregulated in the membrane fraction
, whereas the amount of hhG alpha(h), protein was greatly increased (2
.8-fold) compared with the nonfailing heart. Conclusions The results o
f the present study clearly demonstrate that the alpha(1)-adrenergic r
eceptor in human heart couples with G(h) (TGase II) and indicate that
downregulation of hhG alpha(h) activity is associated with human cardi
ac failure but that the mechanism differs between ischemic and dilated
cardiomyopathies.