Affiliation:
1. the Department of Molecular Cardiology and Center for Anesthesiology Research (W.E.S., C.S.M.), Research Institute, the Cleveland (Ohio) Clinic Foundation.
Abstract
Background
We recently demonstrated that G
h
, which transfers the signal from the α
1
-adrenergic receptor to the 69-kD phospholipase C, is the previously identified tissue-type transglutaminase (TGase II). The α
1
-adrenergic receptor mediates actions of the sympathetic nervous system, including cardiac, arteriolar, and smooth muscle contractions. In human cardiac tissue, the expression of the α
1
-adrenergic receptor is increased under pathophysiological conditions, but changes in the physiological response are small. Therefore, it has been suggested that the other components involved in the α
1
-adrenergic 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 activities of human heart TGase II (hhGα
h
) are downregulated in both ischemic and dilated cardiomyopathic human heart. In ischemic cardiomyopathy, the α
1
-adrenergic receptor number increased twofold (27.0 fmol/mg) compared with the nonfailing (12.8 fmol/mg) and the dilated cardiomyopathic (15.6 fmol/mg) heart tissues, but the coupling of hhGα
h
with the α
1
-adrenergic receptor did not increase. The intrinsic activity of hhGα
h
was greatly decreased in membrane fractions, whereas the cytosolic TGase activity was not changed. In the dilated cardiomyopathic human heart, these intrinsic enzyme activities of hhGα
h
were also downregulated in the membrane fraction, whereas the amount of hhGα
h
protein was greatly increased (2.8-fold) compared with the nonfailing heart.
Conclusions
The results of the present study clearly demonstrate that the α
1
-adrenergic receptor in human heart couples with G
h
(TGase II) and indicate that downregulation of hhGα
h
activity is associated with human cardiac failure but that the mechanism differs between ischemic and dilated cardiomyopathies.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
57 articles.
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