Background We recently demonstrated that G_h, which transfers the signal from the α₁-adrenergic receptor to the 69-kD phospholipase C, is the previously identified tissue-type transglutaminase (TGase II). The α₁-adrenergic receptor mediates actions of the sympathetic nervous system, including cardiac, arteriolar, and smooth muscle contractions. In human cardiac tissue, the expression of the α₁-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 α₁-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 α₁-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 α₁-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 α₁-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.