alpha(1)-Adrenergic receptor coupling with G(h) in the failing human heart

Background We recently demonstrated that G(h), which transfers the signal 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 sympathetic nervous system, including cardiac, arteriolar and smooth muscle contractions. In human cardiac tissue, the expression of the alpha(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 alpha(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 (hhG alpha(h)) are downregulated in both ischemic and dilated cardiomyopathic human heart. In ischemic cardiomyopathy, the alpha(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 hhG alpha(h) with the alpha(1)-adrenergic receptor did not increase. The intrinsic activity of hhG alpha(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 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 of the present study clearly demonstrate that the alpha(1)-adrenergic receptor in human heart couples with G(h) (TGase II) and indicate that downregulation of hhG alpha(h) activity is associated with human cardiac failure but that the mechanism differs between ischemic and dilated cardiomyopathies.