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(Circulation. 1996;94:718-726.)
© 1996 American Heart Association, Inc.

Articles

₁-Adrenergic Receptor Coupling With G_h in the Failing Human Heart

Ki-Chul Hwang, PhD; Caroline D. Gray, MS; Wendy E. Sweet, BS; Christine S. Moravec, PhD; Mie-Jae Im, PhD

the Department of Molecular Cardiology and Center for Anesthesiology Research (W.E.S., C.S.M.), Research Institute, the Cleveland (Ohio) Clinic Foundation.

Correspondence to Mie-Jae Im, PhD, Department of Molecular Cardiology (FFB-37), Research Institute, the Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.

Background We recently demonstrated that G_h, which transfers the signal from the ₁-adrenergic receptor to the 69-kD phospholipase C, is the previously identified tissue-type transglutaminase (TGase II). The 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 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 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_h) are downregulated in both ischemic and dilated cardiomyopathic human heart. In ischemic cardiomyopathy, the 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_h with the ₁-adrenergic receptor did not increase. The intrinsic activity of hhG_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_h were also downregulated in the membrane fraction, whereas the amount of hhG_h protein was greatly increased (2.8-fold) compared with the nonfailing heart.

Conclusions The results of the present study clearly demonstrate that the ₁-adrenergic receptor in human heart couples with G_h (TGase II) and indicate that downregulation of hhG_h activity is associated with human cardiac failure but that the mechanism differs between ischemic and dilated cardiomyopathies.

Key Words: heart failure • receptors, adrenergic, alpha • transglutaminase II • proteins • signal transduction

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