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Alpha 1-adrenergic receptor coupling with Gh in the failing human heart
K C Hwang1, C D Gray, W E Sweet
1Department of Molecular Cardiology, Cleveland Clinic Foundation, OH 44195, USA.
Insights
Human heart tissue-type transglutaminase II (TGase II) activity is reduced in cardiac failure. This downregulation of TGase II activity is linked to heart failure mechanisms, differing between ischemic and dilated cardiomyopathies.
Area of Science:
- Cardiovascular Biology
- Enzymology
- Molecular Signaling
Background:
- Tissue-type transglutaminase (TGase II) functions as Gh, mediating alpha 1-adrenergic receptor signaling.
- Alpha 1-adrenergic receptor signaling is crucial for sympathetic nervous system actions, including cardiac function.
- While alpha 1-adrenergic receptor expression increases in pathological conditions, physiological responses are modest, suggesting alterations in other pathway components.
Purpose of the Study:
- To investigate the role and activity of human heart TGase II (hhG alpha h) in cardiac failure.
- To determine if TGase II activity is altered in ischemic and dilated cardiomyopathies.
- To elucidate the relationship between alpha 1-adrenergic receptor coupling and TGase II activity in failing hearts.
Main Methods:
- Utilized immunological and biochemical analyses on nonfailing and failing human heart tissues.
- Quantified alpha 1-adrenergic receptor number and hhG alpha h coupling.
- Assessed GTP-binding and TGase activities of hhG alpha h in membrane and cytosolic fractions.
Main Results:
- GTP-binding and TGase activities of hhG alpha h were downregulated in both ischemic and dilated cardiomyopathic hearts.
- Alpha 1-adrenergic receptor number increased in ischemic cardiomyopathy, but coupling with hhG alpha h did not increase.
- Intrinsic enzyme activities of hhG alpha h were decreased in membrane fractions of failing hearts, with increased protein in dilated cardiomyopathy.
Conclusions:
- Confirmed that the alpha 1-adrenergic receptor in the human heart couples with Gh (TGase II).
- Demonstrated that downregulation of hhG alpha h activity is associated with human cardiac failure.
- Highlighted distinct mechanisms of TGase II dysfunction in ischemic versus dilated cardiomyopathies.
Background:
We recently demonstrated that Gh, which transfers the signal from the alpha 1-adrenergic receptor to the 69-kD phospholipase 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 nonfailling and failing human heart tissues revealed that the GTP-binding and TGase activities of human heart TGase II (hhG alpha n) 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 Gh (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.