Radioimmunochemical Quantification of Giα in Right and Left Vehicles from Patients with Ischaemic and Dilated Cardiomyopathy and Predominant Left Ventricular Failure

Böhm, Michael; Eschenhagen, Thomas; Gierschik, Peter; Larisch, Katharina; Lensche, Herbert; Mende, Ulrike; Schmitz, Wilhelm; Schnabel, Petra; Scholz, Hasso; Steinfath, Markus; Erdmann, E

doi:10.1006/jmcc.1994.1017

Cited by 110 publications

(39 citation statements)

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“…15 We therefore measured G i␣ activity in the NF, F (both DCM and IHD), and UD groups. The IHD group showed significantly higher G i␣ activity than the NF group (PϽ0.01; Figure 6B), as previously described, 16 yet the DCM group did not show a significant elevation. G i␣ activity in the UD group was similar to that in the IHD group and significantly higher than in the NF group (PϽ0.02; Figure 6B).…”

Section: Inhibitory G-protein (G I␣ ) Activity Is Increased In Ud Myosupporting

confidence: 71%

Myocardial Dysfunction in Donor Hearts

et al. 1999

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Background-Potential cardiac donors show various degrees of myocardial dysfunction, and the most severely affected hearts are unsuitable for transplantation. The cause of this acute heart failure is poorly understood. We investigated whether alterations in calcium-handling proteins, ␤-adrenoceptor density, or the inhibitory G protein G i␣ could account for this phenomenon in unused donor hearts (nϭ4 to 8). We compared these with end-stage failing hearts (nϭ14 to 16) and nonfailing hearts (nϭ3 to 12). Methods and Results-Myocardial samples were obtained from unused donor hearts displaying ejection fractions Ͻ30%. Both trabeculae and isolated myocytes responded as poorly as those from the group of failing hearts to increasing stimulation frequency with regard to inotropic function in vitro. Immunodetectable abundance of sarcoplasmic reticulum calcium-ATPase and sodium calcium exchanger were greater (177%; PϽ0.01) and smaller (29%; PϽ0.01), respectively, in the unused donor hearts relative to the failing group, which suggests that alterations of these proteins are not a common cause of contractile dysfunction in the 2 groups. Myocytes from the unused donor group were desensitized to isoprenaline to a similar degree as those from the failing heart group. However, ␤-adrenoceptor density was reduced in the failing (PϽ0.001) but not in the unused donor heart group (Pϭ0.37) relative to the nonfailing heart group (nϭ5). G i␣ activity was increased in samples from unused donor and failing hearts relative to nonfailing hearts (PϽ0.05). Conclusions-Increased activity of the inhibitory G protein G i␣ is a significant contributory factor for impaired contractility in these acutely failing donor hearts. (Circulation. 1999;99:2565-2570.)

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Section: Inhibitory G-protein (G I␣ ) Activity Is Increased In Ud Myosupporting

confidence: 71%

Myocardial Dysfunction in Donor Hearts

et al. 1999

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“…However, stimulation of the β 2 AR during CHF may also contribute to the pathophysiological advancement of the syndrome. Whereas β 1 AR levels are reduced in the failing heart, G i , a hetrotrimeric G protein that has been shown to couple to the β 2 AR in the heart, is up-regulated (43,44). G i signaling reduces adenylyl cyclase activity and subsequent downstream inotropic responses critical for cardiac contraction while, in a Gβγ-dependent manner, promoting cell survival signaling such as Akt activation (45).…”

Section: Discussionmentioning

confidence: 99%

β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction

Carr

Schilling

Song

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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β-adrenergic receptors (βARs) are critical regulators of acute cardiovascular physiology. In response to elevated catecholamine stimulation during development of congestive heart failure (CHF), chronic activation of G s -dependent β 1 AR and G i -dependent β 2 AR pathways leads to enhanced cardiomyocyte death, reduced β 1 AR expression, and decreased inotropic reserve. β-blockers act to block excessive catecholamine stimulation of βARs to decrease cellular apoptotic signaling and normalize β 1 AR expression and inotropy. Whereas these actions reduce cardiac remodeling and mortality outcomes, the effects are not sustained. Converse to G-protein-dependent signaling, β-arrestin-dependent signaling promotes cardiomyocyte survival. Given that β 2 AR expression is unaltered in CHF, a β-arrestin-biased agonist that operates through the β 2 AR represents a potentially useful therapeutic approach. Carvedilol, a currently prescribed nonselective β-blocker, has been classified as a β-arrestin-biased agonist that can inhibit basal signaling from βARs and also stimulate cell survival signaling pathways. To understand the relative contribution of β-arrestin bias to the efficacy of select β-blockers, a specific β-arrestin-biased pepducin for the β 2 AR, intracellular loop (ICL)1-9, was used to decouple β-arrestin-biased signaling from occupation of the orthosteric ligand-binding pocket. With similar efficacy to carvedilol, ICL1-9 was able to promote β 2 AR phosphorylation, β-arrestin recruitment, β 2 AR internalization, and β-arrestin-biased signaling. Interestingly, ICL1-9 was also able to induce β 2 AR-and β-arrestin-dependent and Ca 2+ -independent contractility in primary adult murine cardiomyocytes, whereas carvedilol had no efficacy. Thus, ICL1-9 is an effective tool to access a pharmacological profile stimulating cardioprotective signaling and inotropic effects through the β 2 AR and serves as a model for the next generation of cardiovascular drug development.B eta-antagonists, also known as β-blockers, have been indicated for the treatment of pathological cardiac diseases, including congestive heart failure (CHF) and high blood pressure, for decades (1, 2). A select number of these agents, including the clinically used carvedilol, have been identified as β-arrestinbiased agonists of β-adrenergic receptors based on their ability to promote β-arrestin-dependent signaling over G-protein activation (3, 4). It is believed that the β-arrestin activation may provide additional cardioprotection based on its ability to mediate antiapoptotic signaling. As these are orthosteric ligands, there have been no means to decouple the activation of receptor-dependent β-arrestin signaling from the occupation of the orthosteric ligandbinding pocket to study their independent contribution to its efficacy as these properties appear inherently linked.Recently, we described the characterization of a library of modulators of the β 2 -adrenergic receptor (β 2 AR) known as pepducins (5). Pepducins are lipidated peptides derived from the intracel...

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“…Increased expression of Ga i protein (speci®cally Ga i2 ) is observed in models of dilated cardiomyopathy (Bohm et al, 1990(Bohm et al, , 1994. Cardiomyocytes isolated from failing hearts show depressed inotropic responses to isoproterenol, which can be restored by inactivating G i with pertussis toxin (Brown and Harding, 1992).…”

Section: Ga I Signaling In Cardiac Apoptosis and Failurementioning

confidence: 99%

G-proteins in growth and apoptosis: lessons from the heart

2001

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The acute contractile function of the heart is controlled by the e ects of released nonepinephrine (NE) on cardiac adrenergic receptors. NE can also act in a more chronic fashion to induce cardiomyocyte growth, characterized by cell enlargement (hypertrophy), increased protein synthesis, alterations in gene expression and addition of sarcomeres. These responses enhance cardiomyocyte contractile function and thus allow the heart to compensate for increased stress. The hypertrophic e ects of NE are mediated through Gq-coupled a 1 -adrenergic receptors and are mimicked by the actions of other neurohormones (endothelin, prostaglandin F 2a angiotensin II) that also act on Gq-coupled receptors. Activation of phospholipase C by Gq is necessary for these responses, and protein kinase C and MAP kinases have also been implicated. Gq stimulated cardiac hypertrophy is also evident in transgenic mouse models. In contrast, stimulation of G s -coupled b-adrenergic receptors or G i -coupled receptors do not directly e ect cardiomyocyte hypertrophy. Apoptosis is also induced by G-protein-coupled receptor stimulation in cardiomyocytes. Sustained or excessive activation of either Gq-or Gs-signaling pathways results in apoptotic loss of cardiomyocytes both in vitro and in vivo. Apoptosis is associated with decreased ventricular function in the failing heart. Cardiomyocytes provide an ideal model system for understanding the basis for G-protein mediated hypertrophy and apoptosis, and the mechanisms responsible for the transition from compensatory to deleterious levels of signaling. This information may prove critical for designing interventions that prevent the pathophysiological consequences of heart failure. Oncogene (2001) 20, 1626 ± 1634.

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Radioimmunochemical Quantification of Giα in Right and Left Vehicles from Patients with Ischaemic and Dilated Cardiomyopathy and Predominant Left Ventricular Failure

Cited by 110 publications

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Myocardial Dysfunction in Donor Hearts

Myocardial Dysfunction in Donor Hearts

β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction

G-proteins in growth and apoptosis: lessons from the heart

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Radioimmunochemical Quantification of Giα in Right and Left Vehicles from Patients with Ischaemic and Dilated Cardiomyopathy and Predominant Left Ventricular Failure

Cited by 110 publications

References 0 publications

Myocardial Dysfunction in Donor Hearts

Myocardial Dysfunction in Donor Hearts

β-arrestin–biased signaling through the β 2 -adrenergic receptor promotes cardiomyocyte contraction

G-proteins in growth and apoptosis: lessons from the heart

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Product

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β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction