1998
DOI: 10.1073/pnas.95.12.7000
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Abstract: Heart failure is accompanied by severely impaired ␤-adrenergic receptor (␤AR) function, which includes loss of ␤AR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of ␤AR function is agonist-stimulated receptor phosphorylation by the ␤AR kinase (␤ARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in ␤AR function contribute to the development of myocardial failure, transgenic mice with cardiac-rest… Show more

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Cited by 454 publications
(360 citation statements)
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References 33 publications
(57 reference statements)
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“…5 Also the finding of improved contractility after gene transfer of Ad-bARKct-GFP in vivo corresponds well with the improvement of LV function and outcome measured in similar disease models 5 or in cardiacspecific bARKct-transgenic mice. 5,9,8 To a similar extent as bARKct, also overexpression of nt-del-phosducin enhanced basal contraction and maximal contractility of both normal or failing cardiomyocytes. Moreover, a clear leftward shift of the concentration-contractility curve occurred ( Figure 6).…”
Section: Discussionmentioning
confidence: 68%
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“…5 Also the finding of improved contractility after gene transfer of Ad-bARKct-GFP in vivo corresponds well with the improvement of LV function and outcome measured in similar disease models 5 or in cardiacspecific bARKct-transgenic mice. 5,9,8 To a similar extent as bARKct, also overexpression of nt-del-phosducin enhanced basal contraction and maximal contractility of both normal or failing cardiomyocytes. Moreover, a clear leftward shift of the concentration-contractility curve occurred ( Figure 6).…”
Section: Discussionmentioning
confidence: 68%
“…Overexpression of bARKct in several models of heart failure has been shown to result in improved hemodynamic conditions, for example, after somatic gene transfer into rabbits with heart failure because of rapid pacing 5 or myocardial infarction. 6,7 Also, crossbreeding of cardiac-specific bARKct-transgenic mice with mouse models of heart failure due to ablation of the muscle LIM protein (MLP (À/À) mice), 8 due to a myosin heavy chain mutant 9 or due to overexpression of calsequestrin 10 prevented the development of heart failure or improved survival. This effect was additive to the treatment of heart failure with b-blockers.…”
Section: Introductionmentioning
confidence: 99%
“…Cardiac-specific overexpression of the ␤-adrenergic receptor kinase inhibitor was also reported to improve cardiac function in the same model of cardiomyopathy (51). Since phospholamban is the major substrate in the cardiac ␤-adrenergic pathway, it is interesting to propose that at least a part of the beneficial effects by the latter genetic manipulation may be mediated by the phosphorylation level of phospholamban.…”
Section: Discussionmentioning
confidence: 99%
“…␤AR move from plasma membranes into endosomal structures where they are either targeted for lysosomal degradation or recycled as fully functional receptors by vesicular trafficking back to plasma membranes (resensitization) (10). Although the roles for GRK-mediated ␤AR receptoreffector uncoupling in cardiac health and disease have been established (11)(12)(13)(14), the pathophysiological roles of modulated ␤AR receptor internalization͞recycling have not been defined, largely because suitable in vivo experimental models do not exist. Herein, we used Rab-GTPases, regulators of inter-vesicular membrane transport (15), to define effects of modulated ␤AR trafficking in the in vivo heart.…”
mentioning
confidence: 99%