ArticleProceedings of the National Academy of Sciences of the United States of America1998
Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1998. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 152 papers.
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Who cites it
152 citing papers in PubMed, 485 citations in OpenAlex.
- Beyond β-Adrenergic Receptor Brake: Compartment-Selective GRK2 Programs from Heart Failure to Cardio-Oncology.Kinases and phosphatases · 2026Article
- Cell-based and isoform-selective G protein-coupled receptor kinase assays for comprehensive inhibitor evaluation.Communications biology · 2026Article
- Canonical or non-canonical, all aspects of G protein-coupled receptor kinase 2 in heart failure.Acta physiologica (Oxford, England) · 2025Review
- Therapeutic Efficacy of a Novel Pharmacologic GRK2 Inhibitor in Multiple Animal Models of Heart Failure.JACC. Basic to translational science · 2025Article
- Review
- Torsional and strain dysfunction precede overt heart failure in a mouse model of dilated cardiomyopathy pathogenesis.American journal of physiology. Heart and circulatory physiology · 2023Article
- Novel roles for G protein-coupled receptor kinases in cardiac injury and repair.Biochemical Society transactions · 2023Review
- GRK2 in cardiovascular disease and its potential as a therapeutic target.Journal of molecular and cellular cardiology · 2022Review
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- G protein-coupled receptor signaling: transducers and effectors.American journal of physiology. Cell physiology · 2022Review
- Double life: How GRK2 and β-arrestin signaling participate in diseases.Cellular signalling · 2022Review
- Understanding the molecular basis of cardiomyopathy.American journal of physiology. Heart and circulatory physiology · 2022Review
- Focus on the Lymphatic Route to Optimize Drug Delivery in Cardiovascular Medicine.Pharmaceutics · 2021Review
- A peptide of the amino-terminus of GRK2 induces hypertrophy and yet elicits cardioprotection after pressure overload.Journal of molecular and cellular cardiology · 2021Article
- Review
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- Identification of Independent and Communal Differentially Expressed Genes as Well as Potential Therapeutic Targets in Ischemic Heart Failure and Non-Ischemic Heart Failure.Pharmacogenomics and personalized medicine · 2021Article
- Genetics of adrenergic signaling drives coronary artery calcification.Atherosclerosis · 2020Article
- Inhalation ofAmerican journal of respiratory cell and molecular biology · 2020Article
- Structure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors.ACS medicinal chemistry letters · 2019Article
92 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
Heart failure is accompanied by severely impaired beta-adrenergic receptor (betaAR) function, which includes loss of betaAR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of betaAR function is agonist-stimulated receptor phosphorylation by the betaAR kinase (betaARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in betaAR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of betaARK1 or the beta2AR were mated into a genetic model of murine heart failure (MLP-/-). In vivo cardiac function was assessed by echocardiography and cardiac catheterization. Both MLP-/- and MLP-/-/beta2AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP-/-/betaARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP-/-/betaARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the MLP-/- mice but less than controls. Importantly, heightened betaAR desensitization in the MLP-/- mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the betaARK1 inhibitor. We report here the striking finding that overexpression of this inhibitor prevents the development of cardiomyopathy in this murine model of heart failure. These findings implicate abnormal betaAR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit betaARK1 as a novel mode of therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.