Targeted inhibition of beta-adrenergic receptor kinase-1-associated phosphoinositide-3 kinase activity preserves beta-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression. 2005

Cinzia Perrino, and Sathyamangla V Naga Prasad, and Mrinali Patel, and Matthew J Wolf, and Howard A Rockman
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

OBJECTIVE Desensitization and down-regulation of beta-adrenergic receptors (betaARs) are prominent features of heart failure largely mediated by increased levels of betaAR kinase-1 (betaARK1). BACKGROUND beta-adrenergic receptor kinase 1 interacts with phosphoinositide-3 kinase (PI3K), and upon agonist stimulation, the betaARK1/PI3K complex is recruited to agonist-stimulated betaARs. Here we tested the hypothesis that in vivo selective inhibition of betaARK1-associated PI3K activity would preserve betaAR signaling and, therefore, improve cardiac function and survival in experimental heart failure. METHODS We used a murine model of heart failure induced by calsequestrin (CSQ) cardiac-specific overexpression; CSQ mice were crossed with mice overexpressing in the heart a catalytically inactive PI3Kgamma (PI3Kgamma(inact)) to competitively displace endogenous PI3K from betaARK1. RESULTS Catalytically inactive PI3KgammaPI3K overexpression in CSQ mice inhibited betaARK1-associated PI3K activity, normalized betaAR levels, and preserved betaAR responsiveness to isoproterenol (ISO). Restoration of betaAR signaling via PI3Kgamma(inact) overexpression resulted in marked improvement of cardiac function and a significant prolongation of survival. Importantly, the effects of PI3Kgamma(inact) overexpression were restricted to betaAR signaling, because cellular PI3K signaling was unaltered, as shown by the similar activation of multiple downstream signaling pathways in both CSQ and CSQ/PI3Kgamma(inact) mice. CONCLUSIONS These data in the CSQ model of cardiac dysfunction indicate that membrane-targeted PI3K activity plays a detrimental role in heart failure, and its inhibition represents a novel therapeutic approach to ameliorate cardiac dysfunction and improve survival.

UI MeSH Term Description Entries
D007160 Immunoproliferative Disorders Disorders characterized by abnormal proliferation of primary cells of the immune system or by excessive production of immunoglobulins. Disorder, Immunoproliferative,Disorders, Immunoproliferative,Immunoproliferative Disorder
D008815 Mice, Inbred Strains Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations, or by parent x offspring matings carried out with certain restrictions. All animals within an inbred strain trace back to a common ancestor in the twentieth generation. Inbred Mouse Strains,Inbred Strain of Mice,Inbred Strain of Mouse,Inbred Strains of Mice,Mouse, Inbred Strain,Inbred Mouse Strain,Mouse Inbred Strain,Mouse Inbred Strains,Mouse Strain, Inbred,Mouse Strains, Inbred,Strain, Inbred Mouse,Strains, Inbred Mouse
D008822 Mice, Transgenic Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN. Transgenic Mice,Founder Mice, Transgenic,Mouse, Founder, Transgenic,Mouse, Transgenic,Mice, Transgenic Founder,Transgenic Founder Mice,Transgenic Mouse
D011943 Receptors, Adrenergic, beta One of two major pharmacologically defined classes of adrenergic receptors. The beta adrenergic receptors play an important role in regulating CARDIAC MUSCLE contraction, SMOOTH MUSCLE relaxation, and GLYCOGENOLYSIS. Adrenergic beta-Receptor,Adrenergic beta-Receptors,Receptors, beta-Adrenergic,beta Adrenergic Receptor,beta-Adrenergic Receptor,beta-Adrenergic Receptors,Receptor, Adrenergic, beta,Adrenergic Receptor, beta,Adrenergic beta Receptor,Adrenergic beta Receptors,Receptor, beta Adrenergic,Receptor, beta-Adrenergic,Receptors, beta Adrenergic,beta Adrenergic Receptors,beta-Receptor, Adrenergic,beta-Receptors, Adrenergic
D002155 Calsequestrin Acidic protein found in SARCOPLASMIC RETICULUM that binds calcium to the extent of 700-900 nmoles/mg. It plays the role of sequestering calcium transported to the interior of the intracellular vesicle.
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015151 Immunoblotting Immunologic method used for detecting or quantifying immunoreactive substances. The substance is identified by first immobilizing it by blotting onto a membrane and then tagging it with labeled antibodies. Dot Immunoblotting,Electroimmunoblotting,Immunoelectroblotting,Reverse Immunoblotting,Immunoblotting, Dot,Immunoblotting, Reverse,Dot Immunoblottings,Electroimmunoblottings,Immunoblottings,Immunoblottings, Dot,Immunoblottings, Reverse,Immunoelectroblottings,Reverse Immunoblottings
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D015536 Down-Regulation A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins. Receptor Down-Regulation,Down-Regulation (Physiology),Downregulation,Down Regulation,Down-Regulation, Receptor

Related Publications

Cinzia Perrino, and Sathyamangla V Naga Prasad, and Mrinali Patel, and Matthew J Wolf, and Howard A Rockman
August 2006, Vascular pharmacology,
Cinzia Perrino, and Sathyamangla V Naga Prasad, and Mrinali Patel, and Matthew J Wolf, and Howard A Rockman
August 2005, Nature cell biology,
Cinzia Perrino, and Sathyamangla V Naga Prasad, and Mrinali Patel, and Matthew J Wolf, and Howard A Rockman
November 2005, American journal of physiology. Heart and circulatory physiology,
Cinzia Perrino, and Sathyamangla V Naga Prasad, and Mrinali Patel, and Matthew J Wolf, and Howard A Rockman
January 2011, Current pharmaceutical design,
Cinzia Perrino, and Sathyamangla V Naga Prasad, and Mrinali Patel, and Matthew J Wolf, and Howard A Rockman
October 2003, The Journal of clinical investigation,
Cinzia Perrino, and Sathyamangla V Naga Prasad, and Mrinali Patel, and Matthew J Wolf, and Howard A Rockman
November 2022, Basic research in cardiology,
Cinzia Perrino, and Sathyamangla V Naga Prasad, and Mrinali Patel, and Matthew J Wolf, and Howard A Rockman
October 2003, Journal of molecular and cellular cardiology,
Cinzia Perrino, and Sathyamangla V Naga Prasad, and Mrinali Patel, and Matthew J Wolf, and Howard A Rockman
June 2001, The Journal of biological chemistry,
Cinzia Perrino, and Sathyamangla V Naga Prasad, and Mrinali Patel, and Matthew J Wolf, and Howard A Rockman
January 1999, Annual review of pharmacology and toxicology,
Cinzia Perrino, and Sathyamangla V Naga Prasad, and Mrinali Patel, and Matthew J Wolf, and Howard A Rockman
October 2016, Cellular signalling,
Copied contents to your clipboard!