Targeting the Receptor-G
            <sub>q</sub>
            Interface to Inhibit in Vivo Pressure Overload Myocardial Hypertrophy

Akhter, Shahab A.; Luttrell, Louis M.; Rockman, Howard A.; Iaccarino, Guido; Lefkowitz, Robert J.; Koch, Walter J.

doi:10.1126/science.280.5363.574

Cited by 420 publications

(323 citation statements)

References 12 publications

Supporting

Mentioning

308

Contrasting

Unclassified

Order By: Relevance

“…It is well known that stimulation of myocytes with hormones that activate IP 3 production, e.g. ET-1, can promote hypertrophy [150][151][152][153][154]. What is not fully understood, however, is how such hormones can affect subtle changes in Ca 2+ -dependent gene transcription inside cells that experience periodic surges of Ca 2+ during excitation-contraction coupling [155].…”

Section: Ip 3 Signaling In Ventricular Myocytesmentioning

confidence: 99%

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

168

149

View full text Add to dashboard Cite

Inositol 1,4,5-trisphosphate (IP 3 ) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP 3 from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). The major action of IP 3 , which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca 2+ release from endogenous stores through IP 3 receptors (IP 3 Rs). Cardiac excitation-contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca 2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP 3 Rs (∼100:1), and furthermore they experience substantial fluxes of Ca 2+ with each heartbeat. Therefore, the role of IP 3 and IP 3 -mediated Ca 2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP 3 Rs may play crucial roles in regulating diverse cardiac functions. Strategic localization of IP 3 Rs in cytoplasmic compartments and the nucleus enables them to participate in subsarcolemmal, bulk cytoplasmic and nuclear Ca 2+ signaling in embryonic stem cell-derived and neonatal cardiomyocytes, and in adult cardiac myocytes from the atria and ventricles. Intriguingly, expression of both IP 3 Rs and membrane receptors that couple to PLC/IP 3 signaling is altered in cardiac disease such as atrial fibrillation or heart failure, suggesting the involvement of IP 3 signaling in the pathology of these diseases. Thus, IP 3 exerts important physiological and pathological functions in the heart, ranging from the regulation of pacemaking, excitation-contraction and excitation-transcription coupling to the initiation and/or progression of arrhythmias, hypertrophy and heart failure. KeywordsInositol 1,4,5-trisphosphate; Cardiac myocyte; Calcium; Inotropy; Arrhythmias; Nucleus; Hypertrophy © 2008 Elsevier Inc. All rights reserved. * Corresponding author. E-mail address: jens.kockskaemper@meduni-graz.at (J. Kockskämper).. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript The discovery of IP 3A quarter of a century ago it was shown that D-myo inositol 1,4,5-trisphosphate (IP 3 ) releases Ca 2+ from a non-mitochondrial internal Ca 2+ store [1]. Since this hallmark discovery, IP 3 has emerged as a ubiquitous intracellular messenger, releasing Ca 2+ from stores through activation of IP 3 receptors (IP 3 Rs) in almost all eukaryotic cells. The major IP 3 -sensitive intracellular Ca 2+ store is the endoplasmic reticulum. However, IP 3 has also been shown to release Ca 2+ stored in other compartments, such as the Golgi and the nuclear envelope [2]. In addition, IP 3 Rs are present on the plasma membrane of some cell types, where they can gate Ca 2+ influx [3]. A crucial role for IP 3 -dependent Ca 2+ release has been demonstrated in many mammalian cell types, ranging from tiny platelets, where it initiates blood clottin...

show abstract

Section: Ip 3 Signaling In Ventricular Myocytesmentioning

confidence: 99%

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

168

149

View full text Add to dashboard Cite

show abstract

“…Evidence that Gaq is su cient to induce hypertrophy in transgenic mice was complemented by several lines of evidence indicating that Gaq activation was necessary for hypertrophy in response to pressure overload induced by transverse aortic constriction. In one study, a Gaq inhibitor peptide previously shown to prevent receptor coupling to Gaq was expressed in the myocardium of transgenic mice (Akhter et al, 1998). Hypertrophy induced by pressure overload was signi®cantly attenuated in these animals.…”

Section: Gq-coupled Receptors In Cardiac Hypertrophymentioning

confidence: 99%

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

2001

View full text Add to dashboard Cite

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.

show abstract

“…b, HUVECs and HUVECs transduced with EGNP-1 were treated with different concentrations of anti-VEGFR-2 (0, 1, 5 g/ml), then stimulated with 10 ng/ml VPF/VEGF or 10 ng/ml EGF for migration assays. specific intracellular G␤␥ antagonist by inhibiting G␤␥-mediated downstream events (33,34). Our results showed that overexpression of h␤ARK1 (495) almost completely reduced the migration of HUVECs mediated by EGNP-1 (Fig.…”

Section: Fig 3 Nrp-1/egnp-1 Alone Mediates Huvec Migration a Huvementioning

confidence: 99%

Neuropilin-1-mediated Vascular Permeability Factor/Vascular Endothelial Growth Factor-dependent Endothelial Cell Migration

Wang

Zeng

Wang

et al. 2003

Journal of Biological Chemistry

190

177

View full text Add to dashboard Cite

Neuropilin-1 (NRP-1) has been found to be expressed by endothelial cells and tumor cells as an isoform-specific receptor for vascular permeability factor/vascular endothelial growth factor (VEGF). Previous studies were mainly focused on the extracellular domain of NRP-1 that can bind to VEGF 165 and, thus, enables NRP-1 to act as a co-receptor for VEGF 165 , which enhances its binding to VEGFR-2 and its bioactivity. However, the exact functional roles and related signaling mechanisms of NRP-1 in angiogenesis are not well understood. In this study we constructed a chimeric receptor, EGNP-1, by fusing the extracellular domain of epidermal growth factor receptor to the transmembrane and intracellular domains of NRP-1 and transduced it into HUVECs with a retroviral expression vector. We observed that NRP-1/EGNP-1 mediates ligand-stimulated migration of human umbilical vein endothelial cells (HUVECs) but not proliferation. Our results show that NRP-1 alone can mediate HUVEC migration through its intracellular domain, and its C-terminal three amino acids (SEA-COOH) are essential for the process. We demonstrate that phosphatidylinositol 3-kinase inhibitor Ly294002 and the p85 dominant negative mutant can block NRP-1-mediated HUVEC migration. NRP-1-mediated migration can be significantly reduced by overexpression of the dominant negative mutant of RhoA (RhoA-19N). In addition, G q family proteins and G␤␥ subunits are also required for NRP-1-mediated HUVEC migration. These results show for the first time that NRP-1 can independently promote cell signaling in endothelial cells and also demonstrate the importance of last three amino acids of NRP-1 for its function.Angiogenesis, the formation of vascular networks by endothelial cells (ECs) 1 sprouting from the vascular bed, occurs in many physiological or pathological processes (1). Vascular permeability factor/vascular endothelial growth factor (VPF/ VEGF) plays a major role in the regulation of angiogenesis; it is regarded as a key contributor to the growth of cancer and vascular disease (2). VPF/VEGF activities are mediated by high affinity receptor tyrosine kinases that are associated primarily with ECs (2). Two important VPF/VEGF binding receptor tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), have been identified, both of which are functionally active during angiogenesis. Recent studies have found a third VPF/ VEGF receptor, neuropilin-1 (NRP-1), that is expressed by ECs and tumor cells (3, 4).NRP-1 is a 130 -135-kDa cell surface glycoprotein. It was originally characterized as a semaphorin III receptor that is important for guiding neural development (5, 6). There is also evidence that NRP-1 mediates angiogenesis. NRP-1-null mice were found to be embryonic lethal and exhibit cardiovascular defects (7). Furthermore, overexpression of NRP-1 in mice resulted in excessive capillary and blood vessel formation and hemorrhaging in embryos (8). NRP-1 also contributes to tumor angiogenesis. Induction of NRP-1 expression in tumor cells in vivo resulted in larger an...

show abstract

Targeting the Receptor-G _q Interface to Inhibit in Vivo Pressure Overload Myocardial Hypertrophy

Cited by 420 publications

References 12 publications

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

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

Neuropilin-1-mediated Vascular Permeability Factor/Vascular Endothelial Growth Factor-dependent Endothelial Cell Migration

Contact Info

Product

Resources

About

Targeting the Receptor-G q Interface to Inhibit in Vivo Pressure Overload Myocardial Hypertrophy

Cited by 420 publications

References 12 publications

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

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

Neuropilin-1-mediated Vascular Permeability Factor/Vascular Endothelial Growth Factor-dependent Endothelial Cell Migration

Contact Info

Product

Resources

About

Targeting the Receptor-G _q Interface to Inhibit in Vivo Pressure Overload Myocardial Hypertrophy