scholarly journals G protein βγ subunits regulate cardiomyocyte hypertrophy through a perinuclear Golgi phosphatidylinositol 4-phosphate hydrolysis pathway

2015 ◽  
Vol 26 (6) ◽  
pp. 1188-1198 ◽  
Author(s):  
S. Malik ◽  
R. G. deRubio ◽  
M. Trembley ◽  
R. Irannejad ◽  
P. B. Wedegaertner ◽  
...  
Keyword(s):  
Heart Failure ◽  
G Protein ◽  
Ventricular Myocytes ◽  
Cardiomyocyte Hypertrophy ◽  
Phosphate Hydrolysis ◽  
Separate Pathway ◽  
Hydrolysis Pathway ◽  
Phosphatidylinositol 4 ◽  
Dependent Pathway

We recently identified a novel GPCR-dependent pathway for regulation of cardiac hypertrophy that depends on Golgi phosphatidylinositol 4-phosphate (PI4P) hydrolysis by a specific isoform of phospholipase C (PLC), PLCε, at the nuclear envelope. How stimuli are transmitted from cell surface GPCRs to activation of perinuclear PLCε is not clear. Here we tested the role of G protein βγ subunits. Gβγ inhibition blocked ET-1–stimulated Golgi PI4P depletion in neonatal and adult ventricular myocytes. Blocking Gβγ at the Golgi inhibited ET-1–dependent PI4P depletion and nuclear PKD activation. Translocation of Gβγ to the Golgi stimulated perinuclear Golgi PI4P depletion and nuclear PKD activation. Finally, blocking Gβγ at the Golgi or PM blocked ET-1–dependent cardiomyocyte hypertrophy. These data indicate that Gβγ regulation of the perinuclear Golgi PI4P pathway and a separate pathway at the PM is required for ET-1–stimulated hypertrophy, and the efficacy of Gβγ inhibition in preventing heart failure maybe due in part to its blocking both these pathways.

Stimulation of calcium influx by platelet activating factor in Dictyostelium

1995 ◽  
Vol 108 (4) ◽  
pp. 1597-1603
Author(s):  
R. Schaloske ◽  
C. Sordano ◽  
S. Bozzaro ◽  
D. Malchow
Keyword(s):  
Plasma Membrane ◽  
G Protein ◽  
Dictyostelium Discoideum ◽  
Calcium Influx ◽  
Platelet Activating Factor ◽  
Inactive Compound ◽  
Time Period ◽  
Dependent Pathway ◽  
Stimulation Of

Platelet activating factor (PAF) induces Ca2+ influx in Dictyostelium discoideum. In this investigation we used this activity to analyze the mechanism of PAF action. We found that PAF activity was confined to the period of spike-shaped oscillations and suggest that the role of PAF is to augment cAMP relay. PAF seems to act only a few times during this time period of two hours, since Ca2+ entry adapted to a subsequent stimulus for about 30 minutes. PAF showed a reduced response in the G protein beta- strain LW14 and was unable to induce Ca2+ influx in the G alpha 2- strains HC85 and JM1. The latter expresses the cAMP receptors cAR1 constitutively, and exhibits cAMP-induced Ca2+ influx, albeit at a reduced level. In order to decide whether the inability of PAF to elicit a Ca2+ response in JM1 cells was due to the lack of differentiation and/or the lack of G alpha 2, we inhibited the IP3-dependent pathway with compound U73122 and found that Ca2+ entry was blocked, whereas a closely related inactive compound, U73343, did not alter the response. In agreement with this, NBD-Cl, an inhibitor of Ca2+ uptake into the IP3-sensitive store in Dictyostelium, also abolished PAF activity. The latter was not inhibited by the plasma membrane antagonists BN-52021 or WEB 2170. Therefore PAF seems to operate intracellularly via the IP3-signalling pathway at or upstream of the IP3-sensitive store.

Abstract 16383: Inhibition of Egfr Signalling Promotes Maladaptive Cardiac Remodelling in Hypertensive Heart Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Susanna Cooper ◽  
Zoe Haines ◽  
Viridiana Alcantara Alonso ◽  
Joshua J Cull ◽  
Feroz Ahmad ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mrna Expression ◽  
Left Ventricular ◽  
Egfr Inhibitors ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Egfr Ligands ◽  
Cardiac Adaptation

Introduction: Epidermal growth factor (EGF) receptors (EGFRs: ERBB1-4) are activated by a family of ligands (e.g. EGF, Hb-EGF, EREG, TGFa), signaling through ERK1/2 and Akt to promote cell division and cancer. Antibody-based inhibition of ERBB2 in breast cancer can cause heart failure, but the role of other receptors and EGFR ligands in the heart, and potential cardiotoxicity of generic EGFR inhibitors is unclear. Hypothesis: We hypothesize that EGFR ligands play an important role in cardiac adaptation to hypertension, acting through EGFRs to promote adaptive remodelling. Methods & Results: EGF ligand/receptor mRNA expression was assessed in human failing hearts and normal controls (n=12/8). EGFRs were expressed at similar levels, but ligand expression differed with significant up- or downregulation of EGF/Hb-EGF vs EREG/TGFa, respectively, in failing hearts (p<0.05). EGF potently activated ERK1/2 and Akt (assessed by immunoblotting) in neonatal rat cardiomyocytes, leading to hypertrophy (p<0.05, n=4). The anti-cancer drug afatinib inhibits EGFRs. To assess the role of EGF signaling in cardiac adaptation to hypertension in vivo , C57Bl/6J mice (n=6) were treated with 0.8 mg/kg/d angiotensin II (AngII; 7d) ± 0.45 mg/kg/d afatinib. AngII promoted cardiac hypertrophy with increased left ventricular (LV) wall thickness (WT) and decreased LV internal diameter (ID; assessed by echocardiography). Afatinib enhanced AngII-induced hypertrophy with significantly increased WT:ID ratios (1.30-fold and 1.54-fold in diastole and systole, respectively; p<0.05) but inhibited AngII-induced increases in Nppb mRNA expression and cardiomyocyte cross-sectional area (208.80±9.78 vs 161.10±3.87μm 2 ; p<0.05). In contrast, Col1a1 mRNA expression was enhanced by afatinib, along with interstitial and perivascular fibrosis (3.21±0.38 vs 5.61±0.46, 0.98±0.06 vs 1.45±0.18 % area; p<0.05). Conclusion: EGFR signaling is modulated in human heart failure, promotes cardiomyocyte hypertrophy and is required for cardiac adaptation to hypertension. Since EGFR inhibition in hypertension prevents adaptive cardiomyocyte hypertrophy whilst promoting fibrosis, EGFR inhibitors are likely to cause cardiac dysfunction and be cardiotoxic in hypertensive patients.

Abstract 507: Activation of the Classically Pro-Apoptotic Death Receptor 5 Promotes Physiological Hypertrophy and Cardiomyocyte Survival

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Toby Thomas ◽  
Miles Tanner ◽  
Laurel Grisanti
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Cardiac Fibrosis ◽  
Death Receptor ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Death Receptor 5 ◽  
Tnf Α ◽  
Cardiomyocyte Survival

Heart failure is hallmarked by a combination of cardiomyocyte hypertrophy and death. Apoptosis, one of the primary mechanisms of cell death, occurs through finely tuned extrinsic or intrinsic pathways. Of the mediators involved in extrinsic apoptotic signaling, some have been extensively studied, such as tumor necrosis factor ((TNF)-α), while others have been relatively untouched. One such receptor is Death Receptor 5 (DR5) which, along with its ligand TNF-Related Apoptosis Inducing Ligand (TRAIL), have recently been implicated as a biomarker in determining the progression and outcome in patients following multiple heart failure etiologies, suggesting a novel role of DR5 signaling in the heart. These studies suggest a potentially protective role for DR5 in the heart; however, the function of TRAIL/DR5 in the heart has been virtually unstudied. Our goal was to explore the role of TRAIL/DR5 in cardiomyocyte hypertrophy and survival with the hypothesis that DR5 promotes cardiomyocyte survival and growth through non-canonical mechanisms. Mice treated with the DR5 agonist bioymifi or a DR5 agonist antibody, MD5-1, were absent of cell death, while an increase in hypertrophy was observed without a decline in cardiac function. In isolated cardiomyocytes, this pro-hypertrophic phenotype was determined to operate through MMP-dependent cleavage of HB-EGFR, leading to transactivation of EGFR and ERK1/2 signaling. To determine the role of DR5 in heart failure, a chronic catecholamine administration model was used and DR5 activation was found to decrease cardiomyocyte death and cardiac fibrosis. ERK1/2, a well characterized pro-survival, pro-hypertrophic kinase is activated in the heart with DR5 agonist administration and may represent the mechanistic link through which DR5 is imparting cardioprotection. In summary, DR5 activation promotes cardiomyocyte hypertrophy and survival and prevents cardiac fibrosis via a non-canonical MMP-EGFR-ERK1/2 pathway. Taken together, these studies identify a previously undetermined role for DR5 in the heart and identify novel therapeutic target for the treatment of heart failure.

scholarly journals Mechanism of cAMP-induced Ca2+ influx in Dictyostelium: role of phospholipase A2

1997 ◽  
Vol 327 (1) ◽  
pp. 233-238 ◽  
Author(s):  
Ralph SCHALOSKE ◽  
Dieter MALCHOW
Keyword(s):  
Phospholipase A2 ◽  
G Protein ◽  
Sequence Similarity ◽  
Similar Extent ◽  
Kinase C ◽  
Maximal Activation ◽  
Receptor Concentration ◽  
Camp Receptor ◽  
Dependent Pathway

cAMP-induced Ca2+ influx in Dictyostelium follows two pathways: a G-protein-dependent pathway where influx is reduced by 50–70% in Gα2 and Gβ-negative strains and a heterotrimeric G-protein-independent pathway. Using a pharmacological approach, we found that phospholipase A2 (PLA2) is the target of both pathways. The products of PLA2 activity, arachidonic acid (AA) and palmitic acid, induced Ca2+ influx to a similar extent as cAMP. Half-maximal activation occurred at 3 μM AA and saturation at 10 μM AA. The response to AA was quantitatively similar throughout early differentiation and thusindependent of cAMP-receptor concentration. Synergy experiments revealed that cAMP and AA acted through identical pathways. The PLA2-activating peptide, a peptide with sequence similarity to the G-protein β-subunit, activated Ca2+ influx. The G-protein-independent pathway was sensitive to genistein but not to blockers of protein kinase C and other kinases, suggesting that tyrosine kinase may directly or indirectly activate PLA2 in this case.

scholarly journals Role of CyPA in cardiac hypertrophy and remodeling

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Mengfei Cao ◽  
Wei Yuan ◽  
Meiling Peng ◽  
Ziqi Mao ◽  
Qianru Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Systolic Function ◽  
Cardiac Fibroblasts ◽  
Cardiomyocyte Hypertrophy ◽  
Pathological Cardiac Hypertrophy ◽  
Complex Process

Abstract Pathological cardiac hypertrophy is a complex process and eventually develops into heart failure, in which the heart responds to various intrinsic or external stress, involving increased interstitial fibrosis, cell death and cardiac dysfunction. Studies have shown that oxidative stress is an important mechanism for this maladaptation. Cyclophilin A (CyPA) is a member of the cyclophilin (CyPs) family. Many cells secrete CyPA to the outside of the cells in response to oxidative stress. CyPA from blood vessels and the heart itself participate in a variety of signaling pathways to regulate the production of reactive oxygen species (ROS) and mediate inflammation, promote cardiomyocyte hypertrophy and proliferation of cardiac fibroblasts, stimulate endothelial injury and vascular smooth muscle hyperplasia, and promote the dissolution of extracellular matrix (ECM) by activating matrix metalloproteinases (MMPs). The events triggered by CyPA cause a decline of diastolic and systolic function and finally lead to the occurrence of heart failure. This article aims to introduce the role and mechanism of CyPA in cardiac hypertrophy and remodeling, and highlights its potential role as a disease biomarker and therapeutic target.

scholarly journals Inhibition of Interactions Between NDPK-B and NDPK-C in Presence of Graphene Oxide

2021 ◽  
Author(s):  
Andrey Zaznaev ◽  
Isaac Macwan
Keyword(s):  
Heart Failure ◽  
Graphene Oxide ◽  
Hydrogen Bonds ◽  
G Protein ◽  
Center Of Mass ◽  
Water Molecules ◽  
Salt Bridges ◽  
Guanine Nucleotide Binding Protein ◽  
Camp Formation

During a heart failure, higher amount of nucleoside diphosphate kinase (NDPK) enzyme in the sarcolemma membrane inhibits the synthesis of second messenger cyclic adenosine monophosphate (cAMP), which is required for the regulation of the calcium ion balance for normal functioning of the heart. In a dependent pathway, NDPK normally phosphorylates the stimulatory guanosine diphosphate, GDP(s), to a guanosine triphosphate, GTP(s), on the heterotrimeric (α, β and γ subunits) guanine nucleotide binding protein (G protein), resulting in the stimulation of the cAMP formation. In case of a heart failure, an increased quantity of NDPK also reacts with the inhibitory GDP(i), which is converted to a GTP(i), resulting in the inhibition of the cAMP formation. Typically, the βγ dimer of the G protein binds with hexameric NDPK-B/C complex and receives the phosphate at the residue His266 from residue His118 of NDPK-B. It is known that NDPK-C is required for NDPK-B to phosphorylate the G protein. In this work, the interactions between NDPK-B and NDPK-C are quantified in the presence and absence of graphene oxide (GO) as well as those between NDPK-B and GO through stability analysis involving hydrogen bonds, center of mass (COM), root mean square deviation (RMSD), and salt bridges, and energetics analysis involving van der Waals (VDW) and electrostatic energies. Furthermore, the role of water molecules at the interface of NDPK-B and NDPK-C as well as between NDPK-B and GO is investigated to understand the nature of interactions. It is found that the adsorption of NDPK-B on GO triggers a potential conformational change in the structure of NDPK-B, resulting in a diminished interaction with NDPK-C. This is confirmed through a reduced center of mass (COM) distance between NDPK-B and GO (from 40 Å to 30 Å) and an increased COM distance between NDPK-B and NDPK-C (from 50 Å to 60 Å). Furthermore, this is also supported by fewer salt bridges between NDPK-B and NDPK-C, and an increased number of hydrogen bonds formed by the interfacial water molecules. As NDPK-C is crucial to be complexed with NDPK-B for successful interaction of NDPK-B with the G protein, this finding shows that GO can suppress the interactions between NDPK-B/C and G proteins, thereby providing an additional insight into the role of GO in the heart failure mechanism.

Abstract 25: The Role of cAMP-Phosphodiesterase 1C Signaling in Pathological Cardiac Remodeling and Dysfunction

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Walter E Knight ◽  
Masayoshi Oikawa ◽  
Clint Miller ◽  
Chen Yan
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Specific Effect ◽  
Cardiomyocyte Hypertrophy ◽  
Protective Mechanism ◽  
Ang Ii ◽  
Camp Phosphodiesterase ◽  
Protein Levels ◽  
Camp And Cgmp

The cyclic nucleotides cAMP and cGMP play important roles in mediating both protective and detrimental signaling in heart failure. By acting as regulators of cAMP and cGMP, the phosphodiesterases play important roles in modulating this signaling. A comparison of PDE expression between control mice and mice given transverse aortic constriction revealed that expression of phosphodiesterase 1C (PDE1C) was increased significantly by TAC, both on the mRNA and protein levels. To determine whether this was protective or maladaptive, we performed TAC on mice with a genetic deletion of PDE1C. While TAC-operated WT mice experienced significant overall cardiac hypertrophy and cardiomyocyte hypertrophy, these were reduced in PDE1C KO mice. Cardiac function, as assessed by echocardiography, was also reduced significantly in WT TAC mice, but was preserved in PDE1C KO TAC mice. Histological analysis indicated that TAC-operated PDE1C KO mice also experienced reduced cardiomyocyte apoptosis compared to WT mice, indicating a potential cardioprotective mechanism for PDE1C deletion. Cardiomyocytes isolated from PDE1C KO mice experienced reduced Ang II or Iso-induced cell death compared to WT myocytes, indicating that this was a cardiomyocytes-specific effect of PDE1C deletion. Ang II-induced cardiomyocyte cell death and apoptosis were also blocked via pharmacological PDE1 inhibition. PDE1C is able to hydrolyze either cAMP or cGMP; therefore, it seemed possible that this protective mechanism was dependent on either PKA- or PKG-mediated signaling. While PKG inhibition did not alter the protective effect of PDE1 inhibition in isolated cardiomyocytes, PKA inhibition blocked it. Overexpression studies also indicated that PDE1C is localized to the cell membrane in cardiomyocytes. Therefore, we propose that by modulating a novel, membrane-localized, anti-apoptotic, cAMP/PKA-dependent pathway in cardiomyocytes, PDE1C potentially represents a novel therapeutic target in heart failure.

scholarly journals Differential Role of G Protein–Coupled Receptor Kinase 5 in Physiological Versus Pathological Cardiac Hypertrophy

2015 ◽  
Vol 117 (12) ◽  
pp. 1001-1012 ◽  
Author(s):  
Christopher J. Traynham ◽  
Alessandro Cannavo ◽  
Yan Zhou ◽  
Alexandre G. Vouga ◽  
Benjamin P. Woodall ◽  
...  
Keyword(s):  
Heart Failure ◽  
G Protein ◽  
Nuclear Translocation ◽  
Nuclear Accumulation ◽  
G Protein Coupled Receptor ◽  
Littermate Control ◽  
G Protein Coupled ◽  
Physiological Hypertrophy ◽  
Nontransgenic Littermate

Rationale : G protein–coupled receptor kinases (GRKs) are dynamic regulators of cellular signaling. GRK5 is highly expressed within myocardium and is upregulated in heart failure. Although GRK5 is a critical regulator of cardiac G protein–coupled receptor signaling, recent data has uncovered noncanonical activity of GRK5 within nuclei that plays a key role in pathological hypertrophy. Targeted cardiac elevation of GRK5 in mice leads to exaggerated hypertrophy and early heart failure after transverse aortic constriction (TAC) because of GRK5 nuclear accumulation. Objective : In this study, we investigated the role of GRK5 in physiological, swimming-induced hypertrophy (SIH). Methods and Results : Cardiac-specific GRK5 transgenic mice and nontransgenic littermate control mice were subjected to a 21-day high-intensity swim protocol (or no swim sham controls). SIH and specific molecular and genetic indices of physiological hypertrophy were assessed, including nuclear localization of GRK5, and compared with TAC. Unlike after TAC, swim-trained transgenic GRK5 and nontransgenic littermate control mice exhibited similar increases in cardiac growth. Mechanistically, SIH did not lead to GRK5 nuclear accumulation, which was confirmed in vitro as insulin-like growth factor-1, a known mediator of physiological hypertrophy, was unable to induce GRK5 nuclear translocation in myocytes. We found specific patterns of altered gene expression between TAC and SIH with GRK5 overexpression. Further, SIH in post-TAC transgenic GRK5 mice was able to preserve cardiac function. Conclusions: These data suggest that although nuclear-localized GRK5 is a pathological mediator after stress, this noncanonical nuclear activity of GRK5 is not induced during physiological hypertrophy.

scholarly journals Early activation of the cardiac CX3CL1/CX3CR1 axis delays β-adrenergic-induced heart failure

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
M. Flamant ◽  
N. Mougenot ◽  
E. Balse ◽  
L. Le Fèvre ◽  
F. Atassi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Adrenergic Stimulation ◽  
Intramyocardial Injection ◽  
In Vivo Experiments ◽  
Concentric Hypertrophy

AbstractWe recently highlighted a novel potential protective paracrine role of cardiac myeloid CD11b/c cells improving resistance of adult hypertrophied cardiomyocytes to oxidative stress and potentially delaying evolution towards heart failure (HF) in response to early β-adrenergic stimulation. Here we characterized macrophages (Mφ) in hearts early infused with isoproterenol as compared to control and failing hearts and evaluated the role of upregulated CX3CL1 in cardiac remodeling. Flow cytometry, immunohistology and Mφ-depletion experiments evidenced a transient increase in Mφ number in isoproterenol-infused hearts, proportional to early concentric hypertrophy (ECH) remodeling and limiting HF. Combining transcriptomic and secretomic approaches we characterized Mφ-enriched CD45+ cells from ECH hearts as CX3CL1- and TNFα-secreting cells. In-vivo experiments, using intramyocardial injection in ECH hearts of either Cx3cl1 or Cx3cr1 siRNA, or Cx3cr1−/− knockout mice, identified the CX3CL1/CX3CR1 axis as a protective pathway delaying transition to HF. In-vitro results showed that CX3CL1 not only enhanced ECH Mφ proliferation and expansion but also supported adult cardiomyocyte hypertrophy via a synergistic action with TNFα. Our data underscore the in-vivo transient protective role of the CX3CL1/CX3CR1 axis in ECH remodeling and suggest the participation of CX3CL1-secreting Mφ and their crosstalk with CX3CR1-expressing cardiomyocytes to delay HF.

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