Dependence of changes in β-adrenoceptor signal transduction on type and stage of cardiac hypertrophy

2007 ◽  
Vol 102 (3) ◽  
pp. 978-984 ◽  
Author(s):  
Rajat Sethi ◽  
Harjot K. Saini ◽  
Xiaobing Guo ◽  
Xi Wang ◽  
Vijayan Elimban ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Adenylyl Cyclase ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Cyclase Activity ◽  
Adenylyl Cyclase Activity ◽  
Hemodynamic Assessment ◽  
Intracellular Ca

To examine whether cardiac hypertrophy is associated with changes in β-adrenoceptor signal transduction mechanisms, pressure overload (PO) was induced by occlusion of the abdominal aorta and volume overload (VO) by creation of an aortocaval shunt for 4 and 24 wk in rats. After hemodynamic assessment of the animals, the left ventricular (LV) particulate fraction was isolated for measurement of β1-adrenoceptors and adenylyl cyclase activity, and cardiomyocytes were isolated for monitoring of the intracellular Ca2+ concentration. Although PO and VO produced cardiac hypertrophy and increased LV end-diastolic pressure at 4 wk, cardiac function was increased in animals subjected to PO but remained unaltered in animals subjected to VO. Cardiac hypertrophy and increased LV end-diastolic pressure were associated with depressed cardiac function at 24 wk of PO or VO, but clinical signs of congestive heart failure were evident only in animals subjected to VO. Isoproterenol-induced increases in cardiac function, activation of adenylyl cyclase activity, and increase in intracellular Ca2+ concentration, as well as β1-adrenoceptor density, were unaltered by PO at 4 wk, augmented by VO at 4 wk, and attenuated by PO and VO at 24 wk. These results suggest that alterations in β1-adrenoceptor signal transduction are dependent on the type and stage of cardiac hypertrophy.

Abstract 212: Inhibition of Protein Phosphatase 2A (PP2A) Leads to Beta-adrenergic Receptor Dysfunction With Cardiac Stress Following Pressure-overload Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Arunachal Chatterjee ◽  
Neelakantan Vasudevan ◽  
Maradumane Mohan ◽  
Elizabeth Martelli ◽  
John George ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Adenylyl Cyclase ◽  
Cardiac Dysfunction ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Cyclase Activity ◽  
Adenylyl Cyclase Activity ◽  
Cardiac Stress ◽  
Phosphatase 2A

Beta-Adrenergic receptors (bARs) play a key role in regulating cardiac function. Loss of surface receptors and desensitization (impaired G-protein coupling) of bARs are hallmarks of a failing heart. Desensitization occurs by phosphorylation of bARs. The bARs are resensitized by protein phosphatase 2A (PP2A) mediated dephosphorylation in the endosomes before recycling to the plasma membrane. While mechanisms of desensitization are well understood, little is known about mechanisms regulating resensitization. Our previous work has shown that PI3Kg phosphorylates an endogenous inhibitor of PP2A (I2PP2A) on serine 9 & 93, which then robustly binds to PP2A inhibiting bAR resensitization. Since it is not known whether resensitization is altered in response to cardiac stress or whether altered bAR resensitization contributes to cardiac hypertrophy and failure, we generated transgenic mice with cardiomyocyte specific overexpression of wild type I2PP2A (WT I2PP2A Tg), I2PP2A phospho-mimetic mutants S9, 93D and mutants with constitutively dephosphorylated S9, 93A state. To test whether resensitization is critical in the development of bAR dysfunction during cardiac hypertrophy, WT I2PP2A Tg mice were subjected to transverse aortic constriction (TAC) for 8 weeks. Echocardiographic analysis post-TAC showed that WT I2PP2A Tg mice had accelerated cardiac dysfunction compared to their littermate controls [HW (mg)/BW(g): Sham: WT - 4.83, WT I2PP2A Tg - 4.82, TAC: WT- 6.47, WT I2PP2A Tg - 7.61; %EF: Sham: WT - 83.53, WT I2PP2A Tg - 74.72, TAC: WT - 70.47, WT I2PP2A Tg - 49.62]. To directly test whether resensitization mechanisms are altered, plasma membranes and endosomes were isolated and in vitro Adenylyl Cyclase activity assessed. Our studies show that compared to littermate controls, WT I2PP2A Tg had altered in vitro adenylyl cyclase activity showing that resensitization mechanisms in the endosomes may in part, contribute to cardiac dysfunction. Mechanistic underpinnings of the resensitization pathways using the I2PP2A S9, 93A and S9, 93D will be presented showing that bAR resensitization a process considered passive is altered in conditions of cardiac stress that in part may contribute to bAR dysfunction leading to cardiac hypertrophy and heart failure.

A neutralizing leptin receptor antibody mitigates hypertrophy and hemodynamic dysfunction in the postinfarcted rat heart

2008 ◽  
Vol 295 (1) ◽  
pp. H441-H446 ◽  
Author(s):  
Daniel M. Purdham ◽  
Venkatesh Rajapurohitam ◽  
Asad Zeidan ◽  
Cathy Huang ◽  
Garrett J. Gross ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Leptin Receptor ◽  
Diastolic Pressure ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Receptor Blockade ◽  
Receptor Antibody ◽  
Postinfarction Remodeling

The 16 kDa adipokine leptin has been shown to exert direct hypertrophic effects on cultured cardiomyocytes although its role as an endogenous contributor to postinfarction remodeling and heart failure has not been determined. We therefore investigated the effect of leptin receptor blockade in vivo on hemodynamic function and cardiac hypertrophy following coronary artery ligation (CAL). Cardiac function and biochemical parameters were measured in rats subjected to 7 or 28 days of left main CAL in the presence and absence of a leptin receptor antibody. Animals subjected to an identical treatment in which the artery was not tied served as sham-operated controls. CAL produced myocardial hypertrophy, which was most pronounced 28 days postinfarction as demonstrated by increases in both left ventricular weight-to-body weight ratio and atrial natriuretic peptide gene expression, both of which were abrogated by leptin receptor antagonism. Leptin receptor blockade also significantly improved left ventricular systolic function, attenuated the increased left ventricular end-diastolic pressure, and reduced the expression of genes associated with extracellular matrix remodeling 28 days following CAL. In conclusion, the ability of a leptin receptor-neutralizing antibody to improve cardiac function offers evidence that endogenous leptin contributes to cardiac hypertrophy following CAL. The possibility exists that targeting the myocardial leptin receptor represents a viable and novel approach toward attenuating postinfarction remodeling.

Volume overload cardiac hypertrophy exhibits decreased expression of Gsα and not of Giα in heart

2000 ◽  
Vol 279 (4) ◽  
pp. C990-C998 ◽  
Author(s):  
Francesco Di Fusco ◽  
Shehla Hashim ◽  
Madhu B. Anand-Srivastava
Keyword(s):  
Cardiac Hypertrophy ◽  
Adenylyl Cyclase ◽  
Weight Ratio ◽  
Volume Overload ◽  
Protein Quantification ◽  
Cyclase Activity ◽  
Dependent Manner ◽  
Adenylyl Cyclase Activity ◽  
Arterial Blood ◽  
Av Shunt

We have recently reported enhanced levels of Giα proteins in genetic and other experimentally induced models of hypertension, whereas the levels of Gsα were decreased in hypertensive rats expressing cardiac hypertrophy. The present studies were undertaken to investigate whether the decreased levels of Gsα are associated with cardiac hypertrophy per se and used an aortocaval fistula (AV shunt; volume overload) rat model that exclusively expresses cardiac hypertrophy. Cardiac hypertrophy in Sprague-Dawley rats (200–250 g) was induced under anesthesia, and, after a period of 10 days, the hearts were used for adenylyl cyclase activity determination, protein quantification, and mRNA level determination. A temporal relationship between the expression of Gsα proteins and cardiac hypertrophy was also examined on days 2, 3, 7, and 10 after induction of AV shunt in the rat. The heart-to-body-weight ratio (mg/g) was significantly increased in AV shunt rats after 3, 7, and 10 days of induction of AV shunt compared with sham-operated controls, whereas arterial blood pressure was not different between the two groups. Guanosine 5′- O-(3-thiotriphosphate) (GTPγS) stimulated adenylyl cyclase activity in a concentration-dependent manner in heart membranes from both groups; however, the degree of stimulation was significantly decreased in AV shunt rats. In addition, the stimulatory effects of isoproterenol were also diminished in AV shunt rats compared with control rats, whereas glucagon-stimulated adenylyl cyclase activity was not different in the two groups. The inhibitory effects of oxotremorine (receptor-dependent Gi functions) and low concentrations of GTPγS on forskolin-stimulated adenylyl cyclase activity (receptor-independent Gi functions) were not different in the two groups. In addition forskolin and NaF also stimulated adenylyl cyclase activity to a lesser degree in AV shunt rats compared with control rats. The levels of Giα-2 and Giα-3 proteins and mRNA, as determined by immunoblotting and Northern blotting, respectively, were not different in both groups; however, the levels of Gsα45 and Gsα47, and not of Gsα52, proteins were significantly decreased in AV shunt rats by days 7 and 10 compared with control rats, whereas no change was observed on days 2 and 3 after induction of AV shunt. These results suggest that the decreased expression of Gsα proteins may not be the cause but the effect of hypertrophy and that the diminished responsiveness of adenylyl cyclase to GTPγS, isoproterenol, NaF, and forskolin in hearts from AV shunt rats may partly be due to the decreased expression of Gsα. It can be concluded from these studies that the decreased expression of Gsα may be associated with cardiac hypertrophy and not with arterial hypertension.

Redistribution and abnormal activity of phospholipase A2 isoenzymes in postinfarct congestive heart failure

2001 ◽  
Vol 280 (3) ◽  
pp. C573-C580 ◽  
Author(s):  
Jane McHowat ◽  
Paramjit S. Tappia ◽  
Song-Yan Liu ◽  
Raetreal McCrory ◽  
Vincenzo Panagia
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Phospholipase D ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Immunoblot Analysis ◽  
Left Ventricular ◽  
Hemodynamic Assessment ◽  
Intracellular Ca ◽  
Contractile Performance

Cardiac sarcolemmal (SL) cis-unsaturated fatty acid sensitive phospholipase D ( cis-UFA PLD) is modulated by SL Ca2+-independent phospholipase A2(iPLA2) activity via intramembrane release of cis-UFA. As PLD-derived phosphatidic acid influences intracellular Ca2+ concentration and contractile performance of the cardiomyocyte, changes in iPLA2 activity may contribute to abnormal function of the failing heart. We examined PLA2 immunoprotein expression and activity in the SL and cytosol from noninfarcted left ventricular (LV) tissue of rats in an overt stage of congestive heart failure (CHF). Hemodynamic assessment of CHF animals showed an increase of the LV end-diastolic pressure with loss of contractile function. In normal hearts, immunoblot analysis revealed the presence of cytosolic PLA2 (cPLA2) and secretory PLA2 (sPLA2) in the cytosol, with cPLA2 and iPLA2 in the SL. Intracellular PLA2 activity was predominantly Ca2+independent, with minimal sPLA2 activity. CHF increased cPLA2 immunoprotein and PLA2 activity in the cytosol and decreased SL iPLA2 and cPLA2immunoprotein and SL PLA2 activity. sPLA2activity and abundance decreased in the cytosol and increased in SL in CHF. The results show that intrinsic to the pathophysiology of post-myocardial infarction CHF are abnormalities of SL PLA2isoenzymes, suggesting that PLA2-mediated bioprocesses are altered in CHF.

TNF-alpha inhibits isoproterenol-stimulated adenylyl cyclase activity in cultured airway smooth muscle cells

1997 ◽  
Vol 272 (4) ◽  
pp. L644-L650 ◽  
Author(s):  
C. W. Emala ◽  
J. Kuhl ◽  
C. L. Hungerford ◽  
C. A. Hirshman
Keyword(s):  
Signal Transduction ◽  
Smooth Muscle ◽  
Adenylyl Cyclase ◽  
Airway Smooth Muscle ◽  
Adrenergic Receptor ◽  
Cyclase Activity ◽  
Tnf Alpha ◽  
Adenylyl Cyclase Activity ◽  
Beta Adrenergic Receptor ◽  
Beta Adrenergic

Inflammation, increased cytokine production, and decreased responsiveness of airway smooth muscle (ASM) to beta-adrenergic agonists are characteristics of asthma. We questioned whether the cytokine tumor necrosis factor-alpha (TNF-alpha) directly impaired beta-adrenergic signal transduction in cultured canine ASM cells. Confluent ASM cells exposed to TNF-alpha (0.1-10 ng/ml) for 72 h showed lower maximal levels of adenylyl cyclase activity in response to isoproterenol (10 ng/ml; 14 +/- 4.3 vs. 7.5 +/- 1.3 pmol adenosine 3',5'-cyclic monophosphate x well(-1) x 20 min(-1), control vs. treated, respectively), despite no changes in beta-adrenergic receptor numbers (maximum number of binding sites = 4.8 +/- 0.72 vs. 4.5 +/- 0.81 fmol/mg protein, control vs. treated, respectively). Adenylyl cyclase activities in response to prostaglandin E1, NaF, or forskolin were not different in treated and untreated cells. These results demonstrate that a cytokine known to be increased during exacerbation of asthmatic symptoms directly impairs beta-adrenergic function in ASM cells and suggests a mechanism by which inflammation impairs beta-adrenergic receptor signal transduction in asthma.

Strain-dependent β-adrenergic receptor function influences myocardial responses to isoproterenol stimulation in mice

2005 ◽  
Vol 289 (1) ◽  
pp. H30-H36 ◽  
Author(s):  
Michael D. Faulx ◽  
Paul Ernsberger ◽  
Dorothy Vatner ◽  
Robert D. Hoffman ◽  
William Lewis ◽  
...  
Keyword(s):  
Body Weight ◽  
Adenylyl Cyclase ◽  
Adrenergic Receptor ◽  
Left Ventricular ◽  
Cyclase Activity ◽  
Affinity Binding ◽  
Adenylyl Cyclase Activity ◽  
High Affinity Binding ◽  
High Affinity ◽  
Cardiac Phenotype

Recently, we showed that compared with the A/J inbred mouse strain, C57BL/6J (B6) mice have an athlete's cardiac phenotype. We postulated that strain differences would result in greater left ventricular (LV) hypertrophy in response to isoproterenol in B6 than A/J mice and tested the hypothesis that a differential response could be explained partly by differences in β-adrenergic receptor (β-AR) density and/or coupling. A/J and B6 mice were randomized to receive daily isoproterenol (100 mg/kg sc) or isovolumic vehicle for 5 days. Animals were studied using echocardiography, tail-cuff blood pressure, histopathology, β-AR density and percent high-affinity binding, and basal and stimulated adenylyl cyclase activities. One hundred twenty-eight mice (66 A/J and 62 B6) were studied. Isoproterenol-treated A/J mice demonstrated greater percent increases in echocardiographic LV mass/body weight (97 ± 11 vs. 20 ± 10%, P = 0.001) and in gravimetric heart mass/body weight versus same-strain controls than B6 mice. Histopathology scores (a composite of myocyte hypertrophy, nuclear changes, fibrosis, and calcification) were greater in isoproterenol-treated A/J vs. B6 mice (2.8 ± 0.2 vs.1.9 ± 0.3, P < 0.05), as was quantitation of myocyte damage (22.3 ± 11.5 vs. 4.3 ± 3.5%). Interstrain differences in basal β-AR density, high-affinity binding, and adenylyl cyclase activity were not significant. However, whereas isoproterenol-treated A/J mice showed nonsignificant increases in all β-AR activity measures, isoproterenol-treated B6 mice had lower β-AR density (57 ± 6 vs. 83 ± 8 fmol/mg, P < 0.05), percent high-affinity binding (15 ± 2 vs. 26 ± 3%, P < 0.005), and GTP + isoproterenol-stimulated adenylyl cyclase activity (10 ± 1.1 vs. 5.8 ± 1.5 pmol cAMP·mg−1·min−1) compared with controls. High-dose, short-term isoproterenol produces greater macro- and microscopic cardiac hypertrophy and injury in A/J than B6 mice. A/J mice, unlike B6 mice, do not experience β-AR downregulation or uncoupling in response to isoproterenol. Abnormalities in β-adrenergic regulation may contribute to strain-related differences in the vulnerability to isoproterenol-induced cardiac changes.

Esmolol Improves Left Ventricular Function via  Enhanced β-Adrenergic Receptor Signaling in a Canine Model of Coronary Revascularization

2002 ◽  
Vol 97 (1) ◽  
pp. 162-169 ◽  
Author(s):  
John V. Booth ◽  
Donat R. Spahn ◽  
Robert L. McRae ◽  
Lynn C. Chesnut ◽  
Habib El-Moalem ◽  
...  
Keyword(s):  
Left Ventricular Function ◽  
Adenylyl Cyclase ◽  
Ventricular Function ◽  
Adrenergic Receptor ◽  
Canine Model ◽  
Left Ventricular ◽  
Cyclase Activity ◽  
Control Group ◽  
Adenylyl Cyclase Activity ◽  
Plasma Catecholamine Concentrations

Background Recent American Heart Association guidelines highlight the paucity of data on effectiveness and/or mechanisms underlying use of beta-adrenergic receptor (beta AR) antagonists after acute coronary syndromes in patients subsequently undergoing revascularization. It is important to assess whether beta AR antagonists might protect the heart and improve ventricular function in this scenario. The authors therefore used esmolol (an ultra-short-acting beta AR antagonist) to determine whether beta AR antagonist treatment improves left ventricular function in a canine model of acute reversible coronary ischemia followed by coronary reperfusion during cardiopulmonary bypass (CPB). The authors also tested whether the mechanism includes preserved beta AR signaling. Methods Dogs were randomized to either esmolol or saline infusions administered during CPB (n = 29). Pre-CPB and end-CPB transmyocardial left ventricular biopsies were obtained; plasma catecholamine concentrations, myocardial beta AR density, and adenylyl cyclase activity were measured. In addition, left ventricular systolic shortening and postsystolic shortening were determined immediately prior to each biopsy. Results While beta AR density remained unchanged in each group, isoproterenol-stimulated adenylyl cyclase activity decreased 26 +/- 6% in the control group but increased 38 +/- 10% in the esmolol group (pre-CPB to end-CPB, mean +/- SD, P = 0.0001). Left ventricular systolic shortening improved in both groups after release of coronary (LAD) ligature; however, the esmolol group increased to 72 +/- 23% of pre-CPB values compared to 48 +/- 12% for the control group (P = 0.0008). Conclusions These data provide prospective evidence that esmolol administration results in improved myocardial function. Furthermore, the mechanism appears to involve enhanced myocardial beta AR signaling.

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