Targeting Phospholamban by Gene Transfer in Human Heart Failure

Monte, Federica del; Harding, Siân E.; Dec, GW; Gwathmey, Judith K.; Hajjar, Roger J.

doi:10.1161/hc0802.105564

Cited by 249 publications

(161 citation statements)

References 25 publications

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“…However, sustained ␤AR activation is associated with cardiac myocyte apoptosis (58,59), which is not seen in animals expressing nuclear Akt (40) or AC VI (56). Reduction of PLB through antisense suppression or genetic ablation increases sarcoplasmic reticulum calcium cycling and increases cardiac function (60,61), and cardiac-directed expression of PLB decreases heart function (62). In contrast, increased expression of AC VI in cardiac myocytes not only reduces the expression of PLB (8), but also, as we show here, increases PLB phosphorylation through increased Akt activity, effects which would be predicted to have beneficial effects on cardiac function.…”

Section: Discussionmentioning

confidence: 99%

Adenylyl Cyclase Type VI Increases Akt Activity and Phospholamban Phosphorylation in Cardiac Myocytes

Gao

Tang

Guo

et al. 2008

Journal of Biological Chemistry

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Increased expression of adenylyl cyclase VI has beneficial effects on the heart, but strategies that increase cAMP production in cardiac myocytes usually are harmful. Might adenylyl cyclase VI have beneficial effects unrelated to increased ␤-adrenergic receptor-mediated signaling? We previously reported that adenylyl cyclase VI reduces cardiac phospholamban expression. Our focus in the current studies is how adenylyl cyclase VI influences phospholamban phosphorylation. In cultured cardiac myocytes, increased expression of adenylyl cyclase VI activates Akt by phosphorylation at serine 473 and threonine 308 and is associated with increased nuclear phospho-Akt. Activated Akt phosphorylates phospholamban, a process that does not require ␤-adrenergic receptor stimulation or protein kinase A activation. These previously unrecognized signaling events would be predicted to promote calcium handling and increase contractile function of the intact heart independently of ␤-adrenergic receptor activation. We speculate that phospholamban phosphorylation, through activation of Akt, may be an important mechanism by which adenylyl cyclase VI increases the function of the failing heart. Adenylyl cyclase (AC) 4 catalyzes ATP to generate cAMP, a second messenger that is required for many intracellular events. AC is the effector molecule in the ␤-adrenergic receptor (␤AR)-Gs-AC signaling pathway and for many other G-protein-coupled receptors in cardiac myocytes and other cells (1-2). Cardiac myocytes express predominantly AC type V and AC type VI (AC VI ) (3). Cardiac-directed expression of AC VI in murine cardiomyopathy increases cardiac function, attenuates myocardial hypertrophy, and increases survival (4, 5). However, when cardiac-directed ␤AR expression is used in this same model, life is shortened (6, 7). Clearly there are marked differences in effects that are evoked by these two elements in the ␤AR-Gs-AC signaling pathway, even though both strategies increase cAMP.The objective of the current study was to determine whether increased AC VI expression has effects not directly linked with ␤AR stimulation and protein kinase A (PKA) activation, thereby providing a mechanistic explanation for the unanticipated favorable effects of increased cardiac AC VI expression in heart failure. We previously reported that AC VI reduces cardiac phospholamban (PLB) expression through increased expression of activating transcription factor-3, which suppresses PLB promoter activity (8). We now focus on how AC VI influences PLB phosphorylation. We test the hypothesis that AC VI increases PLB phosphorylation independently of ␤AR stimulation and PKA activation. This would result in increased cardiac function but would circumvent deleterious effects of sustained PKA activation (9).

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Section: Discussionmentioning

confidence: 99%

Adenylyl Cyclase Type VI Increases Akt Activity and Phospholamban Phosphorylation in Cardiac Myocytes

Gao

Tang

Guo

et al. 2008

Journal of Biological Chemistry

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“…Phosphorylation of phospholamban, for example, relieves its inhibition of SERCA2, the Ca 2ϩ -transporting ATPase of the sarcoplasmic reticulum (26,27). Ablation of phospholamban in cardiac myocytes of MLP Ϫ/Ϫ mice with dilated cardiomyopathy restores normal chamber size and contractility, whereas decreasing phospholamban expression in myocytes from failing hearts improves contractility (28,29). These observations suggest that increased phosphorylation of phospholamban is beneficial.…”

Section: Identification Of Pde3 Protein Isoforms In Cardiacmentioning

confidence: 98%

Isoforms of Cyclic Nucleotide Phosphodiesterase PDE3A in Cardiac Myocytes

Wechsler¹,

Choi²,

Krall³

et al. 2002

Journal of Biological Chemistry

118

122

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PDE3A cyclic nucleotide phosphodiesterases regulate cAMP-and cGMP-mediated intracellular signaling in cardiac myocytes. We used antibodies to different regions of PDE3A to demonstrate the presence of three PDE3A isoforms in these cells. These isoforms, whose apparent molecular weights are 136,000, 118,000, and 94,000 ("PDE3A-136," "PDE3A-118," and "PDE3A-94"), are identical save for the deletion of different lengths of N-terminal sequence containing two membrane-association domains and sites for phosphorylation/activation by protein kinase B ("PK-B") and protein kinase A ("PK-A"). PDE3A-136 contains both membrane-association domains and the PK-B and PK-A sites. PDE3A-118 contains only the downstream membrane-association domain and the PK-A sites. PDE3A-94 lacks both membrane localization domains and the PK-B and PK-A sites. The three isoforms are translated from two mRNAs derived from the PDE3A1 gene: PDE3A-136 is translated from PDE3A1 mRNA, whereas PDE3A-118 and PDE3A-94 are translated from PDE3A2 mRNA. Experiments involving in vitro transcription/translation indicate that PDE3A-118 and PDE3A-94 may be translated from different AUGs in PDE3A2 mRNA. These findings suggest that alternative transcriptional and post-transcriptional processing of the PDE3A gene results in the generation of two mRNAs and three protein isoforms in cardiac myocytes that differ with respect to intracellular localization and may be regulated through different signaling pathways.

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“…Vesnarinone prolongs action potential duration through modulation of K ϩ channels, thereby prolonging opening of L-type calcium channels and increasing Ca 2ϩ entry. Through gene transfer of SERCA2a, 48 modified phospholamban (mPL), 49 or antisense phospholamban (asPL), 50 SRATPase activity can be increased, which enhances SR Ca 2ϩ content, inotropic and lusitropic state. At level of cardiomyocyte, several stimuli, including endothelin-1 (ET-1), phenylephrine, and angiotensin, are involved in development of hypertrophy through Gq-coupled receptors.…”

Section: Congestion and Apparent Hypoperfusionmentioning

confidence: 99%

Clinical Use of Inotropic Therapy for Heart Failure: Looking Backward or Forward? Part I: Inotropic Infusions During Hospitalization

Stevenson

2003

Circulation

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Targeting Phospholamban by Gene Transfer in Human Heart Failure

Cited by 249 publications

References 25 publications

Adenylyl Cyclase Type VI Increases Akt Activity and Phospholamban Phosphorylation in Cardiac Myocytes

Adenylyl Cyclase Type VI Increases Akt Activity and Phospholamban Phosphorylation in Cardiac Myocytes

Isoforms of Cyclic Nucleotide Phosphodiesterase PDE3A in Cardiac Myocytes

Clinical Use of Inotropic Therapy for Heart Failure: Looking Backward or Forward? Part I: Inotropic Infusions During Hospitalization

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