Beneficial Effects of Chronic Pharmacological Manipulation of β-Adrenoreceptor Subtype Signaling in Rodent Dilated Ischemic Cardiomyopathy

Ahmet, Ismayil; Krawczyk, Melissa; Heller, Phillip F.; Moon, Chanil; Lakatta, Edward G.; Talan, Mark I.

doi:10.1161/01.cir.0000139844.15045.f9

Cited by 111 publications

(116 citation statements)

References 31 publications

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“…For example, ␤AR stimulation, through PKA activation, phosphorylates PLB, which disinhibits sarcoplasmic reticulum Ca 2ϩ ATPase and facilitates Ca 2ϩ uptake into the sarcoplasmic reticulum, increasing cardiac function (57). 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).…”

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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“…18 In a rat model of myocardial infarction, treating with β2-AR agonists for 2 weeks preserved cardiac contractility and reduced the number of apoptotic cardiomyocytes. 19 The β3-AR expression is upregulated in the failing heart. 20 It is reported that β3-AR negatively modulates ventricular contractility by activating endothelial nitric oxide synthase.…”

Section: β-Ar-mediated Apoptosis Of Cardiomyocytesmentioning

confidence: 99%

Apoptosis in Heart Failure - The Role of the .BETA.-Adrenergic Receptor-Mediated Signaling Pathway and p53-Mediated Signaling Pathway in the Apoptosis of Cardiomyocytes -

Fujita

Ishikawa

2011

Circ J

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The heart works as a driving force to deliver oxygen and nutrients to the whole body. Interrupting this function for only several minutes can cause critical and permanent damage to the human body. Thus, heart failure (HF) or attenuated cardiac function is an important factor that affects both patient's the quality of life and longevity. Numerous clinical and basic studies have been performed to clarify the complex pathophysiology of HF and to develop effective therapies. Modulating the β-adrenergic receptor-mediated signaling pathway has been one of the most crucial targets for HF therapy. Impressively, recent reports identified p53, a well-known tumor suppressor, as a major player in the development of HF. The present review highlights the apoptosis of cardiomyocytes, which is one of the important mechanisms that leads to HF and can be induced by both β-adrenergic signaling and p53. Consideration of the cross-talk among these major pathways will be important when developing effective and safe therapies for HF. (Circ J 2011; 75: 1811 - 1818

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“…Accordingly, it has been suggested that chronic treatment with β 2 AR-agonists might exert beneficial effects in CHF (48). In fact, Ahmet et al have recently shown that in rats with ischemic cardiomyopathy (ICM) due to myocardial infarction, longterm treatment with the β 2 AR-agonists zinterol and fenoterol exerted beneficial effects (attenuation of disease progression) that were mainly due to their antiapoptotic effects (49). However, before extrapolating from these data obtained in rats with experimental heart failure to the human situation, the following caveats should be considered: a) while zinterol appears to belong to those β 2 AR-agonists that can signal via the G s -and G i -protein pathway, fenoterol has been shown by two different groups to signal selectively via the G s -protein pathway (see above).…”

Section: Role Of Changes In G I -Proteinmentioning

confidence: 99%

Cardiac Adrenoceptors: Physiological and Pathophysiological Relevance

Brodde¹,

Bruck²,

Leineweber³

2006

J Pharmacol Sci

210

161

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Abstract. At present, nine adrenoceptor (AR) subtypes have been identified: α 1A -, α 1B -, α 1D -, α 2A -, α 2B -, α 2C -, β 1 -, β 2 -, and β 3 AR. In the human heart, β 1 -and β 2 AR are the most powerful physiologic mechanism to acutely increase cardiac performance. Changes in βAR play an important role in chronic heart failure (CHF). Thus, due to increased sympathetic activity in CHF, βAR are chronically (over)stimulated, and that results in β 1 AR desensitization and alterations of down-stream mechanisms. However, several questions remain open: What is the role of β 2 AR in CHF? What is the role of increases in cardiac G i -protein in CHF? Do increases in G-protein-coupled receptor kinase (GRK)s play a role in CHF? Does βAR-blocker treatment cause its beneficial effects in CHF, at least partly, by reducing GRK-activity? In this review these aspects of cardiac AR pharmacology in CHF are discussed. In addition, new insights into the functional importance of β 1 -and β 2 AR gene polymorphisms are discussed. At present it seems that for cardiovascular diseases, βAR polymorphisms do not play a role as disease-causing genes; however, they might be risk factors, might modify disease, and / or might influence progression of disease. Furthermore, βAR polymorphisms might influence drug responses. Thus, evidence has accumulated that a β 1 AR polymorphism (the Arg389Gly β 1 AR) may affect the response to βAR-blocker treatment.

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Beneficial Effects of Chronic Pharmacological Manipulation of β-Adrenoreceptor Subtype Signaling in Rodent Dilated Ischemic Cardiomyopathy

Cited by 111 publications

References 31 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

Apoptosis in Heart Failure - The Role of the .BETA.-Adrenergic Receptor-Mediated Signaling Pathway and p53-Mediated Signaling Pathway in the Apoptosis of Cardiomyocytes -

Cardiac Adrenoceptors: Physiological and Pathophysiological Relevance

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