Dilated Cardiomyopathy and Sudden Death Resulting From Constitutive Activation of Protein Kinase A

Antos, Christopher L.; Frey, Norbert; Marx, Steven O.; Reiken, Steven; Gaburjáková, Marta; Richardson, James A.; Marks, Andrew R.; Olson, Eric N.

doi:10.1161/hh2301.100003

Cited by 254 publications

(183 citation statements)

References 41 publications

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“…Besides HDAC5, PKA has many other substrates including ryanodine receptor and phospholamban, L-type calcium channels, and cardiac troponin I (36). It is possible that pathways independent of HDAC5 may be involved in the cardiomyocyte hypertrophy induced in mice by sustained PKA activation (39,40). In addition, we observed that the β-AR agonist isoproterenol inhibited the nuclear export of HDAC5 in cultured cardiomyocytes.…”

Section: Pka-dependent Phosphorylation and Nuclear Retention Of Hdac5mentioning

confidence: 60%

“…It has been documented that sustained β-AR stimulation induces cardiomyocyte apoptosis and heart failure through cAMP/PKA-dependent and independent pathways (36-38). Antos et al (39) reported that overexpression of the constitutively active PKA catalytic subunit in mouse heart led to dilated cardiomyopathy and cardiomyocyte hypertrophy, although there was no significant change in the heart-to-body weight ratio in PKA transgenic mice. Besides HDAC5, PKA has many other substrates including ryanodine receptor and phospholamban, L-type calcium channels, and cardiac troponin I (36).…”

Section: Pka-dependent Phosphorylation and Nuclear Retention Of Hdac5mentioning

confidence: 99%

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PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy

Kim

Zhao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

113

116

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Dynamic nucleocytoplasmic shuttling of class IIa histone deacetylases (HDACs) is a fundamental mechanism regulating gene transcription. Recent studies have identified several protein kinases that phosphorylate HDAC5, leading to its exportation from the nucleus. However, the negative regulatory mechanisms for HDAC5 nuclear exclusion remain largely unknown. Here we show that cAMPactivated protein kinase A (PKA) specifically phosphorylates HDAC5 and prevents its export from the nucleus, leading to suppression of gene transcription. PKA interacts directly with HDAC5 and phosphorylates HDAC5 at serine 280, an evolutionarily conserved site. Phosphorylation of HDAC5 by PKA interrupts the association of HDAC5 with protein chaperone 14-3-3 and hence inhibits stress signal-induced nuclear export of HDAC5. An HDAC5 mutant that mimics PKA-dependent phosphorylation localizes in the nucleus and acts as a dominant inhibitor for myocyte enhancer factor 2 transcriptional activity. Molecular manipulations of HDAC5 show that PKA-phosphorylated HDAC5 inhibits cardiac fetal gene expression and cardiomyocyte hypertrophy. Our findings identify HDAC5 as a substrate of PKA and reveal a cAMP/PKA-dependent pathway that controls HDAC5 nucleocytoplasmic shuttling and represses gene transcription. This pathway may represent a mechanism by which cAMP/PKA signaling modulates a wide range of biological functions and human diseases such as cardiomyopathy.nucleocytoplasmic shuttling | phosphorylation G ene transcription is governed in part by the acetylation and deacetylation of histones, the latter of which is mediated by histone deacetylases (HDACs) (1-4). In particular, class IIa HDACs, such as HDAC5, acting as transcriptional repressors, have been implicated in cardiac hypertrophy, skeletal muscle differentiation, and angiogenesis (5-10). Dynamic nucleocytoplasmic shuttling has been proposed as a fundamental mechanism regulating the function of class IIa HDACs (1, 11-13). Recent studies have identified several protein kinases, including calmodulin-dependent protein kinases (CaMKs), protein kinase D (PKD) and salt-inducible kinase, that phosphorylate HDAC5, leading to its export from the nucleus (1, 9, 14). However, much less is understood about the negative regulatory mechanisms for the nuclear exclusion of HDAC5 (15). To date, specific protein kinases that may inhibit export of HDAC5 from the nucleus have not been identified.The cAMP/protein kinase A (PKA) signaling pathway regulates a variety of cellular functions and numerous important biological processes (16,17). Many of the effects of cAMP/PKA are mediated via changes in gene transcription. A large body of research has defined the cAMP-response element binding (CREB) proteins as PKA substrates that mediate an increase in gene expression in response to cAMP (18)(19)(20). However, whether and how the cAMP/PKA pathway inhibits gene expression remains unclear. In this study, we found that cAMP/PKA signaling represses gene transcription and cardiomyocyte hypertrophy by phosphorylating HDAC5 ...

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Section: Pka-dependent Phosphorylation and Nuclear Retention Of Hdac5mentioning

confidence: 60%

Section: Pka-dependent Phosphorylation and Nuclear Retention Of Hdac5mentioning

confidence: 99%

PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy

Kim

Zhao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

113

116

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“…Sympathetic nervous system and βAR activity increase with age, and this increase may hasten the development of age-related cardiomyopathies (Lakatta 1993;Swynghedauw et al 1995). Mouse models of chronic βAR stimulation at the receptor (Du et al 2000;Engelhardt et al 1999;Liggett et al 2000), G protein (Iwase et al 1996), or PKA (Antos et al 2001;Yan et al 2007) levels increase mortality and decrease stress resistance.…”

Section: Discussionmentioning

confidence: 99%

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

Spindler

Mote

et al. 2013

AGE

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Chronic treatment with β-adrenergic receptor (βAR) agonists increases mortality and morbidity while βAR antagonists (β-blockers) decrease allcause mortality for those at risk of cardiac disease. Levels of sympathetic nervous system βAR agonists and βAR activity increase with age, and this increase may hasten the development of age-related mortality.Here, we show that β-blockers extend the life span of healthy metazoans. The β-blockers metoprolol and nebivolol, administered in food daily beginning at 12 months of age, significantly increase the mean and median life span of isocalorically fed, male C3B6F1 mice, by 10 and 6.4 %, respectively (P< 0.05). Neither drug affected the weight or food intake of the mice, indicating that induced CR is not responsible for these effects, and that energy absorption and utilization are not altered by the drugs. Both β-blockers were investigated to control for their idiosyncratic, off-target effects. Metoprolol and nebivolol extended Drosophila life span, without affecting food intake or locomotion. Thus, βAR antagonists are capable of directly extending the life span of two widely divergent metazoans, suggesting that these effects are phylogenetically highly conserved. Thus, long-term use of β-blockers, which are generally well-tolerated, may enhance the longevity of healthy humans.

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“…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).…”

mentioning

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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Dilated Cardiomyopathy and Sudden Death Resulting From Constitutive Activation of Protein Kinase A

Cited by 254 publications

References 41 publications

PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy

PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

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

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