Mechanisms of Disease: ion channel remodeling in the failing ventricle

Nass, Robert D.; Aiba, Takeshi; Tomaselli, Gordon F.; Akar, Fadi G.

doi:10.1038/ncpcardio1130

Cited by 86 publications

(76 citation statements)

References 98 publications

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“…suming cardiac function (3). Defects in heart rate, myocardial conduction, and repolarization that reduce metabolic demand by the weakened myocardium are often associated with the onset of cardiomyopathy (48). We previously reported that whole-body ERR␥ KO mice exhibited neonatal lethality and slightly prolonged QRS complex and QT intervals (22,49).…”

Section: Resultsmentioning

confidence: 99%

Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

Wang

McDonald

Petrenko

et al. 2015

Molecular and Cellular Biology

106

108

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f Almost all cellular functions are powered by a continuous energy supply derived from cellular metabolism. However, it is little understood how cellular energy production is coordinated with diverse energy-consuming cellular functions. Here, using the cardiac muscle system, we demonstrate that nuclear receptors estrogen-related receptor ␣ (ERR␣) and ERR␥ are essential transcriptional coordinators of cardiac energy production and consumption. On the one hand, ERR␣ and ERR␥ together are vital for intact cardiomyocyte metabolism by directly controlling expression of genes important for mitochondrial functions and dynamics. On the other hand, ERR␣ and ERR␥ influence major cardiomyocyte energy consumption functions through direct transcriptional regulation of key contraction, calcium homeostasis, and conduction genes. Mice lacking both ERR␣ and cardiac ERR␥ develop severe bradycardia, lethal cardiomyopathy, and heart failure featuring metabolic, contractile, and conduction dysfunctions. These results illustrate that the ERR transcriptional pathway is essential to couple cellular energy metabolism with energy consumption processes in order to maintain normal cardiac function. E very cell's own survival and vital functions are supported by energy-generating metabolic pathways. The cellular energy supply and demand must be coordinated, and an imbalance results in cellular dysfunctions and diseases from heart failure to obesity (1, 2). Although the regulation of cellular energy production and consumption individually are focuses of intensive research, it is little understood how these two processes are coordinated. One possible mechanism lies at the level of transcription where the expression of genes critical in both cellular energy production and utilization processes can be regulated in an orchestrated manner. However, such transcription coordinators that directly regulate multiple energy-generating cellular metabolic pathways and energy-consuming cellular functions remain to be established.The heart offers an ideal system for studying coordination of energy production and consumption. It continuously pumps blood to all the organs, involving energy-demanding processes such as myocardial contraction and electrical conduction (3). Accordingly, cardiomyocytes maintain an exceedingly high metabolic rate and depend on vigorous fatty acid oxidation (FAO), oxidative phosphorylation (OxPhos), and dynamic mitochondrial networks to generate energy that supports these functions (4, 5). Indeed, defects in cardiomyocyte metabolism and mitochondrial function are underlying causes of, or are associated with, many cardiac diseases, including cardiomyopathy and heart failure, that affect millions of people (6-9).Nuclear receptors (NRs) are ligand-activated transcription factors with important roles in both physiological and pathological settings (10-12). Among the 48 NRs in the human genome, several NRs and their coactivators have been identified as key regulators of cardiac metabolism (13-16). In particular, recent work has revealed...

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Section: Resultsmentioning

confidence: 99%

Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

Wang

McDonald

Petrenko

et al. 2015

Molecular and Cellular Biology

106

108

View full text Add to dashboard Cite

show abstract

“…Initially, these adaptations are beneficial to maintain cardiac function (e.g., at pressure overload) but in later stages of the diseases they contribute to contractile abnormalities and sudden death. On the cellular level, irregular expression of ion channels involved in the control of cardiac contractility and automaticity plays an important role in remodeling (176,285,286,323,392).…”

Section: Cardiac Remodeling and Arrhythmiamentioning

confidence: 99%

Hyperpolarization-Activated Cation Channels: From Genes to Function

Biel

Wahl‐Schott²,

Michalakis³

et al. 2009

Physiological Reviews

856

974

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family comprises four members (HCN1-4) that are expressed in heart and nervous system. The current produced by HCN channels has been known as Ih (or If or Iq). Ih has also been designated as pacemaker current, because it plays a key role in controlling rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. Extensive studies over the last decade have provided convincing evidence that Ih is also involved in a number of basic physiological processes that are not directly associated with rhythmicity. Examples for these non-pacemaking functions of Ih are the determination of the resting membrane potential, dendritic integration, synaptic transmission, and learning. In this review we summarize recent insights into the structure, function, and cellular regulation of HCN channels. We also discuss in detail the different aspects of HCN channel physiology in the heart and nervous system. To this end, evidence on the role of individual HCN channel types arising from the analysis of HCN knockout mouse models is discussed. Finally, we provide an overview of the impact of HCN channels on the pathogenesis of several diseases and discuss recent attempts to establish HCN channels as drug targets.

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“…Ion channel remodeling, in particular a decreased I to , and subsequent AP prolongation are hallmarks of the failing heart and heart failure (HF)-related arrhythmias and are associated with the occurrence of afterdepolarizations and triggered arrhythmia (1,27). HF is defined as the heart's inability to cover the body's blood demand and is the common end stage of various cardiac diseases including ischemic or dilated cardiomyopathy.…”

mentioning

confidence: 99%

CREB critically regulates action potential shape and duration in the adult mouse ventricle

Schulte

Seidl

Nunes

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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FU. CREB critically regulates action potential shape and duration in the adult mouse ventricle. Am J Physiol Heart Circ Physiol 302: H1998 -H2007, 2012. First published March 16, 2012; doi:10.1152/ajpheart.00057.2011The cAMP response element binding protein (CREB) belongs to the CREB/ cAMP response element binding modulator/activating transcription factor 1 family of cAMP-dependent transcription factors mediating a regulation of gene transcription in response to cAMP. Chronic stimulation of ␤-adrenergic receptors and the cAMP-dependent signal transduction pathway by elevated plasma catecholamines play a central role in the pathogenesis of heart failure. Ion channel remodeling, particularly a decreased transient outward current (Ito), and subsequent action potential (AP) prolongation are hallmarks of the failing heart. Here, we studied the role of CREB for ion channel regulation in mice with a cardiomyocyte-specific knockout of CREB (CREB KO). APs of CREB KO cardiomyocytes were prolonged with increased AP duration at 50 and 70% repolarization and accompanied by a by 51% reduction of I to peak amplitude as detected in voltageclamp measurements. We observed a 29% reduction of Kcnd2/Kv4.2 mRNA in CREB KO cardiomyocytes mice while the other I to-related channel subunits Kv4.3 and KChIP2 were not different between groups. Accordingly, Kv4.2 protein was reduced by 37% in CREB KO. However, we were not able to detect a direct regulation of Kv4.2 by CREB. The I to-dependent AP prolongation went along with an increase of I Na and a decrease of ICa,L associated with an upregulation of Scn8a/Nav1.6 and downregulation of Cacna1c/Cav1.2 mRNA in CREB KO cardiomyocytes. Our results from mice with cardiomyocyte-specific inactivation of CREB definitively indicate that CREB critically regulates the AP shape and duration in the mouse ventricle, which might have an impact on ion channel remodeling in situations of altered cAMP-dependent signaling like heart failure. ion channel remodeling; heart; transcriptional regulation; adenosine 3=,5=-cyclic monophosphate response element binding protein; transient outward current

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Mechanisms of Disease: ion channel remodeling in the failing ventricle

Cited by 86 publications

References 98 publications

Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

Hyperpolarization-Activated Cation Channels: From Genes to Function

CREB critically regulates action potential shape and duration in the adult mouse ventricle

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