β-Adrenergic receptor stimulated Ncx1 upregulation is mediated via a CaMKII/AP-1 signaling pathway in adult cardiomyocytes

Mani, Santhosh K.; Egan, Erin A.; Addy, Benjamin; Grimm, Michael; Kasiganesan, Harinath; Thiyagarajan, Thirumagal; Renaud, Ludivine; Brown, Joan Heller; Kern, Christine B.; Menick, Donald R.

doi:10.1016/j.yjmcc.2009.11.007

Cited by 36 publications

(36 citation statements)

References 67 publications

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“…JNK activates the c-jun/AP-1 pathway (52), known to upregulate pro-apoptotic genes. CaMKIIδ can also activate the AP-1 transcription factor family independent of the JNK pathway (158), suggesting direct regulation of AP-1 directed gene transcription by CaMKII. CaMKIIγ-dependent phosphorylation of JNK occurs downstream of ER stress and was found to induce the Fas death receptor (237).…”

Section: Heart Failure Pathophysiologymentioning

confidence: 99%

CaMKII in the Cardiovascular System: Sensing Redox States

Erickson

Grumbach

et al. 2011

Physiological Reviews

209

191

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The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is now recognized to play a central role in pathological events in the cardiovascular system. CaMKII has diverse downstream targets that promote vascular disease, heart failure and arrhythmias, so improved understanding of CaMKII signaling has the potential to lead to new therapies for cardiovascular disease. CaMKII is a multimeric serine-threonine kinase that is initially activated by binding calcified calmodulin (Ca2+/CaM). Under conditions of sustained exposure to elevated Ca2+/CaM CaMKII transitions into a Ca2+/CaM-autonomous enzyme by two distinct but parallel processes. Autophosphorylation of threonine 287 in the CaMKII regulatory domain ‘traps’ CaMKII into an open configuration even after Ca2+/CaM unbinding. More recently, our group identified a pair of methionines (281/282) in the CaMKII regulatory domain that undergo a partially reversible oxidation which, like autophosphorylation, prevents CaMKII from inactivating after Ca2+/CaM unbinding. Here we review roles of CaMKII in cardiovascular disease with an eye to understanding how CaMKII may act as a transduction signal to connect pro-oxidant conditions into specific downstream pathological effects that are relevant to rare and common forms of cardiovascular disease.

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Section: Heart Failure Pathophysiologymentioning

confidence: 99%

CaMKII in the Cardiovascular System: Sensing Redox States

Erickson

Grumbach

et al. 2011

Physiological Reviews

209

191

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“…This contributes to SR Ca 2+ depletion during HF, but also increases arrhythmogenic current generation during acute Ca 2+ overload [27]. Recent studies have suggested that these transcriptional effects may be orchestrated by CaMKII [57,58]. If confirmed, this mechanism would constitute one of the most important CaMKII-mediated pro-arrhythmic outcomes.…”

Section: Ca2+-handling Targetsmentioning

confidence: 99%

The promise of CaMKII inhibition for heart disease: preventing heart failure and arrhythmias

Westenbrink

Edwards

McCulloch

et al. 2013

Expert Opinion on Therapeutic Targets

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Introduction Calcium-calmodulin-dependent protein kinase II (CaMKII) has emerged as a central mediator of cardiac stress responses which may serve several critical roles in the regulation of cardiac rhythm, cardiac contractility and growth. Sustained and excessive activation of CaMKII during cardiac disease has, however, been linked to arrhythmias, and maladaptive cardiac remodeling, eventually leading to heart failure (HF) and sudden cardiac death. Areas covered In the current review, the authors describe the unique structural and biochemical properties of CaMKII and focus on its physiological effects in cardiomyocytes. Furthermore, they provide evidence for a role of CaMKII in cardiac pathologies, including arrhythmogenesis, myocardial ischemia and HF development. The authors conclude by discussing the potential for CaMKII as a target for inhibition in heart disease. Expert opinion CaMKII provides a promising nodal point for intervention that may allow simultaneous prevention of HF progression and development of arrhythmias. For future studies and drug development there is a strong rationale for the development of more specific CaMKII inhibitors. In addition, an improved understanding of the differential roles of CaMKII subtypes is required.

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“…9 Oxidation can also lead to CaMKII activation. 10 Downstream targets phosphorylated by CaMKIIδ include proteins important for the modulation of Ca 2+ handling such as phospholamban (PLN), ryanodine receptors (RyR2), voltage sensitive L-type Ca 2+ channels, and the Na v 1.5 Na + channel subunit 1, 2, 11–14 CaMKIIδ can also regulate gene transcription, for example by phosphorylation of type II histone deacetylases (HDACs) which derepress myocyte enhancer factor-2 (MEF2), 15–17 or through AP-1 18, 19 or GATA4. 20 …”

Section: Introductionmentioning

confidence: 99%

Location Matters

Mishra

Gray

Miyamoto

et al. 2011

Circulation Research

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Rationale Differential effects of δB and δC subtypes of Ca2+/calmodulin dependent protein kinase (CaMKII) on cardiomyocyte Ca2+ handling and survival have been suggested to result from their respective nuclear vs. cytosolic localizations. CaMKIIδ subtype localization and its relationship to enzyme activation and target phosphorylation has not, however, been systematically evaluated. Objective To determine whether CaMKIIδ subtypes are restricted to a particular subcellular location and assess the relationship of localization to enzyme activation and function. Methods and Results CaMKIIδ is highly expressed in mouse heart and cardiomyocytes and concentrated in sarcoplasmic reticulum (SR)/membrane and nuclear fractions. CaMKIIδB and δC subtypes differ by a nuclear localization sequence, but both are present in nuclear and SR/membrane fractions. Nonselective subtype distribution is also seen in mice overexpressing CaMKIIδB or δC, even in a CaMKIIδ null background. Fluorescently-tagged CaMKIIδB expressed in cardiomyocytes concentrates in nuclei whereas δC concentrates in cytosol but neither localization is exclusive. Mouse hearts exposed to phenylephrine (PE) show selective CaMKIIδ activation in the nuclear (vs. SR) compartment whereas caffeine selectively activates CaMKIIδ in SR (vs. nuclei), independent of subtype. Compartmentalized activation extends to functional differences in target phosphorylation at CaMKII sites: PE increases histone deacetylase 5 phosphorylation (Ser498) but not phospholamban (Thr17), while the converse holds for caffeine. Conclusions These studies demonstrate that CaMKIIδB and δC are not exclusively restricted to the nucleus and cytosol, and that spatial and functional specificity in CaMKIIδ activation is elicited by mobilization of different Ca2+ stores rather than by compartmentalized subtype localization.

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β-Adrenergic receptor stimulated Ncx1 upregulation is mediated via a CaMKII/AP-1 signaling pathway in adult cardiomyocytes

Cited by 36 publications

References 67 publications

CaMKII in the Cardiovascular System: Sensing Redox States

CaMKII in the Cardiovascular System: Sensing Redox States

The promise of CaMKII inhibition for heart disease: preventing heart failure and arrhythmias

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