Ankyrin-B Protein in Heart Failure

Kashef, Farshid; Li, Jingdong; Wright, Patrick; Snyder, John P.; Suliman, Faroug; Kilic, Ahmet; Higgins, Robert S.D.; Anderson, Mark E.; Binkley, Philip F.; Hund, Thomas J.; Mohler, Peter J.

doi:10.1074/jbc.m112.368415

Cited by 26 publications

(14 citation statements)

References 54 publications

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“…Genetic defects in ankyrins cause altered Na + and Ca 2+ transport and enhanced RyR2 openings contributing to loss of [Ca 2+ ] i homeostasis 160 , activation of CaMKII and arrhythmias 161 . It was recently reported that ankyrin B plays a cardioprotective role against ischemia induced cardiac dysfunction and ankyrin-B levels are decreased in human heart failure 162 .…”

Section: Defective Ecc and Alterations Of Ca2+ Handling Proteins mentioning

confidence: 99%

Mechanisms of Altered Ca ²⁺ Handling in Heart Failure

Luo

Anderson

2013

Circulation Research

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Ca2+ plays a crucial role in connecting membrane excitability with contraction in myocardium. The hallmark features of heart failure are mechanical dysfunction and arrhythmias; defective intracellular Ca2+ homeostasis is a central cause of contractile dysfunction and arrhythmias in failing myocardium. Defective Ca2+ homeostasis in heart failure can result from pathological alteration in the expression and activity of an increasingly understood collection of Ca2+ homeostatic binding proteins, ion channels and enzymes. This review focuses on the molecular mechanisms of defective Ca2+ cycling in heart failure and consider how fundamental understanding of these pathways may translate into novel and innovative therapies.

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Section: Defective Ecc and Alterations Of Ca2+ Handling Proteins mentioning

confidence: 99%

Mechanisms of Altered Ca ²⁺ Handling in Heart Failure

Luo

Anderson

2013

Circulation Research

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319

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“…49 Furthermore, Kashef et al showed decreased expression of AnkB and its downstream targets in human ischemic and non-ischemic failing heart tissue, and calpain, a calcium-dependent protease, was identified as a regulator of AnkB in ischemic disease. 50 …”

Section: Human Ank2 Variantsmentioning

confidence: 99%

The evolving role of ankyrin-B in cardiovascular disease

Koenig

Mohler

2017

Heart Rhythm

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Over the last decade, ankyrin-B has been identified as a prominent player in cardiac physiology. Ankyrin-B has a multitude of functions, with roles in expression, localization, and regulation of proteins critical for cardiac excitability, cytoskeletal integrity, and signaling. Further, human ANK2 variants that result in ankyrin-B loss-of-function are associated with ‘Ankyrin-B syndrome’, a complex cardiac phenotype that may include bradycardia and heart rate variability, conduction block, atrial fibrillation, QT interval prolongation, and potentially fatal catecholaminergic polymorphic ventricular tachycardia. However, our understanding of the molecular mechanisms underlying ankyrin-B function at baseline and in disease is still not fully resolved due to the complexity of ankyrin-B gene regulation, number of ankyrin-B-associated molecules, multiple roles of ankyrin-B in the heart and other organs that modulate cardiac function, and a host of unexpected clinical phenotypes. Here, we summarize known roles of ankyrin-B in the heart and the impact of ankyrin-B dysfunction in animal models and in human disease, as well as highlight important new findings illustrating the complexity of ankyrin-B signaling.

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“…While there is an obvious reserve of Na channels in the heart, optimal function will depend on their location and anchoring by ankyrin-G. In the acute phase of remodeling of ischemia, it is likely ankyrin-G levels are acutely reduced by the calcium-activated, calcium-dependent calpain, similar to ankyrin-B [24]. Thus, we suggest that following 48 hours, ankyrin-G levels recover and stabilize in an effort to actively regulate Na v 1.5 channel protein recruitment to sarcolemmal membrane.…”

Section: Discussionmentioning

confidence: 99%

Ankyrin-G Participates in INa Remodeling in Myocytes from the Border Zones of Infarcted Canine Heart

et al. 2013

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Cardiac Na channel remodeling provides a critical substrate for generation of reentrant arrhythmias in border zones of the infarcted canine heart. Recent studies show that Nav1.5 assembly and function are linked to ankyrin-G, gap, and mechanical junction proteins. In this study our objective is to expound the status of the cardiac Na channel, its interacting protein ankyrinG and the mechanical and gap junction proteins at two different times post infarction when arrhythmias are known to occur; that is, 48 hr and 5 day post coronary occlusion. Previous studies have shown the origins of arrhythmic events come from the subendocardial Purkinje and epicardial border zone. Our Purkinje cell (Pcell) voltage clamp study shows that INa and its kinetic parameters do not differ between Pcells from the subendocardium of the 48hr infarcted heart (IZPCs) and control non-infarcted Pcells (NZPCs). Immunostaining studies revealed that disturbances of Nav1.5 protein location with ankyrin-G are modest in 48 hr IZPCs. Therefore, Na current remodeling does not contribute to the abnormal conduction in the subendocardial border zone 48 hr post myocardial infarction as previously defined. In addition, immunohistochemical data show that Cx40/Cx43 co-localize at the intercalated disc (IDs) of control NZPCs but separate in IZPCs. At the same time, Purkinje cell desmoplakin and desmoglein2 immunostaining become diffuse while plakophilin2 and plakoglobin increase in abundance at IDs. In the epicardial border zone 5 days post myocardial infarction, immunoblot and immunocytochemical analyses showed that ankyrin-G protein expression is increased and re-localized to submembrane cell regions at a time when Nav1.5 function is decreased. Thus, Nav1.5 and ankyrin-G remodeling occur later after myocardial infarction compared to that of gap and mechanical junctional proteins. Gap and mechanical junctional proteins remodel in IZPCs early, perhaps to help maintain Nav1.5 subcellular location position and preserve its function soon after myocardial infarction.

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Ankyrin-B Protein in Heart Failure

Cited by 26 publications

References 54 publications

Mechanisms of Altered Ca ²⁺ Handling in Heart Failure

Mechanisms of Altered Ca ²⁺ Handling in Heart Failure

The evolving role of ankyrin-B in cardiovascular disease

Ankyrin-G Participates in INa Remodeling in Myocytes from the Border Zones of Infarcted Canine Heart

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Ankyrin-B Protein in Heart Failure

Cited by 26 publications

References 54 publications

Mechanisms of Altered Ca 2+ Handling in Heart Failure

Mechanisms of Altered Ca 2+ Handling in Heart Failure

The evolving role of ankyrin-B in cardiovascular disease

Ankyrin-G Participates in INa Remodeling in Myocytes from the Border Zones of Infarcted Canine Heart

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Product

Resources

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Mechanisms of Altered Ca ²⁺ Handling in Heart Failure

Mechanisms of Altered Ca ²⁺ Handling in Heart Failure