Ankyrin-B protein in heart failure: identification of a new component of metazoan cardioprotection.
Ankyrins (ankyrin-R, -B, and -G) are adapter proteins linked with defects in metazoan physiology. Ankyrin-B (encoded by ANK2) loss-of-function mutations are directly associated with human cardiovascular phenotypes including sinus node disease, atrial fibrillation, ventricular tachycardia, and sudden cardiac death. Despite the link between ankyrin-B dysfunction and monogenic disease, there are no data linking ankyrin-B regulation with common forms of human heart failure. Here, we report that ankyrin-B levels are altered in both ischemic and non-ischemic human heart failure. Mechanistically, we demonstrate that cardiac ankyrin-B levels are tightly regulated downstream of reactive oxygen species, intracellular calcium, and the calcium-dependent protease calpain, all hallmarks of human myocardial injury and heart failure. Surprisingly, β(II)-spectrin, previously thought to mediate ankyrin-dependent modulation in the nervous system and heart, is not coordinately regulated with ankyrin-B or its downstream partners. Finally, our data implicate ankyrin-B expression as required for vertebrate myocardial protection as hearts deficient in ankyrin-B show increased cardiac damage and impaired function relative to wild-type mouse hearts following ischemia reperfusion. In summary, our findings provide the data of ankyrin-B regulation in human heart failure, provide insight into candidate pathways for ankyrin-B regulation in acquired human cardiovascular disease, and surprisingly, implicate ankyrin-B as a molecular component for cardioprotection following ischemia.
Dorothy M. Davis Heart and Lung Research Institute, Columbus, OH 43210, USA.
Farshid
F
Kashef
Jingdong
J
Li
Patrick
P
Wright
Jedidiah
J
Snyder
Faroug
F
Suliman
Ahmet
A
Kilic
Robert S D
RS
Higgins
Mark E
ME
Anderson
Philip F
PF
Binkley
Thomas J
TJ
Hund
Peter J
PJ
Mohler
D000818:Animals; D017487:Ankyrins / Q000096:biosynthesis* / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012804:Sick Sinus Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013049:Spectrin
D017487:Ankyrins; D002118:Calcium; D002352:Carrier Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D017382:Reactive Oxygen Species; D013049:Spectrin; C498994:ANK2 protein, human; C498995:Ank2 protein, mouse