title: Ankyrin-G participates in INa remodeling in myocytes from the border zones of infarcted canine heart.
abstract: 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.
authors.affiliation: Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, New York, United States of America.
authors.forename: Wen
authors.initials: W
authors.lastname: Dun
authors.forename: John S
authors.initials: JS
authors.lastname: Lowe
authors.forename: Patrick
authors.initials: P
authors.lastname: Wright
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Boyden
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000737:chemistry / Q000378:metabolism*; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D004285:Dogs; D017629:Gap Junctions / Q000378:metabolism; D015640:Ion Channel Gating; D007700:Kinetics; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000378:metabolism*; D010496:Pericardium / Q000378:metabolism / Q000473:pathology; D011689:Purkinje Cells / Q000378:metabolism; D013997:Time Factors; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017487:Ankyrins; D018031:Connexin 43; D017630:Connexins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D000097003:Gap Junction alpha-5 Protein