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Cardioprotection by Genetic Deletion of Kvβ2 in Ischemia Reperfusion Injury
Author(s) -
Chapalamadugu Kalyan C.,
Badole Sachin L.,
Tur Jared,
Tipparaju Srinivas M.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1007.45
Subject(s) - nad+ kinase , reperfusion injury , ischemia , troponin i , cardioprotection , lactate dehydrogenase , medicine , chemistry , cardiology , potassium channel , endocrinology , biochemistry , myocardial infarction , enzyme
Background Ischemia reperfusion (I/R) injury increases the levels of NADH in the heart leading to increased NADH/NAD + ratio. Voltage‐gated potassium channel (Kv) β‐subunits bind to ion channels and contractile proteins resulting in modulation of cardiac function. Previous studies demonstrated high affinity binding of voltage‐gated potassium channel beta subunit 2 (Kvβ2) to pyridine nucleotides (NAD[P] + , NAD[P]H). Hypothesis We hypothesized that Kvβ2 plays a major role in sensing I/R injury. Methods and Results Hearts from wild type (WT) and Kvβ2 knockout (KO) mice were perfused using Langendorff apparatus and subjected to 45 min no‐flow global ischemia followed by 120 min reperfusion. At the end of reperfusion, hearts were sectioned and stained with 2,3,5‐triphenyltetrazolium chloride (TTC). Cardiac perfusates were collected before ischemia and during reperfusion at 0, 30 and 120 min, and cardiac troponin I (cTnI) was measured. Intracardiac levels of NAD + and NADH were measured in I/R injured hearts. Infarct size was measured, and normalized to total area of the heart. I/R challenge of WT mice hearts resulted in a significant myocardial damage where the infarct size was 46.6±5.4%. However, infarct size in Kvβ2 KO hearts was only 12±2.3% (n=5), which clearly demonstrates that the KO hearts show significant resistance to injury ( p<0.05 ), despite similar changes in NADH/NAD ratio in both groups. Baseline cTnI levels (ng/ml) in the perfusate were similar between the WT and KO hearts (n=3). During reperfusion, cTnI levels in the perfusate from KO hearts were significantly ( p<0.05 ) decreased when compared to WT. Conclusions This study shows that Kvβ2 deletion is cardioprotective in I/R injury. It is plausible that Kvβ2:NADH/NAD axis may serve as a metabolic sensor in I/R injury, where Kvβ2 subunit senses and relays the increased NADH/NAD levels to target proteins in WT hearts, whereas deletion of Kvβ2 abrogates relaying the information leading to protection.