The rs9982601 polymorphism of the region between the SLC5A3/MRPS6 and KCNE2 genes associated with a prevalence of myocardial infarction and subsequent long-term mortality

Sudden cardiac death (SCD) is the leading global cause of mortality. SCD often arises from cardiac ischemia reperfusion (IR) injury, pathologic sequence variants within ion channel genes, or a combination of the two. Alternative approaches are needed to prevent or ameliorate ventricular arrhythmias linked to SCD. Here, we investigated the efficacy of remote ischemic preconditioning (RIPC) of the limb versus the liver in reducing ventricular arrhythmias in a mouse model of SCD. Mice lacking the Kcne2 gene, which encodes a potassium channel β subunit associated with acquired Long QT syndrome were exposed to IR injury via coronary ligation. This resulted in ventricular arrhythmias in all mice (15/15) and SCD in 5/15 mice during reperfusion. Strikingly, prior RIPC (limb or liver) greatly reduced the incidence and severity of all ventricular arrhythmias and completely prevented SCD. Biochemical and pharmacological analysis demonstrated that RIPC cardioprotection required ERK1/2 and/or AKT phosphorylation. A lack of alteration in GSK‐3β phosphorylation suggested against conventional reperfusion injury salvage kinase (RISK) signaling pathway protection. If replicated in human studies, limb RIPC could represent a noninvasive, nonpharmacological approach to limit dangerous ventricular arrhythmias associated with ischemia and/or channelopathy‐linked SCD.

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“…), prevalence of and mortality linked to MI (Szpakowicz et al. ), and predisposition to coronary artery disease (Sabater‐Lleal et al. ).…”

Section: Introductionmentioning

confidence: 99%

AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2 -dependent sudden cardiac death

Liu

Zhou

et al. 2019

Physiol Rep

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“…Joining the mt-SSU, bS6m forms mitochondria-specific intersubunit bridge mB2 with uL2m of the mt-LSU [13,15,21]. As a result of a genome-wide association study, the polymorphism rs9982601 (C>T) in the noncoding region between SLC5A3/MRPS6 and KCNE2 genes was found to be an increased risk factor for early-onset myocardial infarction [155,156]. This observation further supports the role of mitochondrial translation in cardiac function.…”

Section: Bs6mmentioning

confidence: 87%

The Diseased Mitoribosome

2020

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Mitochondria control life and death in eukaryotic cells. Harboring a unique circular genome, a by-product of an ancient endosymbiotic event, mitochondria maintains a specialized and evolutionary divergent protein synthesis machinery, the mitoribosome. Mitoribosome biogenesis depends on elements encoded in both the mitochondrial genome (the RNA components) and the nuclear genome (all ribosomal proteins and assembly factors). Recent cryo-EM structures of mammalian mitoribosomes have illuminated their composition and provided hints regarding their assembly and elusive mitochondrial translation mechanisms. A growing body of literature involves the mitoribosome in inherited primary mitochondrial disorders. Mutations in genes encoding mitoribosomal RNAs, proteins, and assembly factors impede mitoribosome biogenesis, causing protein synthesis defects that lead to respiratory chain failure and mitochondrial disorders such as encephalo-and cardiomyopathy, deafness, neuropathy, and developmental delays. In this article, we review the current fundamental understanding of mitoribosome assembly and function, and the clinical landscape of mitochondrial disorders driven by mutations in mitoribosome components and assembly factors, to portray how basic and clinical studies combined help us better understand both mitochondrial biology and medicine.

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“…After the original report linking a SNP near the human KCNE2 locus to early-onset myocardial infarction (MI) [25], a different SNP within the human KCNE2 gene itself was reported to be associated with predisposition to CAD [20], and related findings have followed [38,39]. These discoveries suggested a link between human KCNE2 and CAD, but functional and mechanistic data were lacking.…”

Section: Discussionmentioning

confidence: 99%

The focal adhesion protein Testin modulates KCNE2 potassium channel β subunit activity

2021

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Coronary Artery Disease (CAD) typically kills more people globally each year than any other single cause of death. A better understanding of genetic predisposition to CAD and the underlying mechanisms will help to identify those most at risk and contribute to improved therapeutic approaches. KCNE2 is a functionally versatile, ubiquitously expressed potassium channel β subunit associated with CAD and cardiac arrhythmia susceptibility in humans and mice. Here, to identify novel KCNE2 interaction partners, we employed yeast two-hybrid screening of adult and fetal human heart libraries using the KCNE2 intracellular C-terminal domain as bait. Testin (encoded by TES ), an endothelial cell-expressed, CAD-associated, focal adhesion protein, was identified as a high-confidence interaction partner for KCNE2. We confirmed physical association between KCNE2 and Testin in vitro by co-immunoprecipitation. Whole-cell patch clamp electrophysiology revealed that KCNE2 negative-shifts the voltage dependence and increases the rate of activation of the endothelial cell and cardiomyocyte-expressed Kv channel α subunit, Kv1.5 in CHO cells, whereas Testin did not alter Kv1.5 function. However, Testin nullified KCNE2 effects on Kv1.5 voltage dependence and gating kinetics. In contrast, Testin did not prevent KCNE2 regulation of KCNQ1 gating. The data identify a novel role for Testin as a tertiary ion channel regulatory protein. Future studies will address the potential role for KCNE2-Testin interactions in arterial and myocyte physiology and CAD.

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The rs9982601 polymorphism of the region between the SLC5A3/MRPS6 and KCNE2 genes associated with a prevalence of myocardial infarction and subsequent long-term mortality

Cited by 13 publications

References 4 publications

AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2 -dependent sudden cardiac death

AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2 -dependent sudden cardiac death

The Diseased Mitoribosome

The focal adhesion protein Testin modulates KCNE2 potassium channel β subunit activity

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