Transgenic overexpression of the SUR2A-55 splice variant in mouse heart reduces infract size and promotes protective mitochondrial function

Abstract

ATP-sensitive potassium channels found in both the sarcolemma (sarcKATP) and mitochondria (mitoKATP) of cardiomyocytes are important mediators of cardioprotection during ischemic heart disease. Sulfonylurea receptor isoforms (SUR2), encoded by Abcc9, an ATP-binding cassette family member, form regulatory subunits of the sarcKATP channel and are also thought to regulate mitoKATP channel activity. A short-form splice variant of SUR2 (SUR2A-55) was previously shown to target mitochondria and display diaxoxide and ATP insensitive KATP activity when co-expressed with the inward rectifier channels Kir6.2 and Kir6.1. We hypothesized that mice with cardiac specific overexpression of SUR2A-55 would mediate cardioprotection from ischemia by altering mitoKATP properties. Mice overexpressing SUR2A-55 (TGSUR2A-55) in cardiomyocytes were generated and showed no significant difference in echocardiographic measured chamber dimension, percent fractional shortening, heart to body weight ratio, or gross histologic features compared to normal mice at 11–14 weeks of age. TGSUR2A-55 had improved hemodynamic functional recovery and smaller infarct size after ischemia reperfusion injury compared to WT mice in an isolated hanging heart model. The mitochondrial membrane potential of TGSUR2A-55 mice was less sensitive to ATP, diazoxide, and Ca2+ loading. These data suggest that the SUR2A-55 splice variant favorably affects mitochondrial function leading to cardioprotection. These data support a role for the regulation of mitoKATP activity by SUR2A-55.

Overexpression of a Short Sulfonylurea Splice Variant Increases Cardiac Glucose Uptake and Uncouples Mitochondria by Regulating ROMK Activity

“…Recent studies showed that CCDC51 pairs with ABCB8 to form a mitochondrial ATP sensitive K + channel [10]. During this same period, we observed that the overexpression of a short (55 kDa) splice variant of the sulfonylurea receptor isoform 2A (SUR2A-55) led to cardio-protection and enhanced mitoK ATP activity at rest [11]. In addition, we found that SUR2A-55 associates with glucose handling proteins and may confer cardio-protection via glucose metabolism [14].…”

“…For each experiment, three to six male WT or TG SUR2A−55 mice aged 8-12 weeks were used. TG SUR2A−55 mice were previously generated by overexpression of a SUR2A-55 construct by the αmyosin heavy chain promoter [11].…”

“…This makes pharmacologic targeting challenging. The current constituents include coiled-coil domain containing 51 (CCDC51), renal outer medullary K + channel isoform 2 (ROMK2) and the regulatory subunits: ATP binding cassette subfamily B member 8 (ABCB8) and the short splice variant of SUR2A [10][11][12][13].…”

Complex consequences of Cantu syndrome SUR2 variant R1154Q in genetically modified mice

“…Specific deletion of exon 5 of ABCC9 , to ablate expression of both plasma membrane and the mitoSUR2 short form, resulted in neonatal cardiomyopathy, potentially due to failure of the heart to transition normally from fetal to mature myocardial metabolism ( 47 ). Conversely, mice overexpressing the 55 kDa short-form protein had improved recovery from ischemia/reperfusion injury relative to WT hearts ( 48 ).…”

Genetic Discovery of ATP-Sensitive K + Channels in Cardiovascular Diseases

“…In addition to the cell membrane, K ATP channels have been reported to be present in mitochondria, and to be involved in regulation of oxidative phosphorylation, and protection from ischemia-reperfusion injury [31][32][33][34] . Recent studies have suggested that this proposed mitoK ATP may contain Kir1.1 and/or SUR2A-55 [35][36][37][38] , but direct evidence is lacking, and even the constitution of any mitoK ATP remains unclear.…”