Improved adaptation to physical stress in mice overexpressing SUR2A is associated with changes in the pattern of Q-T interval

Abstract

The purpose of this study was to determine whether increased expression of SUR2A, a regulatory subunit of sarcolemmal ATP-sensitive K + (K ATP) channels, improves adaptation to physical stress and regulates cardiac electrophysiology in physical stress. All experiments have been done on transgenic mice in which SUR2A expression was controlled by cytomegalovirus immediate-early (CMV) promoter (SUR2A) and their littermate wild-type controls (WT). The levels of mRNA in heart tissue were measured by real-time RT-PCR. Electrocardiogram (ECG) was monitored with telemetry. The physical adaptation to stress was elucidated using treadmill. We have found that SUR2A mice express 8.34 ± 0.20 times more myocardial SUR2A mRNA than WT (n = 8-18). The tolerated workload on exercise stress test was more than twofold higher in SUR2A than in WT (n = 5-7; P = 0.01). The pattern of Q-T interval from the beginning of the exercise test until drop point was as follows in the wild type: (1) increase in Q-T interval, (2) decrease in Q-T interval, (3) steady stage with a further decrease in Q-T interval, and (4) a sharp increase in Q-T interval. The pattern of Q-T interval was different in transgenic mice and the following stages have been observed: (1) increase in Q-T interval, (2) decrease in Q-T interval, and (3) prolonged steady-state stage with a slight decrease in Q-T interval. In SUR2A mice, no stage 4 (a sharp increase in Q-T interval) was observed. Based on the obtained results, we conclude that an increase in the expression of SUR2A improves adaptation to physical stress and physical endurance by increasing the number of sarcolemmal K ATP channels and, by virtue of their channel activity, improving Ca 2+ homeostasis in the heart.

Incorrectly corrected? QT interval analysis in rats and mice

“…Nevertheless, at least for the circadian data it might be possible that analysis of light and dark phases separately for QT-RR relationships may over-control for endogenous changes in rate and repolarization mediated by circadian fluctuations in rhythm and autonomic modulation. Sudhir et al ( Sudhir et al, 2020 ) recently explored adaptation of QT to physical stress in mice overexpressing SUR2A, a regulatory subunit of sarcolemmal ATP-sensitive K + (K ATP ) channels. Although the results show highly complex pattern of changes over time in both transgenic and control mice, only corrected QT intervals (using Mitchell’s formula) are presented in the study, limiting ability to evaluate the effects of exercise on the native QT interval.…”

“…Nevertheless, at least for the circadian data it might be possible that analysis of light and dark phases separately for QT-RR relationships may over-control for endogenous changes in rate and repolarization mediated by circadian fluctuations in rhythm and autonomic modulation. Sudhir et al (Sudhir et al, 2020) (Kmecova and Klimas, 2010) for rats and by Mitchell et al (1998) for mice, resulted in marked difference between the measured QT interval and the QTc interval for a wide range of atrial pacing rates in both species (Figure 1). At the present, it is hard to conclude what is the optimal way of QT correction in rodent and if correction is required at all.…”

Rapamycin treatment unmasks a sex‐specific pattern of scar expansion of the infarcted rat heart: The relationship between mTOR and KATP channel

“…Increased SUR2A protein expression was reported to exert an important biological impact on cardiac function as selective upregulation of the subunit in the heart provided improved tolerance and endurance to stress by increasing the density of sarcolemmal K ATP channels and presumably activity. 30 To confirm that increased SUR2A protein expression in response to PDBu proceeded via the mTORC1 complex, NNVMs were pre-treated with rapamycin. The macrolide attenuated PDBu-mediated hypertrophy, suppressed basal mTOR phosphorylation, and inhibited the increased phosphorylation of the threonine 389 residue of p70S6K.…”

“…Lastly, coincident with p70S6K recruitment and the concomitant hypertrophic response, PDBu treatment led to the upregulation of the K ATP channel subunit SUR2A whereas no change in Kir6.2 protein levels was observed. Increased SUR2A protein expression was reported to exert an important biological impact on cardiac function as selective upregulation of the subunit in the heart provided improved tolerance and endurance to stress by increasing the density of sarcolemmal K ATP channels and presumably activity 30 . To confirm that increased SUR2A protein expression in response to PDBu proceeded via the mTORC1 complex, NNVMs were pre‐treated with rapamycin.…”

Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases

“…Early evidence indicated that sarcolemma ATP-sensitive potassium (sarcK ATP ) channels play a crucial role in ischemic preconditioning and myocardial resistance to ischemia, which close during general conditions and open in response to increased [ADP]/[ATP], linking membrane excitability to the balance of ATP production and shortening action potential (AP) duration (APD) via the efflux of K + ( Garrott et al, 2017 ; Sudhir et al, 2020 ). SarcK ATP channels improve adaptation to physical stress and profoundly alter membrane excitability and other membrane potential-related functions, such as Ca 2+ overload, thus helping to maintain cellular homeostasis during cardiac challenge (i.v.…”