Insulin down-regulates cardioprotective SUR2A in the heart-derived H9c2 cells: A possible explanation for some adverse effects of insulin therapy

Du, Qingyou; Jovanović, Sofija; Sukhodub, Andriy; Ngoi, Yong Shi; Lal, Aashray; Zheleva, Marina; Jovanović, Aleksandar

doi:10.1016/j.bbrep.2018.08.005

Cited by 4 publications

(3 citation statements)

References 44 publications

(98 reference statements)

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“…Mitochondrial ATP‐sensitive K + channel in the mitochondrial inner membrane is involved in cardioprotective pathways to against heart diseases including I/R injury. Several studies suggest that sulfonylurea receptor 2A which serves as a subunit of ATP‐sensitive K + channel is involved in regulation of myocardial resistance to metabolic and oxidative stress and IES SUR2B is a possible part of mitochondrial ATP‐sensitive K+ channel mediating cardioprotection . On the other hand, VDAC is another important channel on the outer mitochondrial membrane .…”

Section: Discussionmentioning

confidence: 99%

MiR‐183‐5p protects rat hearts against myocardial ischemia/reperfusion injury through targeting VDAC1

Lin

Cui

et al. 2019

BioFactors

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MicroRNAs have been reported to be implicated in myocardial ischemia/reperfusion (I/R) injury. The purpose of this study was to investigate the effect of miR-183-5p on I/R injury. Overexpression of miR-183-5p by agomiR transfection alleviated cardiac dysfunction and significantly reduced the infarct size in rats with myocardial I/R. MiR-183-5p also alleviated myocardial apoptosis with reduced apoptotic cells and lower levels of apoptosis associated proteins. in vitro experiments were conducted on rat H9c2 cells treated with anoxia/reoxygenation (A/R).Annexin V/propidium iodide (PI) staining and flow cytometry reported that the ratio of apoptotic cells decreased by miR-183-5p transfection before A/R treatment.Moreover, according to binding sequence prediction and Dual luciferase reporter assay, we explored that voltage-dependent anion channel 1 (VDAC1), which aggravates myocardial injury and apoptosis reported in our former research, was a target of miR-183-5p. In conclusion, miR-183-5p can efficiently attenuate I/R injury and miR-183-5p may exert its effect through repressing VDAC1 expression.

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Section: Discussionmentioning

confidence: 99%

MiR‐183‐5p protects rat hearts against myocardial ischemia/reperfusion injury through targeting VDAC1

Lin

Cui

et al. 2019

BioFactors

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“…While ischemic heart disease is the leading cause of morbidity and mortality [17], it does not per se explain the preservation of K ATP channels through evolution [7]. We have previously shown that and increase in SUR2A and consequent increase in K ATP channel levels increase physical endurance and prolong lifespan [15,22] while decreased SUR2A levels decrease cellular resistance to metabolic stress [5]. However, no connection between cardiac electrophysiology and improved adaptation to physical stress in mice overexpressing SUR2A has been made so far.…”

Section: Introductionmentioning

confidence: 99%

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

Sudhir

Sukhodub

et al. 2020

Pflugers Arch - Eur J Physiol

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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.

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“…An increase in intracellular SUR2A level increases levels of fully assembled K ATP channels, which, in turn, confers cardioprotection [5]. On the other hand, a decrease in SUR2A levels results in increased cardiac susceptibility to metabolic stress [6]. As pyrazinamide affects NAD and NADH levels, it could affect the level of SUR2A as well.…”

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confidence: 99%

Pyrazinamide may possess cardioprotective properties

Sinha

Jovanović

et al. 2019

J Antibiot

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Pyrazinamide is an anti-tubercular agent, used as a part of a three-drug regime (any three of the following: rifampicin, isoniazid, pyrazinamide, streptomycin or ethambutol) for the initial phase of treatment. One of the effects pyrazinamide has on mammalian cells is to regulate NAD+/NADH levels. We have recently found that changes in NAD+/NADH are associated with regulation of expression levels of SUR2A, a cardioprotective protein serving as a regulatory subunit of cardiac ATP-sensitive K+ (KATP) channels. Here, we have tested whether pyrazinamide regulate expression of SUR2A/KATP channel subunits and resistance to metabolic stress in embryonic heart-derived H9c2 cells. We have found that 24-h-long treatment with pyrazinamide (3 mcg/ml) increased mRNA levels of SUR2A, SUR2B and Kir6.1 without affecting mRNA levels of other KATP channel subunits. This treatment with pyrazinamide (3 mcg/ml) protected H9c2 cells against stress induced by 10 mM 2,4-dinitrophenol (DNP). The survival rate of DNP-treated cells was 45.6 ± 2.3% (n = 5) if not treated with pyrazinamide and 90.8 ± 2.3% (n = 5; P < 0.001) if treated with pyrazinamide. We conclude that pyrazinamide increases resistance to metabolic stress in heart H9c2 cells probably by increasing SUR2A and SUR2B expression. Our results of this study indicate that pyrazinamide should be seriously considered as a drug of choice for patients with tuberculosis and ischaemic heart disease.

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Insulin down-regulates cardioprotective SUR2A in the heart-derived H9c2 cells: A possible explanation for some adverse effects of insulin therapy

Cited by 4 publications

References 44 publications

MiR‐183‐5p protects rat hearts against myocardial ischemia/reperfusion injury through targeting VDAC1

MiR‐183‐5p protects rat hearts against myocardial ischemia/reperfusion injury through targeting VDAC1

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

Pyrazinamide may possess cardioprotective properties

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