Functional crosstalk between the mitochondrial PTP and KATP channels determine arrhythmic vulnerability to oxidative stress

Xie, Changchun; Kauffman, Justin; Akar, Fadi G.

doi:10.3389/fphys.2014.00264

Cited by 17 publications

(16 citation statements)

References 36 publications

(65 reference statements)

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“…This effect of Cys A had been described and attributed to a non‐specific binding (Griffiths & Halestrap, ; Ragone & Consolini, ; Xie et al . ). The findings suggest that the inhibition of mNCX produced a mitochondrial Ca 2+ overload sufficient to open the mPTP in HpT hearts, but not in this model of stunning in EuT ventricles.…”

Section: Discussionmentioning

confidence: 97%

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Cardioprotective effect of hyperthyroidism on the stunned rat heart during ischaemia–reperfusion: energetics and role of mitochondria

Ragone

Bonazzola

Colareda

et al. 2015

Experimental Physiology

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New Findings r What is the central question of this study?Hyperthyroidism is a cardiac risk factor, but thyroid therapy is used on myocardial stunning. What is the consequence of hyperthyroidism for mitochondrial metabolism and Ca 2+handling of the postischaemic stunned heart? r What is the main finding and its importance?Hyperthyroidism reduced stunning and improved muscle economy of the postischaemic rat heart. The activities of the mitochondrial sodium-calcium exchanger and mitochondrial K + channel in hyperthyroid rat hearts were different from those in the euthyroid rat hearts. These findings contribute to the understanding of mitochondrial bioenergetics in pathology and support thyroid therapy in the stunning induced by ischaemia.Transient ischaemia and hyperthyroidism are cardiovascular risk factors. Nevertheless, 3,5,3 -triiodothyronine/thyroxine therapy has been used to revert myocardial stunning. We studied the influence of hyperthyroidism on the role played by mitochondria in myocardial stunning consequent to ischaemia-reperfusion. Rats were injected s.c. daily with 20 μg kg −1 triiodothyronine for 15 days (HpT group). Isolated ventricles from either HpT or euthyroid (EuT) rats were perfused in a calorimeter, and left intraventricular pressure (in millimetres of mercury) and heat release (Ht; in milliwatts per gram) were measured. Stunning was evoked by 20 min of no-flow ischaemia and 45 min reperfusion. The HpT hearts developed higher postischaemic contractile recovery (PICR) and improved total muscle economy (P/Ht) with lower diastolic contracture ( LVEDP) than EuT hearts. Release of Ca 2+ from the sarcoplasmic reticulum during reperfusion with 10 mm caffeine in low-[Na + ] Krebs solution evoked a higher contracture in EuT than in HpT hearts. Blockade of the mitochondrial sodium-calcium exchanger with clonazepam increased LVEDP and reduced P/Ht and PICR in HpT but not in EuT hearts. The clonazepam-induced dysfunction in HpT hearts was reduced by ciclosporin, suggesting a dependance on activation of the mitochondrial permeability transition pore. Blockade of the mitochondrial Ca 2+ uniporter with Ru360 reduced P/Ht and PICR to ß10% in both HpT and EuT hearts. Blockade of mitochondrial K + channels with 5-hydroxydecanoate increased LVEDP and reduced PICR and P/Ht in HpT hearts, while it only increased LVEDP in EuT hearts. The results suggest that hyperthyroidism prevents the stunning with high dependence on the mitochondrial sodium-calcium exchanger and mitochondrial K + channels. IntroductionThyroid dysfunction, either clinical or subclinical, has been related to the increase in morbidity and mortality associated with cardiovascular episodes (Klein & Danzi, 2007). In particular, hyperthyroidism predisposes to long-term cardiac conditions such as hypertrophy and cardiac remodelling. Severe and untreated hyperthyroidism induces tachycardia, high cardiac workload and a risk of atrial fibrillation related to the upregulation of β-adrenergic receptors (Nyirenda et al. 2005). Some patients suffer symptoms...

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Section: Discussionmentioning

confidence: 97%

“…This is in agreement with a recent report on the functional cross‐talk between mPTP and mK ATP channels because both are targets of protein kinase C; consequently, the blockade of mK ATP channels abolished the protective effect of Cys A (Xie et al . ). The findings suggest that 5HD is likely to have induced mPTP activation in HpT hearts.…”

Section: Discussionmentioning

confidence: 97%

Cardioprotective effect of hyperthyroidism on the stunned rat heart during ischaemia–reperfusion: energetics and role of mitochondria

Ragone

Bonazzola

Colareda

et al. 2015

Experimental Physiology

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“…Besides the unequivocal role of mK ATP openers in reducing infarct size, an emerging research direction is represented by their role in preserving the electrical stability of the heart (reviewed in Muntean et al (2015)). Interestingly, a functional crosstalk between mPTP and mK ATP that determined the arrhythmic vulnerability to oxidative stress has been recently reported (Xie et al 2014).…”

Section: Mitochondrial H 2 O 2 Productionmentioning

confidence: 99%

Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues

Mioc

Duicu

Sturza

et al. 2015

Can. J. Physiol. Pharmacol.

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A substantial body of evidence indicates that pharmacological activation of mitochondrial ATP-sensitive potassium channels (mK ATP ) in the heart is protective in conditions associated with ischemia/reperfusion injury. Several mechanisms have been postulated to be responsible for cardioprotection, including the modulation of mitochondrial respiratory function. The aim of the present study was to characterize the dose-dependent effects of novel synthetic benzopyran analogues, derived from a BMS-191095, a selective mK ATP opener, on mitochondrial respiration and reactive oxygen species (ROS) production in isolated rat heart mitochondria. Mitochondrial respiratory function was assessed by high-resolution respirometry, and H 2 O 2 production was measured by the Amplex Red fluorescence assay. Four compounds, namely KL-1487, KL-1492, KL-1495, and KL-1507, applied in increasing concentrations (50, 75, 100, and 150 mol/L, respectively) were investigated. When added in the last two concentrations, all compounds significantly increased State 2 and 4 respiratory rates, an effect that was not abolished by 5-hydroxydecanoate (5-HD, 100 mol/L), the classic mK ATP inhibitor. The highest concentration also elicited an important decrease of the oxidative phosphorylation in a K + independent manner. Both concentrations of 100 and 150 mol/L for KL-1487, KL-1492, and KL-1495, and the concentration of 150 mol/L for KL-1507, respectively, mitigated the mitochondrial H 2 O 2 release. In isolated rat heart mitochondria, the novel benzopyran analogues act as protonophoric uncouplers of oxidative phosphorylation and decrease the generation of reactive oxygen species in a dose-dependent manner.

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“…Guinea pig (Cavia porcellus) is not able to synthesize ascorbic acid, which ranks among the most important low molecular weight antioxidants. That is the main reason why guinea pig is widely used laboratory model for examining of the oxidative stress (9)(10)(11). The inability to produce endogenous ascorbic acid makes results from guinea pigs extrapolatable to humans (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Effect of Intramuscular Injection on Oxidative Homeostasis in Laboratory Guinea Pig Model

Kracmarova

Banďouchová

Pikula

et al. 2016

Acta Med. (Hradec Kralove, Czech Repub.)

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In animal models, there was observed alteration of various physiological processes caused by microtraumas. Here reported experiment was aimed on the research of link between injection and development of an oxidative imbalance. Laboratory guinea pig was chosen as a suitable model for examining of the oxidative stress. Markers indicating oxidative homeostasis were assayed in the frontal, temporal and occipital brain lobe, cerebellum, liver, kidney, spleen and heart one hour after an intramuscular injection. Common biochemical parameters were measured in plasma samples as well. The most extensive effect was observed in the heart where the thiobarbituric acid reactive substances value was more than twice increased after the injection. The level of carbonylated proteins was significantly elevated in the kidney and ferric reducing antioxidant power value was increased in the brain compartments. The enzyme activities in the organs were not influenced except the activity of superoxide dismutase, which was moderately decreased in the brain. In the plasma samples, there was observed increase of the blood urea nitrogen. The results showed significant the influence of the intramuscular injection on a development of an oxidative insult. The injection can be considered as an adverse effect with quite extensive stress consequences.

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Functional crosstalk between the mitochondrial PTP and KATP channels determine arrhythmic vulnerability to oxidative stress

Cited by 17 publications

References 36 publications

Cardioprotective effect of hyperthyroidism on the stunned rat heart during ischaemia–reperfusion: energetics and role of mitochondria

Cardioprotective effect of hyperthyroidism on the stunned rat heart during ischaemia–reperfusion: energetics and role of mitochondria

Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues

Effect of Intramuscular Injection on Oxidative Homeostasis in Laboratory Guinea Pig Model

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