Loss of Intralipid®- but Not Sevoflurane-Mediated Cardioprotection in Early Type-2 Diabetic Hearts of Fructose-Fed Rats: Importance of ROS Signaling

Lou, Phing‐How; Lucchinetti, Eliana; Zhang, Liyan; Affolter, Andreas; Gandhi, Manoj; Hersberger, Martin; Warren, Blair E.; Lemieux, Hélène; Sobhi, Hany F.; Clanachan, Alexander S.; Zaugg, Michael

doi:10.1371/journal.pone.0104971

Cited by 12 publications

(12 citation statements)

References 57 publications

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“…Of relevance to the issue raised by Kolwicz et al (1), we have also reported the effects of Intralipid postconditioning in type 2 diabetic rat hearts (4). Our experiments showed that Intralipid completely lost its protective action in diabetic hearts.…”

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confidence: 72%

Comment on Kolwicz et al. Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress. Diabetes 2015;64:2817–2827

2016

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Kolwicz et al. (1) presented an interesting and elegantly conducted study where they examined the role of diacylglycerol transferase 1 (DGAT1) overexpression in cardiac triacylglycerol turnover rates under ischemia-reperfusion conditions. Mice with myosin heavy-chain-mediated cardiac-specific overexpression of DGAT1 exhibited elevated triacylglycerol contents and ischemia-induced lipolysis. Furthermore, enhanced triacylglycerol turnover was associated with improved functional recovery during reperfusion. The authors concluded that elevated triacylglycerol content and turnover provide protection from ischemia-reperfusion injury in nondiabetic hearts. In the discussion of their results, the authors raised the interesting question of whether Intralipid supply during reperfusion would be an appropriate strategy to improve outcomes in ischemic diabetic hearts.Multiple research groups (2,3) have investigated the effect of Intralipid administration at the time of reperfusion on postischemic outcomes in healthy nondiabetic hearts, which is usually referred to as Intralipid postconditioning. Our group (2) investigated the mechanisms underlying the beneficial effects of Intralipid administration at the time of reperfusion. Using rat hearts in a working-heart set-up, we demonstrated that Intralipid administration at early reperfusion inhibits complex IV of the respiratory chain, which increases reactive oxygen species (ROS) formation and activates reperfusion injury salvage kinase (RISK) signaling. We observed that the rate of exogenous palmitate oxidation was unaffected by Intralipid, indicating no significant role of Intralipid as a source of competing fatty acid substrates. We therefore concluded that protection by Intralipid is primarily due to protective ROS signaling elicited by the inhibition of the respiratory chain rather than by a cardiotonic action in response to increased energy supply.Of relevance to the issue raised by Kolwicz et al. (1), we have also reported the effects of Intralipid postconditioning in type 2 diabetic rat hearts (4). Our experiments showed that Intralipid completely lost its protective action in diabetic hearts. In contrast to the conditions in healthy hearts, Intralipid was unable to increase ROS generation and RISK signaling during early reperfusion. Our mechanistic experiments revealed that Intralipid inhibited complex IV significantly less in diabetic hearts and further reduced ROS production by enhanced uncoupling of the respiratory chain.In summary, our experiments provide evidence that Intralipid administered at the time of reperfusion does not provide protection in diabetic hearts subjected to ischemia-reperfusion. Our observations also suggest that the administration of triacylglycerols, such as Intralipid, triggers key signaling pathways, which are quite distinct from energy substrate effects. Duality of Interest. No potential conflicts of interest relevant to this article were reported. References 1. Kolwicz SC Jr, Liu L, Goldberg IJ, Tian R. Enhancing cardiac triacylglycerol m...

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confidence: 72%

Comment on Kolwicz et al. Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress. Diabetes 2015;64:2817–2827

2016

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“…Carnitine palmitoyltransferase (CPT) activity was measured in mitochondrial samples using 5,5′‐dithiobis‐(2‐nitrobenzoic acid) (DTNB) to monitor the release of reduced CoA liberated from palmitoyl‐CoA by CPT at 412 nm, as previously described (Lou et al. 2014). β ‐hydroxyacyl‐CoA dehydrogenase ( β ‐HCAD) activity of mitochondrial isolates was measured in buffer containing 97 mmol L −1 potassium phosphate, and 100 μ mol L −1 NADH, pH 7.3.…”

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confidence: 99%

“…Aconitase activity was assayed as previously outlined (Lou et al. 2014). Oxalomalate (2 mmol L −1 , Cayman), a competitive inhibitor of aconitase, was included in a separate set of samples to ensure assay specificity.…”

Section: Methodsmentioning

confidence: 99%

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Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

et al. 2017

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Despite the fact that skeletal muscle insulin resistance is the hallmark of type‐2 diabetes mellitus (T2DM), inflexibility in substrate energy metabolism has been observed in other tissues such as liver, adipose tissue, and heart. In the heart, structural and functional changes ultimately lead to diabetic cardiomyopathy. However, little is known about the early biochemical changes that cause cardiac metabolic dysregulation and dysfunction. We used a dietary model of fructose‐induced T2DM (10% fructose in drinking water for 6 weeks) to study cardiac fatty acid metabolism in early T2DM and related signaling events in order to better understand mechanisms of disease. In early type‐2 diabetic hearts, flux through the fatty acid oxidation pathway was increased as a result of increased cellular uptake (CD36), mitochondrial uptake (CPT1B), as well as increased β‐hydroxyacyl‐CoA dehydrogenase and medium‐chain acyl‐CoA dehydrogenase activities, despite reduced mitochondrial mass. Long‐chain acyl‐CoA dehydrogenase activity was slightly decreased, resulting in the accumulation of long‐chain acylcarnitine species. Cardiac function and overall mitochondrial respiration were unaffected. However, evidence of oxidative stress and subtle changes in cardiolipin content and composition were found in early type‐2 diabetic mitochondria. Finally, we observed decreased activity of SIRT1, a pivotal regulator of fatty acid metabolism, despite increased protein levels. This indicates that the heart is no longer capable of further increasing its capacity for fatty acid oxidation. Along with increased oxidative stress, this may represent one of the earliest signs of dysfunction that will ultimately lead to inflammation and remodeling in the diabetic heart.

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“…In their comment, Zaugg et al (1) highlighted some of their recent work investigating the effects of Intralipid administration on postischemic outcomes in rat models of both healthy nondiabetic (2) and early diabetic hearts (3). This was prodded by a discussion point raised in a recent article by my colleagues and I on whether the provision of a mixture of unsaturated fats, such as Intralipid, could improve functional recovery in the ischemic, diabetic myocardium (4).…”

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confidence: 99%

Response to Comment on Kolwicz et al. Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress. Diabetes 2015;64:2817–2827

Kolwicz

2016

Diabetes

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Loss of Intralipid®- but Not Sevoflurane-Mediated Cardioprotection in Early Type-2 Diabetic Hearts of Fructose-Fed Rats: Importance of ROS Signaling

Cited by 12 publications

References 57 publications

Comment on Kolwicz et al. Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress. Diabetes 2015;64:2817–2827

Comment on Kolwicz et al. Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress. Diabetes 2015;64:2817–2827

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

Response to Comment on Kolwicz et al. Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress. Diabetes 2015;64:2817–2827

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