Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose

Abstract

Bhatt NM, Aon MA, Tocchetti CG, Shen X, Dey S, Ramirez-Correa G, O=Rourke B, Gao WD, Cortassa S. Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose. Am J Physiol Heart Circ Physiol 308: H291-H302, 2015. First published December 3, 2014; doi:10.1152/ajpheart.00378.2014.-Hearts from type 2 diabetic (T2DM) subjects are chronically subjected to hyperglycemia and hyperlipidemia, both thought to contribute to oxidizing conditions and contractile dysfunction. How redox alterations and contractility interrelate, ultimately diminishing T2DM heart function, remains poorly understood. Herein we tested whether the fatty acid palmitate (Palm), in addition to its energetic contribution, rescues function by improving redox [glutathione (GSH), NAD(P)H, less oxidative stress] in T2DM rat heart trabeculae subjected to high glucose. Using cardiac trabeculae from Zucker Diabetic Fatty (ZDF) rats, we assessed the impact of low glucose (EG) and high glucose (HG), in absence or presence of Palm or insulin, on force development, energetics, and redox responses. We found that in EG ZDF and lean trabeculae displayed similar contractile work, yield of contractile work (Ycw), representing the ratio of force time integral over rate of O2 consumption. Conversely, HG had a negative impact on Ycw, whereas Palm, but not insulin, completely prevented contractile loss. This effect was associated with higher GSH, less oxidative stress, and augmented matrix GSH/thioredoxin (Trx) in ZDF mitochondria. Restoration of myocardial redox with GSH ethyl ester also rescued ZDF contractile function in HG, independently from Palm. These results support the idea that maintained redox balance, via increased GSH and Trx antioxidant activities to resist oxidative stress, is an essential protective response of the diabetic heart to keep contractile function. contractile work; rate of respiration; redox environment; antioxidant systems; oxidative phosphorylation; mitochondrial ros emission; Zucker diabetic fatty rat A COMMON COMPLICATION OF TYPE 2 diabetes mellitus (T2DM) is cardiomyopathy, characterized by diastolic and systolic dysfunction, which is likely impacted by alterations in metabolic substrate availability. Although the healthy heart is flexible regarding fuel selection, the high levels of glucose and fat in T2DM lead to questions about which factors contribute to dysfunction and which are beneficial as energy source or redox donors (35).Fatty acids (FA) and glucose are the two major fuels driving heart contraction, and in T2DM and obesity existing evidence indicates increased FA oxidation (12, 15). The idea that FAs excess negatively regulates glucose oxidation in diabetes according to the Randle mechanism (33) remains a central postulate explaining some negative consequences of substrate shift in this metabolic disorder. However, it is now increasingly appreciated that hyperglycemia per se can trigger cellular damage, independently from FA utilization (11). The multiple mechanisms throug...

Protective Mechanisms of Mitochondria and Heart Function in Diabetes

“…The more oxidizing conditions under which the heart functions in diabetes impair contractility and Ca 2 + handling. As a result of mitochondrial redox impairment, energetic and heart contraction become dysfunctional; contractility and Ca 2 + transients are lower and relaxation is slower (16,187). Compartmentalization plays a significant role in the control of ROS levels, the RE, and dynamic behavior, as suggested by experimentally validated computational modeling (105).…”

“…The increase in TxnIP occurred in experimental models of T1DM (streptozotocin [STZ]-treated rats) and T2DM (Goto-Kakizaki rats), as well as in human biopsy specimens from patients with T2DM and coronary artery disease (46). In two animal models of T2DM, the Zucker Diabetic Fatty (ZDF) rat and the db/db mouse (16,55,187), the increase in polyols mediates, at least in part, the redox imbalance exhibited by the diabetic heart ( Fig. 1) (55).…”

“…In response to oxidative stress, the ROS-scavenging systems in the mitochondrial matrix can be up-modulated. The key role played by redox balance in diabetic muscle was demonstrated by preincubating cardiomyocytes or heart trabeculae from T2DM mice and rat with the cell permeable GSH ethyl ester (GSHee) to rescue contractility in high glucose (16,187).…”

“…As a result of mitochondrial redox impairment, energetics and heart contraction become dysfunctional; contraction and Ca 2 + transients are lower and relaxation is slower. In T2DM diabetic mice as compared with control animals, energy/redox stressful conditions produced evident contractile impairment (15,16,51,187). From an energetic standpoint, three main deficits were observed (Table 1): (i) lower mitochondrial respiration; (ii) reduced activity of individual respiratory complexes; and (iii) impaired OxPhos coupling.…”

Metabolic Alterations Induce Oxidative Stress in Diabetic and Failing Hearts: Different Pathways, Same Outcome

“…The authors of this study demonstrate that palmitate is able to rescue contractile function of heart trabeculae harvested from diabetic (but not from normal) hearts exposed to high glucose. These beneficial effects are associated with an increased scavenging capacity of the antioxidant system (glutathione and thioredoxin) and reduced oxidative stress (8). In this regard, Aon et al recently reviewed the cellular management of lipid excess focusing on the involvement of lipid droplets and hypothesized a ''metabolic channeling of lipid utilization from close contacts between mitochondria and lipid droplets'' (3).…”