Aging related functional and structural changes in the heart and aorta: MitoTEMPO improves aged-cardiovascular performance

Olğar, Yusuf; Değirmenci, Sinan; Durak, Ayşegül; Billur, Deniz; Can, Belgin; Kaykı-Mutlu, Gizem; E, Ebru Arioglu-Inan; Turan, Belma

doi:10.1016/j.exger.2018.06.012

Cited by 51 publications

(41 citation statements)

References 60 publications

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“…Measurement of ROS production was performed in CM-H2DCFDA loaded (5 µM with 45-min incubation at 37 °C) cardiomyocytes, as described previously [ 23 ]. Briefly, the fluorescence changes were recorded in the cells due to their response rate to H 2 O 2 exposure (100 µM; maximum fluorescence intensity, F max ) by using confocal microscopy (Leica TCS SP5, Germany).…”

Section: Methodsmentioning

confidence: 99%

A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats

Durak

Olğar

Değirmenci

et al. 2018

Cardiovasc Diabetol

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131

109

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BackgroundMetabolic syndrome (MetS) is a prevalent risk factor for cardiac dysfunction. Although SGLT2-inhibitors have important cardioprotective effects in hyperglycemia, their underlying mechanisms are complex and not completely understood. Therefore, we examined mechanisms of a SGLT2-inhibitor dapagliflozin (DAPA)-related cardioprotection in overweight insulin-resistant MetS-rats comparison with insulin (INSU), behind its glucose-lowering effect.MethodsA 28-week high-carbohydrate diet-induced MetS-rats received DAPA (5 mg/kg), INSU (0.15 mg/kg) or vehicle for 2 weeks. To validate MetS-induction, we monitored all animals weekly by measuring body weight, blood glucose and HOMO-IR index, electrocardiograms, heart rate, systolic and diastolic pressures.ResultsDAPA-treatment of MetS-rats significantly augmented the increased blood pressure, prolonged Q–R interval, and low heart rate with depressed left ventricular function and relaxation of the aorta. Prolonged-action potentials were preserved with DAPA-treatment, more prominently than INSU-treatment, at most, through the augmentation in depressed voltage-gated K+-channel currents. DAPA, more prominently than INSU-treatment, preserved the depolarized mitochondrial membrane potential, and altered mitochondrial protein levels such as Mfn-1, Mfn-2, and Fis-1 as well as provided significant augmentation in cytosolic Ca2+-homeostasis. Furthermore, DAPA also induced significant augmentation in voltage-gated Na+-currents and intracellular pH, and the cellular levels of increased oxidative stress, protein-thiol oxidation and ADP/ATP ratio in cardiomyocytes from MetS rats. Moreover, DAPA-treatment normalized the increases in the mRNA level of SGLT2 in MetS-rat heart.ConclusionsOverall, our data provided a new insight into DAPA-associated cardioprotection in MetS rats, including suppression of prolonged ventricular-repolarization through augmentation of mitochondrial function and oxidative stress followed by improvement of fusion–fission proteins, out of its glucose-lowering effect.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0790-0) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats

Durak

Olğar

Değirmenci

et al. 2018

Cardiovasc Diabetol

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131

109

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“…[295][296][297] Moreover, enhanced mitochondrial antioxidant capacity following MitoTEMPO treatment improved insulin sensitivity and preserved cardiovascular function in animals with metabolic syndrome or diabetes, as well as in aged animals. [298][299][300] Analysis of ROS-sensitive networks, particularly those associated with MitoTEMPO treatment, highlighted that increased mitochondrial ROS in the metabolically diseased heart disrupts the normal coupling between cytosolic signals and nuclear gene programs underpinning mitochondrial respiratory function, antioxidant capacity, Ca 2+ handling and action potential repolarization. [301][302][303][304] Resveratrol, a natural polyphenol, is a multitarget compound and has been widely studied in the context of diabetes.…”

Section: Improving Mitochondrial Functionmentioning

confidence: 99%

Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

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Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

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“…Structural alterations of mitochondria have been described in different tissues of various species across a spectrum of ages. Examples include mouse tissue from the heart, skeletal muscle, and optic nerve and human tissue from the retina and skin [54][55][56][57][58]. Electron microscopic analysis of cardiomyocytes in aged rats showed disorganized and degenerated mitochondria with fewer and shorter cristae, as well as irregular assembly [54,55].…”

Section: Structural Changes In Mitochondriamentioning

confidence: 99%

“…Examples include mouse tissue from the heart, skeletal muscle, and optic nerve and human tissue from the retina and skin [54][55][56][57][58]. Electron microscopic analysis of cardiomyocytes in aged rats showed disorganized and degenerated mitochondria with fewer and shorter cristae, as well as irregular assembly [54,55]. Mitochondria in the optic nerve axons of aged mice displayed various abnormalities, including expanded mito-chondrial volume but reduced numbers of the organelle [56].…”

Section: Structural Changes In Mitochondriamentioning

confidence: 99%

Age-Related Deterioration of Mitochondrial Function in the Intestine

Schneider

Özsoy

Zimmermann

et al. 2020

Oxidative Medicine and Cellular Longevity

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Aging is an important and inevitable biological process in human life, associated with the onset of chronic disease and death. The mechanisms behind aging remain unclear. However, changes in mitochondrial function and structure, including reduced activity of the mitochondrial respiratory chain and increased production of reactive oxygen species—thus oxidative damage—are believed to play a major role. Mitochondria are the main source of cellular energy, producing adenosine triphosphate (ATP) via oxidative phosphorylation. Accumulation of damaged cellular components reduces a body’s capacity to preserve tissue homeostasis and affects biological aging and all age-related chronic conditions. This includes the onset and progression of classic degenerative diseases such as cardiovascular disease, kidney failure, neurodegenerative diseases, and cancer. Clinical manifestations of intestinal disorders, such as mucosal barrier dysfunction, intestinal dysmotility, and chronic obstipation, are highly prevalent in the elderly population and have been shown to be associated with an age-dependent decline of mitochondrial function. This review summarizes our current understanding of the role of mitochondrial dysfunction in intestinal aging.

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Aging related functional and structural changes in the heart and aorta: MitoTEMPO improves aged-cardiovascular performance

Cited by 51 publications

References 60 publications

A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats

A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats

Altered mitochondrial metabolism in the insulin‐resistant heart

Age-Related Deterioration of Mitochondrial Function in the Intestine

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