1. Targeting cardiovascular risk factors through dietary adaptations and caloric restriction mimeticsJulia Voglhuber, Senka Ljubojevic-Holzer, Mahmoud Abdellatif, Simon Sedej, 2021, pregledni znanstveni članek Opis: The average human life expectancy continues to rise globally and so does the prevalence and absolute burden of cardiovascular disease. Dietary restriction promotes longevity and improves various cardiovascular risk factors, including hypertension, obesity, diabetes mellitus, and metabolic syndrome. However, low adherence to caloric restriction renders this stringent dietary intervention challenging to adopt as a standard practice for cardiovascular disease prevention. Hence, alternative eating patterns and strategies that recapitulate the salutary benefits of caloric restriction are under intense investigation. Here, we first provide an overview of alternative interventions, including intermittent fasting, alternate-day fasting and the Mediterranean diet, along with their cardiometabolic effects in animal models and humans. We then present emerging pharmacological alternatives, including spermidine, NAD+ precursors, resveratrol, and metformin, as promising caloric restriction mimetics, and briefly touch on the mechanisms underpinning their cardiometabolic and health-promoting effects. We conclude that implementation of feasible dietary approaches holds the promise to attenuate the burden of cardiovascular disease and facilitate healthy aging in humans.
Ključne besede: autophagy, caloric restriction, caloric restriction mimetics, cardiovascular risk factors, dietary regimens, hypertension, intermittent fasting, obesity
Objavljeno v DKUM: 21.10.2024; Ogledov: 0; Prenosov: 2
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2. Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cyclingSenka Ljubojevic-Holzer, Simon Kraler, Nataša Djalinac, Mahmoud Abdellatif, Julia Voglhuber, Julia Schipke, Marlene Schmidt, Katharina-Maria Kling, Greta Therese Franke, Viktoria Herbst, Simon Sedej, 2022, izvirni znanstveni članek Opis: Aims: Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure.
Methods and results: RT-qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5-/-). Before manifesting cardiac dysfunction, Atg5-/- mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high-frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load, and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5-/- cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5-/- cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload.
Conclusion: Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve.
Ključne besede: autophagy, beta-adrenergic signalling, calcium, cardiomyocytes, mitochondria
Objavljeno v DKUM: 26.09.2024; Ogledov: 0; Prenosov: 2
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3. Nicotinamide for the treatment of heart failure with preserved ejection fractionMahmoud Abdellatif, Viktoria Herbst, Franziska Koser, Sylvère Durand, Rui Adão, Francisco Vasques-Nóvoa, Johanna K Freundt, Julia Voglhuber, Maria Rosaria Pricolo, Michael Kasa, Simon Sedej, 2021, izvirni znanstveni članek Opis: Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.
Ključne besede: heart failure, hypertension, niacinamide, metabolic syndrome
Objavljeno v DKUM: 06.08.2024; Ogledov: 89; Prenosov: 5
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4. Spermidine supplementation influences mitochondrial number and morphology in the heart of aged miceJil Messerer, Christoph Wrede, Julia Schipke, Christina Brandenberger, Mahmoud Abdellatif, Tobias Eisenberg, Frank Madeo, Simon Sedej, Christian Mühlfeld, 2023, izvirni znanstveni članek Opis: Aging is associated with cardiac hypertrophy and progressive decline in heart function. One of the hallmarks of cellular aging is the dysfunction of mitochondria. These organelles occupy around 1/4 to 1/3 of the cardiomyocyte volume. During cardiac aging, the removal of defective or dysfunctional mitochondria by mitophagy as well as the dynamic equilibrium between mitochondrial fusion and fission is distorted. Here, we hypothesized that these changes affect the number of mitochondria and alter their three-dimensional (3D) characteristics in aged mouse hearts. The polyamine spermidine stimulates both mitophagy and mitochondrial biogenesis, and these are associated with improved cardiac function and prolonged lifespan. Therefore, we speculated that oral spermidine administration normalizes the number of mitochondria and their 3D morphology in aged myocardium. Young (4-months old) and old (24-months old) mice, treated or not treated with spermidine, were used in this study (n = 10 each). The number of mitochondria in the left ventricles was estimated by design-based stereology using the Euler-Poincaré characteristic based on a disector at the transmission electron microscopic level. The 3D morphology of mitochondria was investigated by 3D reconstruction (using manual contour drawing) from electron microscopic z-stacks obtained by focused ion beam scanning electron microscopy. The volume of the left ventricle and cardiomyocytes were significantly increased in aged mice with or without spermidine treatment. Although the number of mitochondria was similar in young and old control mice, it was significantly increased in aged mice treated with spermidine. The interfibrillar mitochondria from old mice exhibited a lower degree of organization and a greater variation in shape and size compared to young animals. The mitochondrial alignment along the myofibrils in the spermidine-treated mice appeared more regular than in control aged mice, however, old mitochondria from animals fed spermidine also showed a greater diversity of shape and size than young mitochondria. In conclusion, mitochondria of the aged mouse left ventricle exhibited changes in number and 3D ultrastructure that is likely the structural correlate of dysfunctional mitochondrial dynamics. Spermidine treatment reduced, at least in part, these morphological changes, indicating a beneficial effect on cardiac mitochondrial alterations associated with aging.
Ključne besede: aging, focused ion beam scanning electron microscopy, mitochondria, spermidine, stereology
Objavljeno v DKUM: 17.07.2024; Ogledov: 110; Prenosov: 10
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5. Fine-tuning cardiac insulin-like growth factor 1 receptor signaling to promote health and longevityMahmoud Abdellatif, Viktoria Herbst, Alexander Martin Heberle, Alina Humnig, Tobias Pendl, Sylvère Durand, Giulia Cerrato, Sebastian J Hofer, Moydul Islam, Julia Voglhuber, Simon Sedej, 2022, izvirni znanstveni članek Opis: Background: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial.
Methods: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well.
Results: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity.
Conclusions: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.
Ključne besede: aging, autophagy, cardiomyopathies, insulin-like growth factor 1, mitochondria, mouse, phosphatidylinositol 3-kinases
Objavljeno v DKUM: 11.08.2023; Ogledov: 495; Prenosov: 47
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6. Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heartMahmoud Abdellatif, Frank Madeo, Guido Kroemer, Simon Sedej, 2022, drugi znanstveni članki Opis: Although attenuated IGF1R (insulin-like growth factor 1 receptor) signaling has long been viewed to promote longevity in model organisms, adverse effects on the heart have been the subject of major concern. We observed that IGF1R is overexpressed in cardiac tissues from patients with end-stage non-ischemic heart failure, coupled to the activation of the IGF1R downstream effector AKT/protein kinase B and inhibition of ULK1 (unc-51 like autophagy activating kinase 1). Transgenic overexpression of human IGF1R in cardiomyocytes from mice initially induces physiological cardiac hypertrophy and superior function, but later in life confers a negative impact on cardiac health, causing macroautophagy/autophagy inhibition as well as impaired oxidative phosphorylation, thus reducing life expectancy. Treatment with the autophagy inducer and caloric restriction mimetic spermidine ameliorates most of these IGF1R-induced cardiotoxic effects in vivo. Moreover, inhibition of IGF1R signaling by means of a dominant-negative phosphoinositide 3-kinase (PI3K) mutant induces cardioprotective autophagy, restores myocardial bioenergetics and improves late-life survival. Hence, our results demonstrate that IGF1R exerts a dual biphasic impact on cardiac health, and that autophagy mediates the late-life geroprotective effects of IGF1R inhibition in the heart.
Ključne besede: heart failure, IGF1R, PI3K, human, insulin signaling, longevity, mitochondrial dysfunction, mouse
Objavljeno v DKUM: 08.08.2023; Ogledov: 335; Prenosov: 40
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