The Cardiac Endothelial Cell cGAS-STING Pathway Promotes Doxorubicin-Induced Cardiotoxicity via CD38-Mediated NAD Decline and Mitochondrial Dysfunction
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE226116 | GEO | 2023/03/02
REPOSITORIES: GEO
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Project description:Doxorubicin is an effective chemotherapy drug for treating various types of cancer. However, lethal cardiotoxicity severely limits its clinical use. Recent evidence has indicated that aberrant activation of the cytosolic DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in cardiovascular destruction. Here, we investigate the involvement of this mechanism in doxorubicin-induced cardiotoxicity (DIC).
2023-03-02 | GSE226115 | GEO
Project description:Doxorubicin is an effective chemotherapy drug for treating various types of cancer. However, lethal cardiotoxicity severely limits its clinical use. Recent evidence has indicated that aberrant activation of the cytosolic DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in cardiovascular destruction. Here, we investigate the involvement of this mechanism in doxorubicin-induced cardiotoxicity (DIC).
2023-03-02 | GSE226114 | GEO
Project description:Nicotinamide adenine dinucleotide (NAD) levels decrease during aging and are involved in age-related metabolic decline. To date, the mechanism responsible for the age-related reduction in NAD has not been elucidated. Here we demonstrate that expression and activity of the NADase CD38 increase with aging and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of SIRT3 activity. We also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, indicating that CD38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases.
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Project description:The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2(-/-)) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.
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Project description:Aging is a complex process that involves dysfunction on multiple levels, all of which seem to converge on inflammation. Macrophages are intimately involved in initiating and resolving inflammation, and their dysregulation with age is a primary contributor to inflammaging-a state of chronic, low-grade inflammation that develops during aging. Among the age-related changes that occur to macrophages are a heightened state of basal inflammation and diminished or hyperactive inflammatory responses, which seem to be driven by metabolic-dependent epigenetic changes. In this review article we provide a brief overview of mitochondrial functions and age-related changes that occur to macrophages, with an emphasis on how the inflammaging environment, senescence, and NAD decline can affect their metabolism, promote dysregulation, and contribute to inflammaging and age-related pathologies.
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Project description:Aging is characterized by the development of metabolic dysfunction and frailty. Recent studies show that a reduction in nicotinamide adenine dinucleotide (NAD+) is a key factor for the development of age-associated metabolic decline. We recently demonstrated that the NADase CD38 has a central role in age-related NAD+ decline. Here we show that a highly potent and specific thiazoloquin(az)olin(on)e CD38 inhibitor, 78c, reverses age-related NAD+ decline and improves several physiological and metabolic parameters of aging, including glucose tolerance, muscle function, exercise capacity, and cardiac function in mouse models of natural and accelerated aging. The physiological effects of 78c depend on tissue NAD+ levels and were reversed by inhibition of NAD+ synthesis. 78c increased NAD+ levels, resulting in activation of pro-longevity and health span-related factors, including sirtuins, AMPK, and PARPs. Furthermore, in animals treated with 78c we observed inhibition of pathways that negatively affect health span, such as mTOR-S6K and ERK, and attenuation of telomere-associated DNA damage, a marker of cellular aging. Together, our results detail a novel pharmacological strategy for prevention and/or reversal of age-related NAD+ decline and subsequent metabolic dysfunction.
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Project description:Doxorubicin is a valuable antineoplastic drug although its clinical use is greatly hindered by its severe cardiotoxicity with dismal target therapy available. Luteolin is a natural product extracted from vegetables and fruits with a wide range of biological efficacies including anti-oxidative, anti-tumorigenic, and anti-inflammatory properties. This study was designed to examine the possible effect of luteolin on doxorubicin-induced cardiotoxicity, if any, and the mechanism(s) involved with a focus on mitochondrial autophagy. Luteolin application (10 ?M) in adult mouse cardiomyocytes overtly improved doxorubicin-induced cardiomyocyte contractile dysfunction including elevated peak shortening amplitude and maximal velocity of shortening/relengthening along with unchanged duration of shortening and relengthening. Luteolin alleviated doxorubicin-induced cardiotoxicity including apoptosis, accumulation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential. Furthermore, luteolin attenuated doxorubicin-induced cardiotoxicity through promoting mitochondrial autophagy in association with facilitating phosphorylation of Drp1 at Ser616, and upregulating TFEB expression. In addition, luteolin treatment partially attenuated low dose doxorubicin-induced elongation of mitochondria. Treatment of Mdivi-1, a Drp1 GTPase inhibitor, negated the protective effect of luteolin on levels of TFEB, LAMP1, and LC3B, as well as loss of mitochondrial membrane potential and cardiomyocyte contractile dysfunction in the face of doxorubicin challenge. Taken together, these findings provide novel insights for the therapeutic efficacy of luteolin against doxorubicin-induced cardiotoxicity possibly through improved mitochondrial autophagy.
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Project description:Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.
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Project description:Alzheimer's disease (AD) is a severe neurodegenerative disorder. Clinical trials to identify agents to treat AD have failed, and its underlying molecular pathology and etiology remain elusive. Neuroinflammation is thought to play a key role in the progression of AD. Emerging evidence has identified lower Nicotinamide adenine dinucleotide (NAD+) levels as a major factor in neurodegeneration, especially in AD. NAD+ is an important metabolite in all human cells, as it is at the convergence of many central processes in cellular and mitochondrial maintenance, including DNA repair and mitophagy (the degradation of damaged mitochondria). Our previous work found that treatment of 3xTgAD mice with an NAD+ precursor, nicotinamide riboside (NR), can improve key AD features including tau phosphorylation and learning deficits in mice. Here we used the APP/PS1 AD mouse model to interrogate the effect of NR on neuroinflammation. Microarray analysis revealed major changes in pathways and genes associated with inflammation and the APP/PS1 mice had lower NAD+ levels than WT mice. Thus, seven months old mice were treated with NR for five months and their NAD+/NADH ratio increased. Brain neuroinflammation decreased as determined by decreased activation of astrocytes and microglia, decreased pro-inflammatory cytokines and chemokines in the brains of the APP/PS1 mice. NR decreased neuroinflammation by lowering the NLRP3 inflammasome and NF-κB pathways. NR also attenuated DNA damage and apoptosis in the AD mouse brains. NR dramatically decreased senescence in the hippocampus and cortex of AD mice, relative to controls. Recent studies suggest that cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) activation are associated with DNA damage and senescence. cGAS-STING was activated in AD mice and decreases after NR treatment. Suggesting that NR can diminish neuroinflammation and senescence through the cGAS-STING pathway. NR treatment also greatly improved cognition and synaptic function in the APP/PS1 mice. We propose that the cGAS-STING pathway should be evaluated as a potential novel therapeutic target in AD.
2021-08-25 | GSE135999 | GEO
Project description:UnlabelledMitochondrial ferritin is a functional ferritin that localizes in the mitochondria. It is expressed in the testis, heart, brain, and cells with active respiratory activity. Its overexpression in cultured cells protected against oxidative damage and reduced cytosolic iron availability. However, no overt phenotype was described in mice with inactivation of the FtMt gene. Here, we used the doxorubicin model of cardiac injury in a novel strain of FtMt-null mice to investigate the antioxidant role of FtMt. These mice did not show any evident phenotype, but after acute treatment to doxorubicin, they showed enhanced mortality and altered heart morphology with fibril disorganization and severe mitochondrial damage. Signs of mitochondrial damage were present also in mock-treated FtMt(-/-) mice. The hearts of saline- and doxorubicin-treated FtMt(-/-) mice had higher thiobarbituric acid reactive substance levels, heme oxygenase 1 expression, and protein oxidation, but did not differ from FtMt(+/+) in the cardiac damage marker B-type natriuretic peptide (BNP), ATP levels, and apoptosis. However, the autophagy marker LC3 was activated. The results show that the absence of FtMt, which is highly expressed in the heart, increases the sensitivity of heart mitochondria to the toxicity of doxorubicin. This study represents the first in vivo evidence of the antioxidant role of FtMt.Key messageMitochondrial ferritin (FtMt) expressed in the heart has a protective antioxidant role. Acute treatment with doxorubicin caused the death of all FtMt(-/-) and only of 60 % FtMt(+/+) mice. The hearts of FtMt(-/-) mice showed fibril disorganization and mitochondrial damage. Markers of oxidative damage and autophagy were increased in FtMt(-/-) hearts. This is the first in vivo evidence of the antioxidant role of FtMt.
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