Spermidine Prevents Heart Injury in Neonatal Rats Exposed to Intrauterine Hypoxia by Inhibiting Oxidative Stress and Mitochondrial Fragmentation

Chai, Nannan; Zhang, Hao; Li, Lingxu; Yu, Xue; Liu, Yan; Yan, Lin; Wang, Lina; Yan, Jiamin; Сазонова, Е. Н.; Zhao, Yajun

doi:10.1155/2019/5406468

Cited by 29 publications

(37 citation statements)

References 74 publications

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“…Ultrathin sections (80-nm-thick) were observed with a JEM-1400 transmission electron microscope (TEM) (Jeol, Tokyo, Japan). Mitochondrial injury was blindly determined by a scoring system, as previous described [19].…”

Section: Methodsmentioning

confidence: 99%

MD-1 Deficiency Accelerates Myocardial Inflammation and Apoptosis in Doxorubicin-Induced Cardiotoxicity by Activating the TLR4/MAPKs/Nuclear Factor kappa B (NF-κB) Signaling Pathway

et al. 2019

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Background: Myocardial apoptosis and inflammation play important roles in doxorubicin (DOX)-caused cardiotoxicity. Our prior studies have characterized the effects of myeloid differentiation protein 1(MD-1) in pathological cardiac remodeling and myocardial ischemia/reperfusion (I/R) injury, but its participations and potential molecular mechanisms in DOX-caused cardiotoxicity remain unknown. Material/Methods: In the present study, MD-1 knockout mice were generated, and a single intraperitoneal injection of DOX (15 mg/kg) was performed to elicit DOX-induced cardiotoxicity. Cardiac function, histological change, mitochondrial structure, myocardial death, apoptosis, inflammation, and molecular alterations were measured systemically. Results: The results showed that the protein and mRNA levels of MD-1 were dramatically downregulated in DOX-treated cardiomyocytes. DOX insult markedly accelerated cardiac dysfunction and injury, followed by enhancements of apoptosis and inflammation, all of which were further aggravated in MD-1 knockout mice. Mechanistically, the TLR4/MAPKs/NF-kB pathways, which were over-activated in MD-1-deficient mice, were significantly increased in DOX-damaged cardiomyocytes. Moreover, the abolishment of TLR4 or NF-kB via a specific inhibitor exerted protective effects against the adverse effects of MD-1 loss on DOX-caused cardiotoxicity. Conclusions: Collectively, these findings suggest that MD-1 is a novel target for the treatment of DOX-induced cardiotoxicity.

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Section: Methodsmentioning

confidence: 99%

MD-1 Deficiency Accelerates Myocardial Inflammation and Apoptosis in Doxorubicin-Induced Cardiotoxicity by Activating the TLR4/MAPKs/Nuclear Factor kappa B (NF-κB) Signaling Pathway

et al. 2019

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“…By microarray analysis of human hair follicle mRNA extracts, Ramot et al revealed that SPD can upregulate several key target genes implicated in the control of mitochondrial function [60]. We recently demonstrated that SPD can increase the expression of PGC-1α mRNA in the newborn offspring myocardium exposed to maternal hypoxia [61]. Therefore, the mechanisms underlying SPD-induced mRNA expression changes in signaling molecules of the SIRT1/PGC-1α pathway in the aging myocardium deserve further exploration.…”

Section: Sirt1 Has Been Shown To Increase the Transcriptional Activity Of Pgc-1α By Inducing Its Nuclear Localizationmentioning

confidence: 92%

Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function

Wang

et al. 2020

Aging

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Polyamines have been shown to delay cellular and organismal aging and to provide cardiovascular protection in humans. Because age-related cardiovascular dysfunction is often accompanied by impaired mitochondrial biogenesis and function, we explored the ability of spermidine (SPD), a major mammalian polyamine, to attenuate cardiac aging through activation of mitochondrial biogenesis. Cardiac polyamine levels were reduced in aged (24-month-old) rats. Six-week SPD supplementation restored cardiac polyamine content, preserved myocardial ultrastructure, and inhibited mitochondrial dysfunction. Immunoblotting showed that ornithine decarboxylase (ODC) and SPD/spermine N1-acetyltransferase (SSAT) were downregulated and upregulated, respectively, in the myocardium of older rats. These changes were paralleled by age-dependent downregulation of components of the sirtuin-1/peroxisome proliferator-activated receptor gamma coactivator alpha (SIRT1/PGC-1α) signaling pathway, an important regulator of mitochondrial biogenesis. SPD administration increased SIRT1, PGC-1α, nuclear respiratory factors 1 and 2 (NRF1, NRF2), and mitochondrial transcription factor A (TFAM) expression; decreased ROS production; and improved OXPHOS performance in senescent (H2O2-treated) cardiomyocytes. Inhibition of polyamine biosynthesis or SIRT1 activity abolished these effects. PGC-1α knockdown experiments confirmed that SPD activated mitochondrial biogenesis through SIRT1mediated deacetylation of PGC-1α. These data provide new insight into the antiaging effects of SPD, and suggest potential applicability to protect against deterioration of cardiac function with aging.

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“…ATP13A2 and its transported substrates have been reported before to protect against conditions of oxidative stress and oxidative stress pathways ( 52 – 54 ). ATP13A2’s potent antioxidant effect may be key to confer mitochondrial protection to various ROS-inducing neurotoxins such as rotenone, 6-OHDA, and MPP + .…”

Section: Discussionmentioning

confidence: 99%

ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress

Vrijsen

Besora-Casals

Veen

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Recessive loss-of-function mutations in ATP13A2 (PARK9) are associated with a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD). We recently revealed that the late endo-lysosomal transporter ATP13A2 pumps polyamines like spermine into the cytosol, whereas ATP13A2 dysfunction causes lysosomal polyamine accumulation and rupture. Here, we investigate how ATP13A2 provides protection against mitochondrial toxins such as rotenone, an environmental PD risk factor. Rotenone promoted mitochondrial-generated superoxide (MitoROS), which was exacerbated by ATP13A2 deficiency in SH-SY5Y cells and patient-derived fibroblasts, disturbing mitochondrial functionality and inducing toxicity and cell death. Moreover, ATP13A2 knockdown induced an ATF4-CHOP-dependent stress response following rotenone exposure. MitoROS and ATF4-CHOP were blocked by MitoTEMPO, a mitochondrial antioxidant, suggesting that the impact of ATP13A2 on MitoROS may relate to the antioxidant properties of spermine. Pharmacological inhibition of intracellular polyamine synthesis with α-difluoromethylornithine (DFMO) also increased MitoROS and ATF4 when ATP13A2 was deficient. The polyamine transport activity of ATP13A2 was required for lowering rotenone/DFMO-induced MitoROS, whereas exogenous spermine quenched rotenone-induced MitoROS via ATP13A2. Interestingly, fluorescently labeled spermine uptake in the mitochondria dropped as a consequence of ATP13A2 transport deficiency. Our cellular observations were recapitulated in vivo, in a Caenorhabditis elegans strain deficient in the ATP13A2 ortholog catp-6. These animals exhibited a basal elevated MitoROS level, mitochondrial dysfunction, and enhanced stress response regulated by atfs-1, the C. elegans ortholog of ATF4, causing hypersensitivity to rotenone, which was reversible with MitoTEMPO. Together, our study reveals a conserved cell protective pathway that counters mitochondrial oxidative stress via ATP13A2-mediated lysosomal spermine export.

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Spermidine Prevents Heart Injury in Neonatal Rats Exposed to Intrauterine Hypoxia by Inhibiting Oxidative Stress and Mitochondrial Fragmentation

Cited by 29 publications

References 74 publications

MD-1 Deficiency Accelerates Myocardial Inflammation and Apoptosis in Doxorubicin-Induced Cardiotoxicity by Activating the TLR4/MAPKs/Nuclear Factor kappa B (NF-κB) Signaling Pathway

MD-1 Deficiency Accelerates Myocardial Inflammation and Apoptosis in Doxorubicin-Induced Cardiotoxicity by Activating the TLR4/MAPKs/Nuclear Factor kappa B (NF-κB) Signaling Pathway

Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function

ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress

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