Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice.
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ABSTRACT:
SUBMITTER: Sundaresan NR
PROVIDER: S-EPMC2735933 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cardiac lymphatic vessel growth (lymphangiogenesis) and integrity play an essential role in maintaining tissue fluid balance. Inhibition of lymphatic lymphangiogenesis is involved in cardiac edema and cardiac remodeling after ischemic injury or pressure overload. However, whether lymphatic vessel integrity is disrupted during angiotensin II- (Ang II-) induced cardiac remodeling remains to be investigated. In this study, cardiac remodeling models were established by Ang II (1000 ng/kg/min) in VEGFR-3 knockdown (Lyve-1Cre VEGFR-3f/-) and wild-type (VEGFR-3f/f) littermates. Our results indicated that Ang II infusion not only induced cardiac lymphangiogenesis and upregulation of VEGF-C and VEGFR-3 expression in the time-dependent manner but also enhanced proteasome activity, MKP5 and VE-cadherin degradation, p38 MAPK activation, and lymphatic vessel hyperpermeability. Moreover, VEGFR-3 knockdown significantly inhibited cardiac lymphangiogenesis in mice, resulting in exacerbation of tissue edema, hypertrophy, fibrosis superoxide production, inflammation, and heart failure (HF). Conversely, administration of epoxomicin (a selective proteasome inhibitor) markedly mitigated Ang II-induced cardiac edema, remodeling, and dysfunction; upregulated MKP5 and VE-cadherin expression; inactivated p38 MAPK; and reduced lymphatic vessel hyperpermeability in WT mice, indicating that inhibition of proteasome activity is required to maintain lymphatic endothelial cell (LEC) integrity. Our results show that both cardiac lymphangiogenesis and lymphatic barrier hyperpermeability are implicated in Ang II-induced adaptive hypertrophic remodeling and dysfunction. Proteasome-mediated hyperpermeability of LEC junctions plays a predominant role in the development of cardiac remodeling. Selective stimulation of lymphangiogenesis or inhibition of proteasome activity may be a potential therapeutic option for treating hypertension-induced cardiac remodeling.
| S-EPMC8881141 | biostudies-literature
Project description:Cellular longevity is a complex process relevant to age-related diseases including but not limited to chronic illness such as diabetes and metabolic syndromes. Two gene families have been shown to play a role in the genetic regulation of longevity; the Sirtuin and FOXO families. It is also established that nuclear Sirtuins interact with and under specific cellular conditions regulate the activity of FOXO gene family proteins. Thus, we hypothesize that a mitochondrial Sirtuin (SIRT3) might also interact with and regulate the activity of the FOXO proteins. To address this we used HCT116 cells overexpressing either wild-type or a catalytically inactive dominant negative SIRT3. For the first time we establish that FOXO3a is also a mitochondrial protein and forms a physical interaction with SIRT3 in mitochondria. Overexpression of a wild-type SIRT3 gene increase FOXO3a DNA-binding activity as well as FOXO3a dependent gene expression. Biochemical analysis of HCT116 cells over expressing the deacetylation mutant, as compared to wild-type SIRT3 gene, demonstrated an overall oxidized intracellular environment, as monitored by increase in intracellular superoxide and oxidized glutathione levels. As such, we propose that SIRT3 and FOXO3a comprise a potential mitochondrial signaling cascade response pathway.
| S-EPMC2532794 | biostudies-literature
Project description:Honokiol (HKL) is a natural biphenolic compound derived from the bark of magnolia trees with anti-inflammatory, anti-oxidative, anti-tumour and neuroprotective properties. Here we show that HKL blocks agonist-induced and pressure overload-mediated, cardiac hypertrophic responses, and ameliorates pre-existing cardiac hypertrophy, in mice. Our data suggest that the anti-hypertrophic effects of HKL depend on activation of the deacetylase Sirt3. We demonstrate that HKL is present in mitochondria, enhances Sirt3 expression nearly twofold and suggest that HKL may bind to Sirt3 to further increase its activity. Increased Sirt3 activity is associated with reduced acetylation of mitochondrial Sirt3 substrates, MnSOD and oligomycin-sensitivity conferring protein (OSCP). HKL-treatment increases mitochondrial rate of oxygen consumption and reduces ROS synthesis in wild type, but not in Sirt3-KO cells. Moreover, HKL-treatment blocks cardiac fibroblast proliferation and differentiation to myofibroblasts in a Sirt3-dependent manner. These results suggest that HKL is a pharmacological activator of Sirt3 capable of blocking, and even reversing, the cardiac hypertrophic response.
| S-EPMC4441304 | biostudies-literature
Project description:BackgroundAdipose tissue-derived adipokines are involved in various crosstalk between adipose tissue and other organs. Omentin1, a novel adipokine, exerts vital roles in the maintenance of body metabolism, insulin resistance and the like. However, the protective effect of omentin1 in myocardial ischemia (MI)-induced heart failure (HF) and its specific mechanism remains unclear and to be elucidated.MethodsThe model of MI-induced HF mice and oxygen glucose deprivation (OGD)-injured cardiomyocytes were performed. Mice with overexpression of omentin1 were constructed by a fat-specific adeno-associated virus (AAV) vector system.ResultsWe demonstrated that circulating omentin1 level diminished in HF patients compared with healthy subjects. Furthermore, the fat-specific overexpression of omentin1 ameliorated cardiac function, cardiac hypertrophy, infarct size and cardiac pathological features, and also enhanced SIRT3/FOXO3a signaling in HF mice. Additionally, administration with AAV-omentin1 increased mitochondrial fusion and decreased mitochondrial fission in HF mice, as evidenced by up-regulated expression of Mfn2 and OPA1, and downregulation of p-Drp1(Ser616). Then, it also promoted PINK1/Parkin-dependent mitophagy. Simultaneously, treatment with recombinant omentin1 strengthened OGD-injured cardiomyocyte viability, restrained LDH release, and enhanced the mitochondrial accumulation of SIRT3 and nucleus transduction of FOXO3a. Besides, omentin1 also ameliorated unbalanced mitochondrial fusion-fission dynamics and activated mitophagy, thereby, improving the damaged mitochondria morphology and controlling mitochondrial quality in OGD-injured cardiomyocytes. Interestingly, SIRT3 played an important role in the improvement effects of omentin1 on mitochondrial function, unbalanced mitochondrial fusion-fission dynamics and mitophagy.ConclusionOmentin1 improves MI-induced HF and myocardial injury by maintaining mitochondrial dynamical homeostasis and activating mitophagy via upregulation of SIRT3/FOXO3a signaling. This study provides evidence for further application of omentin1 in cardiovascular diseases from the perspective of crosstalk between heart and adipose tissue.
| S-EPMC9531426 | biostudies-literature
Project description:BackgroundIschaemic preconditioning elicited by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischaemic insult. Here, we test the hypothesis that short-term non-ischaemic stimulation of hypertrophy renders the heart resistant to subsequent ischaemic injury.Methods and resultsTransient transverse aortic constriction (TAC) was performed for 3 days in mice and then withdrawn for 4 days by aortic debanding, followed by subsequent exposure to myocardial ischaemia-reperfusion (I/R) injury. Following I/R injury, myocardial infarct size and apoptosis were significantly decreased, and cardiac dysfunction was markedly improved in the TAC preconditioning group compared with the control group. Mechanistically, TAC preconditioning markedly suppressed I/R-induced autophagy and preserved autophagic flux by deacetylating SOD2 via a SIRT3-dependent mechanism. Moreover, treatment with an adenovirus encoding SIRT3 partially mimicked the effects of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. Furthermore, in vivo lentiviral-mediated knockdown of Beclin 1 in the myocardium ameliorated the I/R-induced impairment of autophagic flux and was associated with a reduction in cell death, whereas treatment with a lentivirus encoding Beclin 1 abolished the cardioprotective effect of TAC preconditioning.ConclusionsThe present study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Specifically, TAC preconditioning reduced myocardial autophagic cell death in a SIRT3/SOD2 pathway-dependent manner.
| S-EPMC8249780 | biostudies-literature
Project description:Soybean is an important oilseed crop that provides high-quality protein and vegetable oil. Salinity constitutes a negative abiotic factor that reduces soybean plant growth, production, and quality. The adsorption of Na+ by chitosan-modified biochar (CMB) has a significant effect on salinity but the application of CMB is limited in soybean. In the current study, CMB was used for characterization of physiological, biochemical, and molecular responses of soybean under salt stress. Comparison of CMB and unmodified (as-is) biochar (BR) demonstrated a significant difference between them shown by using Fourier transform infrared spectroscopy (FTIR), scan electron microscopy (SEM), Brunauer-Emmett-Teller (BET), elemental analysis and z-potential measurement. Pseudo-first and second-order better suited for the analysis of Na+ adsorption kinetics. The salt-stress reduced the soybean plants growth, root architecture characteristics, biomass yield, nutrients acquisition, chlorophyll contents, soluble protein, and sugar contents, while CMB with salt-stress significantly increased the above parameters. Moreover, CMB also reduced the salinity-induced increase in the Na+, glycine betaine (GB), proline, hydrogen peroxide (H2O2), and malondialdehyde (MDA) levels in plants. The antioxidant activity and gene expression levels triggered by salinity but with the application of CMB significantly further boosted the expression profile of four genes (CAT, APX, POD and SOD) encoding antioxidant enzyme and two salt-tolerant conferring genes (GmSALT3 and CHS). Overall, these findings demonstrate the crucial role of CMB in minimizing the adverse effects of high salinity on soybean growth and efficiency of the mechanisms enabling plant protection from salinity through a shift of the architecture of the root system and enhancing the antioxidant defense systems and stress-responsive genes for achieving sustainable crop production.
| S-EPMC7569946 | biostudies-literature
Project description:Vascular endothelial growth factor (VEGF) has a central role in breast cancer development and progression, but the mechanisms that control its expression are poorly understood. Breast cancer tissue microarrays revealed an inverse correlation between the Forkhead transcription factor Forkhead box class O (FOXO)3a and VEGF expression. Using the lapatinib-sensitive breast cancer cell lines BT474 and SKBR3 as model systems, we tested the possibility that VEGF expression is negatively regulated by FOXO3a. Lapatinib treatment of BT474 or SKBR3 cells resulted in nuclear translocation and activation of FOXO3a, followed by a reduction in VEGF expression. Transient transfection and inducible expression experiments showed that FOXO3a represses the proximal VEGF promoter, whereas another Forkhead member, FOXM1, induces VEGF expression. Chromatin immunoprecipitation and oligonucleotide pull-down assays showed that both FOXO3a and FOXM1 bind a consensus Forkhead response element (FHRE) in the VEGF promoter. Upon lapatinib stimulation, activated FOXO3a displaces FOXM1 bound to the FHRE before recruiting histone deacetylase 2 (HDAC2) to the promoter, leading to decreased histones H3 and H4 acetylation, and concomitant transcriptional inhibition of VEGF. These results show that FOXO3a-dependent repression of target genes in breast cancer cells, such as VEGF, involves competitive displacement of DNA-bound FOXM1 and active recruitment of transcriptional repressor complexes.
| S-EPMC3232453 | biostudies-literature
Project description:Background Evidence that a vegetarian diet rich in antioxidants contributes to cardiovascular health are growing, however, the underlying molecular mechanisms remain unknown. HO-1 (heme-oxygenase-1), a marker of adaptive response, is protective against oxidative stress and has shown cardioprotective effects. Therefore, we evaluated circulating HO-1 levels and the effect of plasma from omnivorous and vegetarians in endothelial cells (human umbilical vein endothelial cells) on modulating NRF2 (nuclear factor erythroid 2-like 2)/HO-1 and nitric oxide production. Methods and Results From 745 participants initially recruited, 44 omnivorous and 44 vegetarian men matched by age and absence of cardiovascular risk factors and diseases were included in this study. Circulating HO-1 was measured using ELISA and human umbilical vein endothelial cells were incubated with plasma from omnivorous and vegetarians. Higher circulating HO-1 concentrations were found in omnivorous compared with vegetarians. Plasma from omnivorous and not from vegetarians induced NRF2/HO-1 and nitric oxide production in human umbilical vein endothelial cells, and increased reactive oxygen species production and caspase activity after incubation with stressor stimulus. Conclusions We suggest that HO-1 induction in omnivorous may indicate a pro-oxidative status since HO-1 is activated under oxidative stress a state not seen in vegetarians.
| S-EPMC7429062 | biostudies-literature
Project description:The present study focuses on the investigation of the oxidized cell-free DNA (cfDNA) properties in several experimental models, including cultured cerebellum cells, peripheral blood lymphocytes (PBL), plasma, and hippocampus under an acute and chronic unpredictable stress model in rats. Firstly, our study shows that Spectrum Green fluorescence-labeled oxidized cfDNA fragments were transferred into the cytoplasm of 80% of the cerebellum culture cells; meanwhile, the nonoxidized cfDNA fragments do not pass into the cells. Oxidized cfDNA stimulates the antioxidant mechanisms and induction of transcription factor NRF2 expression, followed by an activation of NRF2 signaling pathway genes-rise of Nrf2 and Hmox1 gene expression and consequently NRF2 protein synthesis. Secondly, we showed that stress increases plasma cfDNA concentration in rats corresponding with the duration of the stress exposure. At the same time, our study did not reveal any significant changes of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) level in PBL of rats under acute or chronic stress, probably due to the significantly increased Nrf2 expression, that we found in such conditions. 8-oxodG is one of the most reliable markers of DNA oxidation. We also found an increased level of 8-oxodG in the hippocampal homogenates and hippocampal dentate gyrus in rats subjected to acute and chronic stress. Taken together, our data shows that oxidized cfDNA may play a significant role in systemic and neuronal physiological mechanisms of stress and adaptation.
| S-EPMC6644271 | biostudies-literature
Project description:UnlabelledSirT1 is a class III histone deacetylase that has been implicated in metabolic and reactive oxygen species control. In the vasculature it has been shown to decrease endothelial superoxide production, prevent endothelial dysfunction and atherosclerosis. However, the mechanisms that mediate SirT1 antioxidant functions remain to be characterized. The transcription factor FoxO3a and the transcriptional coactivator peroxisome proliferator activated receptor ?-coactivator 1? (PGC-1?) have been shown to induce the expression of antioxidant genes and to be deacetylated by SirT1.AimsHere we investigated SirT1 regulation of antioxidant genes and the roles played by FoxO3a and PGC-1? in this regulation.ResultsWe found that SirT1 regulates the expression of several antioxidant genes in bovine aortic endothelial cells, including Mn superoxide dismutase (MnSOD), catalase, peroxiredoxins 3 and 5 (Prx3, Prx5), thioredoxin 2 (Trx2), thioredoxin reductase 2 (TR2), and uncoupling protein 2 (UCP-2) and can be localized in the regulatory regions of these genes. We also found that knockdown of either FoxO3a or PGC-1? prevented the induction of antioxidant genes by SirT1 over-expression. Furthermore, SirT1 increased the formation of a FoxO3a/PGC-1? complex as determined by co-immunoprecipitation (IP) assays, concomitantly reducing H2O2-dependent FoxO3a and PGC-1? acetylation. Data showing that FoxO3a knockdown increases PGC-1? acetylation levels and vice versa, suggest that SirT1 activity on FoxO3a and PGC-1? may be dependent of the formation of a FoxO3a/PGC-1? complex.InnovationA unifying mechanism for SirT1 activities is suggested.ConclusionWe show that SirT1 regulation of antioxidant genes in vascular endothelial cells depends on the formation of a FoxO3a/PGC-1? complex.
| S-EPMC3797451 | biostudies-literature