The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor whose activity can be modulated by polyphenols, such as curcumin. AhR and curcumin have evolutionarily conserved effects on aging. Here, we investigated whether and how the AhR mediates the anti-aging effects of curcumin across species. Using a combination of in vivo, in vitro, and in silico analyses, we demonstrated that curcumin has AhR-dependent or -independent effects in a context-specific manner. We found that in Caenorhabditis elegans, AhR mediates curcumin-induced lifespan extension, most likely through a ligand-independent inhibitory mechanism related to its antioxidant activity. Curcumin also showed AhR-independent anti-aging activities, such as protection against aggregation-prone proteins and oxidative stress in C. elegans and promotion of the migratory capacity of human primary endothelial cells. These AhR-independent effects are largely mediated by the Nrf2/SKN-1 pathway.
Although p38 MAP Kinase α (p38 MAPKα) is generally accepted to play a central role in the cardiac stress response, to date its function in maladaptive cardiac hypertrophy is still not unambiguously defined. To induce a pathological type of cardiac hypertrophy we infused angiotensin II (AngII) for 2 days via osmotic mini pumps in control and tamoxifen-inducible, cardiomyocyte (CM)-specific p38 MAPKα KO mice (iCMp38αKO) and assessed cardiac function by echocardiography, complemented by transcriptomic, histological, and immune cell analysis. AngII treatment after inactivation of p38 MAPKα in CM results in left ventricular (LV) dilatation within 48 h (EDV: BL: 83.8 ± 22.5 µl, 48 h AngII: 109.7 ± 14.6 µl) and an ectopic lipid deposition in cardiomyocytes, reflecting a metabolic dysfunction in pressure overload (PO). This was accompanied by a concerted downregulation of transcripts for oxidative phosphorylation, TCA cycle, and fatty acid metabolism. Cardiac inflammation involving neutrophils, macrophages, B- and T-cells was significantly enhanced. Inhibition of adipose tissue lipolysis by the small molecule inhibitor of adipocytetriglyceride lipase (ATGL) Atglistatin reduced cardiac lipid accumulation by 70% and neutrophil infiltration by 30% and went along with an improved cardiac function. Direct targeting of neutrophils by means of anti Ly6G-antibody administration in vivo led to a reduced LV dilation in iCMp38αKO mice and an improved systolic function (EF: 39.27 ± 14%). Thus, adipose tissue lipolysis and CM lipid accumulation augmented cardiac inflammation in iCMp38αKO mice. Neutrophils, in particular, triggered the rapid left ventricular dilatation. We provide the first evidence that p38 MAPKα acts as an essential switch in cardiac adaptation to PO by mitigating metabolic dysfunction and inflammation. Moreover, we identified a heart–adipose tissue–immune cell crosstalk, which might serve as new therapeutic target in cardiac pathologies.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor whose activity can be modulated by polyphenols such as curcumin. AhR and curcumin have evolutionarily conserved effects on aging. Here, we investigated whether and how the AhR mediates the anti-aging effects of curcumin across species. Using a combination of in vivo, in vitro, and in silico analyses, we demonstrated that curcumin has AhR-dependent or -independent effects in a context-specific manner. We found that in Caenorhabditis elegans, AhR mediates curcumin-induced lifespan extension, most likely through a ligand-independent inhibitory mechanism related to its antioxidant activity. Curcumin also showed AhR-independent anti-aging activities such as protection against aggregation-prone proteins and oxidative stress in C. elegans and promotion of the migratory capacity of human primary endothelial cells. These AhR-independent effects are largely mediated by the Nrf2/SKN-1 pathway.
Question Cardiac metabolic remodeling is one of the early changes driving the progression of heart failure and is present even before overt cardiac dysfunction. Previously we showed that the tamoxifen inducible deletion of cardiomyocyte specific p38 MAPKa (KO) leads to a pronounced left ventricular dilation with a strongly impaired heart function just within 2 days of angiotensin II (ANGII) treatment. Additionally, a strong infiltration of immune cells in the cardiac tissue can be observed. Methods and Results Under baseline conditions no impairment of the heart function in KO mice can be observed. ANGII treatment for 2 days induces a strong left ventricular dilation and poor heart function, indicated by a reduced ejection fraction and an increase in end‐systolic and end‐diastolic volume. KO mice do not get used to constant ANGII treatment even after 7 days of ANGII treatment and cardiac function continues to deteriorate. KO mice transiently loose weight as a consequence of ANGII treatment. On the fourth to fifth day of ANGII treatment, KO animals gain weight again, although the heart function continues to deteriorate. FACS analysis of cardiac tissue revealed a strong infiltration of neutrophils in KO hearts after 48h of ANGII treatment (4.5‐fold increase compared to control hearts). A strong correlation between reduced ejection fraction and increasing amount of neutrophils in the cardiac tissue suggests a particularly important role of neutrophils in the development of cardiac dysfunction. Also an increase of macrophages (1.6‐fold increase), CD4+ T‐helper cells (2.5‐fold increase) and CD8+ cytotoxic T‐cells (2.5‐fold increase) as well as B‐cells (2‐fold increase) could be shown in KO hearts compared to control hearts. After long term ANGII treatment for 7 days, however, the number of neutrophils in the hearts decreased (10‐fold decrease in control hearts and 73‐fold decrease in KO hearts compared to 48h of ANGII treatment) and a strong increase in M2‐like macrophage infiltration, mainly in control hearts (1.6‐fold increase compared to 48h ANGII treatment), could be observed. The infiltrated macrophages were also positive for CCR2, which indicates they originated from monocytes. B‐ and T‐cells were still elevated in KO hearts after 7 days of ANGII treatment. Also in control hearts an increase of B‐ and T‐cells could be observed. In addition, fibrosis developed in the cardiac tissue, which could be shown by histological staining of collagen I and FACS analysis targeting αSMA+ cardiac fibroblasts. Conclusion Immune cells and in particular neutrophils play an important role in the development of cardiac dysfunction after ANGII induced pressure overload in p38 MAPKa KO mice. Over time, however, the number of immune cells in control mice also increases, which underlines the peculiarity of the first neutrophil influx after 48h ANGII treatment for the impairment of cardiac function.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.