Cardamonin protects against lipopolysaccharide-induced myocardial contractile dysfunction in mice through Nrf2-regulated mechanism
- 21 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Pharmacologica Sinica
- Vol. 42 (3), 404-413
- https://doi.org/10.1038/s41401-020-0397-3
Abstract
In patients with sepsis, lipopolysaccharide (LPS) from the outer membrane of gram-negative bacteria triggers cardiac dysfunction and heart failure, but target therapy for septic cardiomyopathy remains unavailable. In this study we evaluated the beneficial effects of cardamonin (CAR), a flavone existing in Alpinia plant, on endotoxemia-induced cardiac dysfunction and the underlying mechanisms with focus on oxidative stress and apoptosis. Adult mice were exposed to LPS (4 mg/kg, i.p. for 6 h) prior to functional or biochemical assessments. CAR (20 mg/kg, p.o.) was administered to mice immediately prior to LPS challenge. We found that LPS challenge compromised cardiac contractile function, evidenced by compromised fractional shortening, peak shortening, maximal velocity of shortening/relengthening, enlarged LV end systolic diameter and prolonged relengthening in echocardiography, and induced apoptosis, overt oxidative stress (O2− production and reduced antioxidant defense) associated with inflammation, phosphorylation of NF-κB and cytosolic translocation of transcriptional factor Nrf2. These deteriorative effects were greatly attenuated or mitigated by CAR administration. However, H&E and Masson’s trichrome staining analysis revealed that neither LPS challenge nor CAR administration significantly affected cardiomyocyte cross-sectional area and interstitial fibrosis. Mouse cardiomyocytes were treated with LPS (4 µg/mL) for 6 h in the absence or presence of CAR (10 μM) in vitro. We found that addition of CAR suppressed LPS-induced defect in cardiomyocyte shortening, which was nullified by the Nrf2 inhibitor ML-385 or the NF-κB activator prostratin. Taken together, our results suggest that CAR administration protects against LPS-induced cardiac contractile abnormality, oxidative stress, apoptosis, and inflammation through Nrf2- and NF-κB-dependent mechanism.Keywords
This publication has 59 references indexed in Scilit:
- Recurrent Exposure to Subclinical Lipopolysaccharide Increases Mortality and Induces Cardiac Fibrosis in MicePLOS ONE, 2013
- Experimental Therapeutics of Nrf2 as a Target for Prevention of Bacterial Exacerbations in COPDProceedings of the American Thoracic Society, 2012
- Retracted: Activation of Akt Rescues Endoplasmic Reticulum Stress-Impaired Murine Cardiac Contractile Function via Glycogen Synthase Kinase-3β-Mediated Suppression of Mitochondrial Permeation Pore OpeningAntioxidants and Redox Signaling, 2011
- Effects of a Potent Peroxynitrite Decomposition Catalyst in Murine Models of Endotoxemia and SepsisShock, 2011
- Up-regulation of p27kip1 contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophyCardiovascular Research, 2011
- Cardiac overexpression of metallothionein rescues cardiac contractile dysfunction and endoplasmic reticulum stress but not autophagy in sepsisJournal of Molecular and Cellular Cardiology, 2010
- Aldehyde dehydrogenase-2 (ALDH2) ameliorates chronic alcohol ingestion-induced myocardial insulin resistance and endoplasmic reticulum stressJournal of Molecular and Cellular Cardiology, 2009
- Peroxynitrite mediates the failure of neutrophil migration in severe polymicrobial sepsis in miceBritish Journal of Pharmacology, 2007
- Cardamonin inhibits COX and iNOS expression via inhibition of p65NF-κB nuclear translocation and Iκ-B phosphorylation in RAW 264.7 macrophage cellsMolecular Immunology, 2007
- A burning issue: do sepsis and systemic inflammatory response syndrome (SIRS) directly contribute to cardiac dysfunction?Frontiers in Bioscience-Landmark, 2006