Publications by authors named "Yuanfei Luo"

2 Publications

  • Page 1 of 1

FUNDC1 insufficiency sensitizes high fat diet intake-induced cardiac remodeling and contractile anomaly through ACSL4-mediated ferroptosis.

Metabolism 2021 Sep 29;122:154840. Epub 2021 Jul 29.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address:

Objective: Ferroptosis is indicated in cardiovascular diseases. Given the prominent role of mitophagy in the governance of ferroptosis and our recent finding for FUN14 domain containing 1 (FUNDC1) in obesity anomalies, this study evaluated the impact of FUNDC1 deficiency in high fat diet (HFD)-induced cardiac anomalies.

Methods And Materials: WT and FUNDC1 mice were fed HFD (45% calorie from fat) or low fat diet (LFD, 10% calorie from fat) for 10 weeks in the presence of the ferroptosis inhibitor liproxstatin-1 (LIP-1, 10 mg/kg, i.p.).

Results: RNAseq analysis for differentially expressed genes (DEGs) reported gene ontology term related to ferroptosis and mitophagy in obese rat hearts, which was validated in obese rodent and human hearts. Although 10-week HFD intake did not alter global metabolism, cardiac geometry and function, ablation of FUNDC1 unmasked metabolic derangement, pronounced cardiac remodeling, contractile, intracellular Ca and mitochondrial anomalies upon HFD challenge, the effects of which with exception of global metabolism were attenuated or mitigated by LIP-1. FUNDC1 ablation unmasked HFD-evoked rises in fatty acid synthase ACSL4, necroptosis, inflammation, ferroptosis, mitochondrial O production, and mitochondrial injury as well as dampened autophagy and DNA repair enzyme 8-oxoG DNA glycosylase 1 (OGG1) but not apoptosis, the effect of which except ACSL4 and its regulator SP1 was reversed by LIP-1. In vitro data noted that arachidonic acid, an ACSL4 substrate, provoked cytochrome C release, cardiomyocyte defect, and lipid peroxidation under FUNDC1 deficiency, the effects were interrupted by inhibitors of SP1, ACSL4 and ferroptosis.

Conclusions: These data suggest that FUNDC1 deficiency sensitized cardiac remodeling and dysfunction with short-term HFD exposure, likely through ACSL4-mediated regulation of ferroptosis.
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http://dx.doi.org/10.1016/j.metabol.2021.154840DOI Listing
September 2021

CD74 knockout protects against LPS-induced myocardial contractile dysfunction through AMPK-Skp2-SUV39H1-mediated demethylation of BCLB.

Br J Pharmacol 2020 04 11;177(8):1881-1897. Epub 2020 Feb 11.

Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Fudan University Zhongshan Hospital, Shanghai, China.

Background And Purpose: Lipopolysaccharides (LPS), an outer membrane component of Gram-negative bacteria, triggers myocardial anomalies in sepsis. Recent findings indicated a role for inflammatory cytokine MIF and its receptor, CD74, in septic organ injury, although little is known of the role of MIF-CD74 in septic cardiomyopathy.

Experimental Approach: This study evaluated the impact of CD74 ablation on endotoxaemia-induced cardiac anomalies. Echocardiographic, cardiomyocyte contractile and intracellular Ca properties were examined.

Key Results: Our data revealed compromised cardiac function (lower fractional shortening, enlarged LV end systolic diameter, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged duration of relengthening and intracellular Ca mishandling) and ultrastructural derangement associated with inflammation, O production, apoptosis, excess autophagy, phosphorylation of AMPK and JNK and dampened mTOR phosphorylation. These effects were attenuated or mitigated by CD74 knockout. LPS challenge also down-regulated Skp2, an F-box component of Skp1/Cullin/F-box protein-type ubiquitin ligase, while up-regulating that of SUV39H1 and H3K9 methylation of the Bcl2 protein BCLB. These effects were reversed by CD74 ablation. In vitro study revealed that LPS facilitated GFP-LC3B formation and cardiomyocyte defects. These effects were prevented by CD74 ablation. Interestingly, the AMPK activator AICAR, the autophagy inducer rapamycin and the demethylation inhibitor difenoconazole inhibited the effects of CD74 ablation against LPS-induced cardiac dysfunction, while the SUV39H1 inhibitor chaetocin or methylation inhibitor 5-AzaC ameliorated LPS-induced GFP-LC3B formation and cardiomyocyte contractile dysfunction.

Conclusion And Implications: Our data suggested that CD74 ablation protected against LPS-induced cardiac anomalies, O production, inflammation and apoptosis through suppression of autophagy in a Skp2-SUV39H1-mediated mechanism.
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http://dx.doi.org/10.1111/bph.14959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070165PMC
April 2020
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