Publications by authors named "Yaguang Bi"

11 Publications

  • Page 1 of 1

NDP52 Protects against Myocardial Infarction-Provoked Cardiac Anomalies through Promoting Autophagosome-Lysosome Fusion via Recruiting TBK1 and RAB7.

Antioxid Redox Signal 2021 Aug 12. Epub 2021 Aug 12.

Zhongshan Hospital Fudan University, 92323, Cardiology, Shanghai, Shanghai, China.

Aims: Acute myocardial infarction (MI), caused by acute coronary artery obstruction, is a common cardiovascular event leading to mortality. Nuclear dot protein 52 (NDP52) is an essential selective autophagy adaptor, although its function in MI is still obscure. This study was designed to examine the function of NDP52 in MI and the associated mechanisms.

Results: Our results revealed that MI challenge overtly impaired myocardial geometry and systolic function, along with cardiomyocyte apoptosis, myocardial interstitial fibrosis, and mitochondrial damage, and NDP52 nullified such devastating responses. Further studies showed the blockade of mitochondrial clearance is related to MI-induced buildup of damaged mitochondria. Mechanistic approaches depicted that 7-day MI induced abnormal mitophagy flux, resulting in poor lysosomal clearance of injured mitochondria. NDP52 promoted mitophagy flux through recruitment of RAB7 and TBK1. Upon protein colocalization, TBK1 phosphorylated RAB7, in line with the finding that chloroquine or a TBK1 inhibitor reversed NDP52-dependent beneficial responses.

Innovation: This study denoted a novel mechanism that NDP52 promotes cardioprotection against ischemic heart diseases through interaction with TBK1 and RAB7, leading to RAB7 phosphorylation, induction of mitophagy to clear ischemia-induced impaired mitochondria, thus preventing cardiomyocyte apoptosis in MI.

Conclusion: Our results indicate that NDP52 promotes autophagic flux and clears damaged mitochondria to diminish ROS and cell death in a TBK1/RAB7-dependent manner and thus limits MI induced injury.
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http://dx.doi.org/10.1089/ars.2020.8253DOI Listing
August 2021

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

Dysregulation of iron metabolism in cardiovascular diseases: From iron deficiency to iron overload.

Biochem Pharmacol 2021 Aug 23;190:114661. Epub 2021 Jun 23.

Department of Cardiology and 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:

Iron deficiency and iron overload are the most prevalent and opposite forms of dysregulated iron metabolism that affect approximately 30 percent of the world population, in particularly, elderly and patients with chronic diseases. Both iron deficiency and overload are frequently observed in a wide range of cardiovascular diseases, contributing to the onset and progression of these diseases. One of the devastating seqeulae for iron overload is the induction of ferroptosis, a newly defined form of regulated cell death which heavily impacts cardiac function through ferroptotic cell death in cardiomyocytes. In this review, we will aim to evaluate iron deficiency and iron overload in cardiovascular diseases. We will summarize current therapeutic strategies to tackle iron deficiency and iron overload, major pitfalls of current studies, and future perspectives.
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http://dx.doi.org/10.1016/j.bcp.2021.114661DOI Listing
August 2021

ER stress in Cardiometabolic Diseases: from Molecular Mechanisms to Therapeutics.

Endocr Rev 2021 Mar 8. Epub 2021 Mar 8.

University of Wyoming College of Health Sciences, Laramie, USA.

The endoplasmic reticulum (ER) hosts linear polypeptides and fosters natural folding of proteins through ER-residing chaperones and enzymes. Failure of the ER to align and compose proper protein architecture leads to accumulation of misfolded/unfolded proteins in the ER lumen, which disturbs ER homeostasis to provoke ER stress. Presence of ER stress initiates the cytoprotective unfolded protein response (UPR) to restore ER homeostasis or instigates a rather maladaptive UPR to promote cell death. Although a wide array of cellular processes such as persistent autophagy, dysregulated mitophagy, and secretion of pro-inflammatory cytokines may contribute to the onset and progression of cardiometabolic diseases, it is well perceived that ER stress also evokes onset and development of cardiometabolic diseases, particularly, cardiovascular diseases, diabetes mellitus, obesity, and chronic kidney disease. Meanwhile, these pathological conditions further aggravate ER stress, creating a rather vicious cycle. Here in this review, we aimed at summarizing and updating the available information on ER stress in cardiovascular diseases, diabetes mellitus, obesity, and chronic kidney disease, hoping to offer novel insights for the management of these cardiometabolic comorbidities through regulation of ER stress.
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http://dx.doi.org/10.1210/endrev/bnab006DOI Listing
March 2021

Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases.

Nat Rev Cardiol 2021 Jul 22;18(7):499-521. Epub 2021 Feb 22.

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

Cardiovascular diseases (CVDs), such as ischaemic heart disease, cardiomyopathy, atherosclerosis, hypertension, stroke and heart failure, are among the leading causes of morbidity and mortality worldwide. Although specific CVDs and the associated cardiometabolic abnormalities have distinct pathophysiological and clinical manifestations, they often share common traits, including disruption of proteostasis resulting in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). ER proteostasis is governed by the unfolded protein response (UPR), a signalling pathway that adjusts the protein-folding capacity of the cell to sustain the cell's secretory function. When the adaptive UPR fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis. ER stress functions as a double-edged sword, with long-term ER stress resulting in cellular defects causing disturbed cardiovascular function. In this Review, we discuss the distinct roles of the UPR and ER stress response as both causes and consequences of CVD. We also summarize the latest advances in our understanding of the importance of the UPR and ER stress in the pathogenesis of CVD and discuss potential therapeutic strategies aimed at restoring ER proteostasis in CVDs.
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http://dx.doi.org/10.1038/s41569-021-00511-wDOI Listing
July 2021

SARS-CoV-2 and cardiovascular complications: From molecular mechanisms to pharmaceutical management.

Biochem Pharmacol 2020 08 21;178:114114. Epub 2020 Jun 21.

Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY 82071 USA; Department of Pathology, University of Washington Seattle, Seattle, WA, USA. Electronic address:

The coronavirus disease 2019 (COVID-19), elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a pandemic public health emergency of global concern. Other than the profound severe pulmonary damage, SARS-CoV-2 infection also leads to a series of cardiovascular abnormalities, including myocardial injury, myocarditis and pericarditis, arrhythmia and cardiac arrest, cardiomyopathy, heart failure, cardiogenic shock, and coagulation abnormalities. Meanwhile, COVID-19 patients with preexisting cardiovascular diseases are often at a much higher risk of increased morbidity and mortality. Up-to-date, a number of mechanisms have been postulated for COVID-19-associated cardiovascular damage including SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) activation, cytokine storm, hypoxemia, stress and cardiotoxicity of antiviral drugs. In this context, special attention should be given towards COVID-19 patients with concurrent cardiovascular diseases, and special cardiovascular attention is warranted for treatment of COVID-19.
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http://dx.doi.org/10.1016/j.bcp.2020.114114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306106PMC
August 2020

Double knockout of Akt2 and AMPK accentuates high fat diet-induced cardiac anomalies through a cGAS-STING-mediated mechanism.

Biochim Biophys Acta Mol Basis Dis 2020 10 5;1866(10):165855. Epub 2020 Jun 5.

Department of Cardiology, Fudan University Zhongshan Hospital, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Fudan University Zhongshan Hospital, Shanghai 200032, China. Electronic address:

High fat diet intake contributes to undesired cardiac geometric and functional changes although the underlying mechanism remains elusive. Akt and AMPK govern to cardiac homeostasis. This study examined the impact of deletion of Akt2 (main cardiac isoform of Akt) and AMPKα2 on high fat diet intake-induced cardiac remodeling and contractile anomalies and mechanisms involved. Cardiac geometry, contractile, and intracellular Ca properties were evaluated using echocardiography, IonOptix® edge-detection and fura-2 techniques in wild-type (WT) and Akt2-AMPK double knockout (DKO) mice receiving low fat (LF) or high fat (HF) diet for 4 months. Our results revealed that fat diet intake elicit obesity, cardiac remodeling (hypertrophy, LV mass, LVESD, and cross-sectional area), contractile dysfunction (fractional shortening, peak shortening, maximal velocity of shortening/relengthening, time-to-90% relengthening, and intracellular Ca handling), ultrastructural disarray, apoptosis, O, inflammation, dampened autophagy and mitophagy. Although DKO did not affect these parameters, it accentuated high fat diet-induced cardiac remodeling and contractile anomalies. High fat intake upregulated levels of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and STING phosphorylation while suppressing phosphorylation of ULK1 (Ser and Ser), with a more pronounced effect in DKO mice. In vitro data revealed that inhibition of cGAS and STING using PF-06928215 and Astin C negated palmitic acid-induced cardiomyocyte contractile dysfunction. Biological function analysis for all differentially expressed genes (DEGs) depicted that gene ontology terms associated with Akt and AMPK signaling processes were notably changed in high fat-fed hearts. Our data indicate that Akt2-AMPK ablation accentuated high fat diet-induced cardiac anomalies possibly through a cGAS-STING-mechanism.
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http://dx.doi.org/10.1016/j.bbadis.2020.165855DOI Listing
October 2020

Enzyme-based autophagy in anti-neoplastic management: From molecular mechanisms to clinical therapeutics.

Biochim Biophys Acta Rev Cancer 2020 08 24;1874(1):188366. Epub 2020 Apr 24.

Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address:

Autophagy is an evolutionarily conserved self-cannibalization process commonly found in all eukaryotic cells. Through autophagy, long-lived or damaged organelles, superfluous proteins, and pathogens are sequestered and encapsulated into the double-membrane autophagosomes prior to fusion with lysosomes for ultimate degradation and recycling. Given that autophagy is deemed both protective and detrimental in malignancies, the clinical therapeutic utilization of autophagy modulators in cancer has attracted immense attentions over the past decades. Dependence of tumor cells on autophagy during amino acid insufficiency or deprivation has prompted us to explore the underlying autophagy regulatory mechanisms to inject amino acid degrading enzymes and enzyme-based strategies into therapeutic maneuvers of autophagy in cancer.
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http://dx.doi.org/10.1016/j.bbcan.2020.188366DOI Listing
August 2020

Phosphoinositide 3-kinase therapy in diabetic cardiomyopathy: unravelling an enigma.

Am J Physiol Heart Circ Physiol 2020 05 13;318(5):H1029-H1031. Epub 2020 Mar 13.

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

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http://dx.doi.org/10.1152/ajpheart.00160.2020DOI Listing
May 2020

Upregulation of connexin43 by glucose deprivation in H9c2 cells via the extracellular signal‑regulated kinase/mitogen‑activated protein kinase signaling pathway.

Mol Med Rep 2018 Jan 6;17(1):729-734. Epub 2017 Nov 6.

Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China.

Cardiac connexin43 (Cx43) serves an essential role in maintaining the functional integrity of the heart. The present study investigated the effect of glucose deprivation (GD) on Cx43 protein expression levels in H9c2 cells, and demonstrated that following 2 h GD, Cx43 protein expression levels in H9c2 cells increased by ~68%. In addition, GD activated the extracellular signal‑regulated kinase (ERK)/mitogen‑activated protein kinase (MAPK) signaling pathway, which regulated the expression levels of cardiac Cx43. A MAPK inhibitor and U0126, an ERK inhibitor, abolished the effects of GD on Cx43 expression levels. Under GD, the protein expression levels of Beclin‑1, p62 and LC3 were augmented, and were decreased in the presence of ERK inhibitor or siRNA‑ERK. In addition, H9c2 cells exposed to GD exhibited marked increase in LDH release and decreased MTT reduction activity, all of which were not significantly reversed by U0126 treatment. Therefore, the ERK/MAPK signaling pathway may be involved in elevating cardiac Cx43 expression levels under GD in H9c2 cells.
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http://dx.doi.org/10.3892/mmr.2017.7967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780149PMC
January 2018

Low-after-high glucose down-regulated Cx43 in H9c2 cells by autophagy activation via cross-regulation by the PI3K/Akt/mTOR and MEK/ERK signal pathways.

Endocrine 2017 May 8;56(2):336-345. Epub 2017 Feb 8.

Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Purpose: Hypoglycemia in diabetes is a strong predictor of cardiovascular events. High-glucose have been reported to alter connexin43 expression and to promote autophagy in cardiomyocytes. We investigated whether low-after-high glucose would influence connexin43 expression and autophagy in H9c2 cells.

Methods: H9c2 cells were incubated in 33.3 mM glucose for 24 h followed by 2.5 mM glucose for 2, 4, 6, or 12 h with or without chloroquine (autophagy inhibitor), U0126 (MEK inhibitor) or LY294002 (PI3K inhibitor). Cells incubated in 5.5, 33.3, or 2.5 mM glucose with or without inhibitors and in the presence of mannitol were used as controls. Protein expression was assayed by western blot, apoptosis was assayed by flow cytometry, cell proliferation was determined by MTT assays, and cytotoxicity was assayed by lactate dehydrogenase measurement.

Results: Cytotoxicity and early apoptosis were increased and cell proliferation was decreased after exposure to low-after-high glucose, and these results were reversed by chloroquine and U0126 but were aggravated by LY294002. Connexin43 expression was downregulated in a time-dependent manner and was accompanied by upregulated expression of LC3-II, Beclin-1, p62, p-Akt, p-mTOR, and p-ERK. Chloroquine suppressed autophagy and reversed the downregulation of connexin43. U0126 inhibited ERK activation and decreased autophagy proteins expression but increased connexin43 expression. LY294002 suppressed p-Akt, activated autophagy, and decreased connexin43 expression. Interestingly, MEK inhibition also increased p-Akt expression, but inhibition of PI3K led to p-ERK downregulation.

Conclusion: Culturing H9c2 cells under low-after-high glucose downregulated connexin43 by promoting autophagy through a mechanism involving the PI3K/Akt/mTOR and MEK/ERK signaling pathways.
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http://dx.doi.org/10.1007/s12020-017-1251-3DOI Listing
May 2017
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