RNA-seq analysis revealed that crizotinib-induced cardiomyocyte death, and cardiac dysfunctionapoptosis is related to autophagosome-lysosome fusion and mitochondrial injury
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ABSTRACT:
PROVIDER: PRJNA864058 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20723948_1.fastq.gz | Fastqsanger.gz | |||
| SRR20723948_2.fastq.gz | Fastqsanger.gz | |||
| SRR20723949_1.fastq.gz | Fastqsanger.gz | |||
| SRR20723949_2.fastq.gz | Fastqsanger.gz | |||
| SRR20723950_1.fastq.gz | Fastqsanger.gz |
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Project description:Crizotinib, a widely used dual ALK/MET/ROS1 inhibitor, have been seriously limited due to cardiac adverse effects. Here, we found that crizotinib caused left ventricular dysfunction, structural damage and pathological remodeling in mice and induced cardiomyocyte apoptosis and mitochondrial injury. Here, we demonstrated that crizotinib lead to aberrant accumulation of MET protein by interrupting autophagosome-lysosome fusion and knockdown of MET expression or re-activating autophagy flux rescued the cardiomyocytes death and mitochondrial injury caused by crizotinib. We identified that inhibition of the phosphorylation of AMPKSer485/491 reduced the transcriptional level of genes required for autophagosome-lysosome fusion by inhibiting the nuclear localization of FoxO1. Recovering the phosphorylation of AMPKSer485/491 by AAV-mediated overexpression of the AMPK (T485D) or metformin treatment rescued the cardiotoxicity caused by crizotinib.
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Project description:Cardiac dysfunction is a serious complication of sepsis-induced multiorgan failure in intensive care units and is characterized by an uncontrolled immune response to overwhelming infection. Type 2 innate lymphoid cells (ILC2s), as a part of the innate immune system, play a crucial role in the inflammatory process of heterogeneous cardiac disorders. However, the role of ILC2 in regulating sepsis-induced cardiac dysfunction and its underlying mechanism remain unknown. The present study demonstrated that autophagic flux blockage exacerbated inflammatory response and cardiac dysfunction, which was associated with mortality of sepsis. Using a cecal ligation and puncture (CLP) mouse sepsis model, we observed an expansion of ILC2s in the septic heart. Furthermore, IL-4 derived from ILC2 mitigated cardiac inflammatory responses and improved cardiac function during sepsis. Additionally, IL-4 restored the impaired autophagic flux and enhanced lysosomal-associated membrane protein 2 (LAMP2) expression to stabilize lysosomal homeostasis during sepsis. Notably, LAMP2 preferentially bound to Flotillin2 (FLOT2) after IL-4 exposure and the interaction enhanced autophagosome-lysosome fusion in cardiac endothelial cells. Loss of FLOT2 reversed the regulatory effects of LAMP2 on autophagy mediated by IL-4, leading to autophagosome accumulation and suppressed autophagosome clearance. Conclusively, these findings provide novel insights that ILC2 regulates incomplete autophagic flux to protect septic heart and expand our understanding of immunoregulation for sepsis.
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Project description:Mutations in lysosomal-associated membrane protein 2 (LAMP-2) gene are associated with Danon disease, which often leads to cardiomyopathy/heart failure through poorly defined mechanisms. Here, we identify the LAMP-2 isoform B (LAMP-2B) as required for autophagosome-lysosome fusion in human cardiomyocytes (CMs). Remarkably, LAMP-2B functions independently of syntaxin 17 (STX17), a protein that is essential for autophagosome-lysosome fusion in non-CMs. Instead, LAMP-2B interacts with autophagy related 14 (ATG14) and vesicle-associated membrane protein 8 (VAMP8) through its C-terminal coiled coil domain (CCD) to promote autophagic fusion. CMs derived from induced pluripotent stem cells (hiPSC-CMs) from Danon patients exhibit decreased colocalization between ATG14 and VAMP8, profound defects in autophagic fusion, as well as mitochondrial and contractile abnormalities. This phenotype was recapitulated by LAMP-2B knockout in non-Danon hiPSC-CMs. Finally, gene correction of LAMP-2 mutation rescues the Danon phenotype. These findings reveal a STX17-independent autophagic fusion mechanism in human CMs, providing an explanation for cardiomyopathy in Danon patients and a foundation for targeting defective LAMP-2B-mediated autophagy to treat this patient population.
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Project description:Autophagy, a conserved catabolic process implicated in a diverse array of human diseases, requires efficient fusion between autophagosomes and lysosomes to function effectively. Recently, SNAP47 has been identified as a key component of the default SNARE complex mediating autophagosome-lysosome fusion in both bulk and selective autophagy. However, the spatiotemporal regulatory mechanisms of this SNARE complex remain unknown. In this study, we found that SNAP47 undergoes acetylation followed by deacetylation during bulk autophagy and mitophagy. The acetylation status of SNAP47 is regulated by the acetyltransferase CBP and the deacetylase HDAC2. Notably, the spatiotemporal regulatory dynamics of SNAP47 acetylation differ between bulk autophagy and mitophagy due to distinct regulation on the activity of acetyltransferase and deacetylase. Acetylated SNAP47 inhibits autophagosome-lysosome fusion by indirectly impeding SNARE complex assembly. Mechanistically, deacetylated SNAP47 recruits HOPS components to autophagic vacuoles, while acetylated SNAP47 inhibits this recruitment, consequently leading to the failure of SNARE complex assembly. Taken together, our study uncovers a SNAP47 acetylation-dependent regulatory mechanism governing autophagosome-lysosome fusion by modulating the recruitment of HOPS to autophagic vacuoles.
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Project description:Crizotinib, a small-molecule tyrosine kinase inhibitor targeting ALK, MET and ROS1, is the first-line drug for ALK-positive metastatic non-small cell lung cancer and is associated with severe, sometimes fatal, cases of cardiac failure, which increases the risk of mortality. However, the underlying mechanism remains unclear, which causes the lack of therapeutic strategy. We established in vitro and in vivo models for crizotinib-induced cardiotoxicity and found that crizotinib caused left ventricular dysfunction, myocardial injury and pathological remodeling in mice and induced cardiomyocyte apoptosis and mitochondrial injury. In addition, we found that crizotinib prevented the degradation of MET protein by interrupting autophagosome-lysosome fusion and silence of MET or re-activating macroautophagy/autophagy flux rescued the cardiomyocytes death and mitochondrial injury caused by crizotinib, suggesting that impaired autophagy activity is the key reason for crizotinib-induced cardiotoxicity. We further confirmed that recovering the phosphorylation of PRKAA/AMPK (Ser485/491) by metformin re-activated autophagy flux in cardiomyocytes and metformin rescued crizotinib-induced cardiomyocyte injury and cardiac complications. In summary, we revealed a novel mechanism for crizotinib-induced cardiotoxicity, wherein the crizotinib-impaired autophagy process causes cardiomyocyte death and cardiac injury by inhibiting the degradation of MET protein, demonstrated a new function of impeded autophagosome-lysosome fusion in drugs-induced cardiotoxicity, pointed out the essential role of the phosphorylation of PRKAA (Ser485/491) in autophagosome-lysosome fusion and confirmed metformin as a potential therapeutic strategy for crizotinib-induced cardiotoxicity.Abbreviations and Acronyms: AAV: adeno-associated virus; ACAC/ACC: acetyl-Co A carboxylase; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATG7: autophagy related 7; CHX: cycloheximide; CKMB: creatine kinase myocardial band; CQ: chloroquine; c-PARP: cleaved poly (ADP-ribose) polymerase; DAPI: 4'6-diamidino-2-phenylindole; EF: ejection fraction; FOXO: forkhead box O; FS: fractional shortening; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HF: heart failure; HW: TL: ratio of heart weight to tibia length; IR: ischemia-reperfusion; KEGG: Kyoto encyclopedia of genes and genomes; LAMP2: lysosomal-associated membrane protein 2; LDH: lactate dehydrogenase; MCMs: mouse cardiomyocytes; MMP: mitochondrial membrane potential; mtDNA: mitochondrial DNA; MYH6: myosin, heavy peptide 6, cardiac muscle, alpha; MYH7: myosin, heavy peptide 7, cardiac muscle, beta; NPPA: natriuretic peptide type A; NPPB: natriuretic peptide type B; PI: propidium iodide; PI3K: phosphoinositide 3-kinase; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; qPCR: quantitative real-time PCR; SD: standard deviation; SRB: sulforhodamine B; TKI: tyrosine kinase inhibitor; WGA: wheat germ agglutinin.
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Project description:Some antihistamines have exhibited significant antitumor activity alone or in combination with other therapies in in vitro and clinical studies. However, the underlying mechanisms of how antihistamines inhibit hepatocellular carcinoma proliferation are still unknown. We first screened the antiproliferation activity of 12 benzocycloheptene structural-analogue drugs, and results showed that deptropine was the most potent inhibitor of both Hep3B and HepG2 human hepatoma cells. Deptropine significantly increased light chain 3B-II (LC3B-II) expression but did not induce sequestosome 1 (SQSTM1/p62) degradation in either cell line. Interestingly, other autophagy-related proteins, such as autophagy-related 7 (ATG7), vacuolar protein sorting 34 (VPS34), phosphorylated adenosine 5'-monophosphate-activated protein kinase (AMPK), and phosphorylated protein kinase B (PKB, also known as Akt), exhibited no significant change in either deptropine-treated cell line. Deptropine also inhibited the processing of cathepsin L from its precursor form to its mature form. Immunofluorescence microscopy showed an increase of autophagosomes in deptropine-treated cells, but deptropine blocked the fusion between autophagosomes and lysosomes. In a xenograft nude mice model, 2.5 mg/kg deptropine showed a great inhibitory effect on Hep3B tumor growth. These results suggest that deptropine can induce in vitro and in vivo hepatoma cell death, and the underlying mechanisms might be mediated through inhibiting autophagy by blocking autophagosome-lysosome fusion.
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