Heart failure(HF)patients in general have a higher risk of developing cancer.Several animal studies have indicated that cardiac remodeling and HF remarkably accelerate tumor progression,highlighting a cause-and-effect...Heart failure(HF)patients in general have a higher risk of developing cancer.Several animal studies have indicated that cardiac remodeling and HF remarkably accelerate tumor progression,highlighting a cause-and-effect relationship between these two disease entities.Targeting ferroptosis,a prevailing form of non-apoptotic cell death,has been considered a promising therapeutic strategy for human cancers.Exosomes critically contribute to proximal and distant organ-organ communications and play crucial roles in regulating diseases in a paracrine manner.However,whether exosomes control the sensitivity of cancer to ferroptosis via regulating the cardiomyocyte-tumor cell crosstalk in ischemic HF has not yet been explored.Here,we demonstrate that myocardial infarction(MI)decreased the sensitivity of cancer cells to the canonical ferroptosis activator erastin or imidazole ketone erastin in a mouse model of xenograft tumor.Post-MI plasma exosomes potently blunted the sensitivity of tumor cells to ferroptosis inducers both in vitro in mouse Lewis lung carcinoma cell line LLC and osteosarcoma cell line K7M2 and in vivo with xenograft tumorigenesis model.The expression of miR-22-3p in cardiomyocytes and plasma-exosomes was significantly upregulated in the failing hearts of mice with chronic MI and of HF patients as well.Incubation of tumor cells with the exosomes isolated from post-MI mouse plasma or overexpression of miR-22-3p alone abrogated erastin-induced ferroptotic cell death in vitro.Cardiomyocyte-enriched miR-22-3p was packaged in exosomes and transferred into tumor cells.Inhibition of cardiomyocyte-specific miR-22-3p by AAV9 sponge increased the sensitivity of cancer cells to ferroptosis.ACSL4,a pro-ferroptotic gene,was experimentally established as a target of miR-22-3p in tumor cells.Taken together,our findings uncovered for the first time that MI suppresses erastin-induced ferroptosis through releasing miR-22-3p-enriched exosomes derived from cardiomyocytes.Therefore,targeting exosome-mediated cardiomyocyte/tumor pathological communication may offer a novel approach for the ferroptosis-based antitumor therapy.展开更多
Hypoxia is beneficial for the differentiation of stem cells transplanted for myocardial injury,but mechanisms underlying this benefit remain unsolved. Here, we report the impact of hypoxia-induced Jagged1 expression i...Hypoxia is beneficial for the differentiation of stem cells transplanted for myocardial injury,but mechanisms underlying this benefit remain unsolved. Here, we report the impact of hypoxia-induced Jagged1 expression in cardiomyocytes(CMs) for driving the differentiation of cardiac stem cells(CSCs).Forced hypoxia-inducible factor 1α(HIF-1α) expression and physical hypoxia(5% O_2) treatment could induce Jagged1 expression in neonatal rat CMs. Pharmacological inhibition of HIF-1α by YC-1 attenuated hypoxia-promoted Jagged1 expression in CMs. An ERK inhibitor(PD98059), but not inhibitors of JNK(SP600125), Notch(DAPT), NF-κB(PTDC), JAK(AG490), or STAT3(Stattic) suppressed hypoxiainduced Jagged1 protein expression in CMs. c-Kit^+ CSCs isolated from neonatal rat hearts using a magnetic-activated cell sorting method expressed GATA4, SM22α or vWF, but not Nkx2.5 and cTnI.Moreover, 87.3% of freshly isolated CSCs displayed Notch1 receptor expression. Direct co-culture of CMs with BrdU-labeled CSCs enhanced CSCs differentiation, as evidenced by an increased number of BrdU^+/Nkx2.5^+ cells, while intermittent hypoxia for 21 days promoted co-culture-triggered differentiation of CSCs into CM-like cells. Notably, YC-1 and DAPT attenuated hypoxia-induced differentiation.Our results suggest that hypoxia induces Jagged1 expression in CMs primarily through ERK signaling,and facilitates early cardiac lineage differentiation of CSCs in CM/CSC co-cultures via HIF-1α/Jagged1/Notch signaling.展开更多
基金the National Natural Science Fund of China(U21A20339,82273928,82273026)CAMS Innovation Fund for Medical Sciences(CIFMS)2019-I2M-5-078+2 种基金Outstanding Youth Project of Natural Science Fund of Heilongjiang Province(YQ2020H010,YQ2020H019)Heilongjiang Innovative Talent Training Fund for Young Teachers(to Ye Yuan in 2020)College of Pharmacy,Harbin Medical University,Excellent Young Talents Funding(2019-YQ-13).
文摘Heart failure(HF)patients in general have a higher risk of developing cancer.Several animal studies have indicated that cardiac remodeling and HF remarkably accelerate tumor progression,highlighting a cause-and-effect relationship between these two disease entities.Targeting ferroptosis,a prevailing form of non-apoptotic cell death,has been considered a promising therapeutic strategy for human cancers.Exosomes critically contribute to proximal and distant organ-organ communications and play crucial roles in regulating diseases in a paracrine manner.However,whether exosomes control the sensitivity of cancer to ferroptosis via regulating the cardiomyocyte-tumor cell crosstalk in ischemic HF has not yet been explored.Here,we demonstrate that myocardial infarction(MI)decreased the sensitivity of cancer cells to the canonical ferroptosis activator erastin or imidazole ketone erastin in a mouse model of xenograft tumor.Post-MI plasma exosomes potently blunted the sensitivity of tumor cells to ferroptosis inducers both in vitro in mouse Lewis lung carcinoma cell line LLC and osteosarcoma cell line K7M2 and in vivo with xenograft tumorigenesis model.The expression of miR-22-3p in cardiomyocytes and plasma-exosomes was significantly upregulated in the failing hearts of mice with chronic MI and of HF patients as well.Incubation of tumor cells with the exosomes isolated from post-MI mouse plasma or overexpression of miR-22-3p alone abrogated erastin-induced ferroptotic cell death in vitro.Cardiomyocyte-enriched miR-22-3p was packaged in exosomes and transferred into tumor cells.Inhibition of cardiomyocyte-specific miR-22-3p by AAV9 sponge increased the sensitivity of cancer cells to ferroptosis.ACSL4,a pro-ferroptotic gene,was experimentally established as a target of miR-22-3p in tumor cells.Taken together,our findings uncovered for the first time that MI suppresses erastin-induced ferroptosis through releasing miR-22-3p-enriched exosomes derived from cardiomyocytes.Therefore,targeting exosome-mediated cardiomyocyte/tumor pathological communication may offer a novel approach for the ferroptosis-based antitumor therapy.
基金supported by grants from the National Natural Science Foundation of China (Grant Nos.81170121,81460042,81541004 and 81670254)Science and Technology Project of Guangdong Province (2016A020214016)+1 种基金YangFan Plan of Guangdong Province (4YF16007G)Excellent Graduate Student Training Program of Guangdong Medical University (YS2014013)
文摘Hypoxia is beneficial for the differentiation of stem cells transplanted for myocardial injury,but mechanisms underlying this benefit remain unsolved. Here, we report the impact of hypoxia-induced Jagged1 expression in cardiomyocytes(CMs) for driving the differentiation of cardiac stem cells(CSCs).Forced hypoxia-inducible factor 1α(HIF-1α) expression and physical hypoxia(5% O_2) treatment could induce Jagged1 expression in neonatal rat CMs. Pharmacological inhibition of HIF-1α by YC-1 attenuated hypoxia-promoted Jagged1 expression in CMs. An ERK inhibitor(PD98059), but not inhibitors of JNK(SP600125), Notch(DAPT), NF-κB(PTDC), JAK(AG490), or STAT3(Stattic) suppressed hypoxiainduced Jagged1 protein expression in CMs. c-Kit^+ CSCs isolated from neonatal rat hearts using a magnetic-activated cell sorting method expressed GATA4, SM22α or vWF, but not Nkx2.5 and cTnI.Moreover, 87.3% of freshly isolated CSCs displayed Notch1 receptor expression. Direct co-culture of CMs with BrdU-labeled CSCs enhanced CSCs differentiation, as evidenced by an increased number of BrdU^+/Nkx2.5^+ cells, while intermittent hypoxia for 21 days promoted co-culture-triggered differentiation of CSCs into CM-like cells. Notably, YC-1 and DAPT attenuated hypoxia-induced differentiation.Our results suggest that hypoxia induces Jagged1 expression in CMs primarily through ERK signaling,and facilitates early cardiac lineage differentiation of CSCs in CM/CSC co-cultures via HIF-1α/Jagged1/Notch signaling.
