The international journal of biochemistry & cell biology · 2026
Midkine, a heparin-binding growth factor, exacerbates heart failure in dilated cardiomyopathy via NRXN1 regulation and inflammatory responses.
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Cui Yuhui, Wu Chunrong, Huang Liou, Qi Yue, Tang Jianguo
Аннотация
OBJECTIVE: Dilated cardiomyopathy (DCM) is the most prevalent cardiomyopathy and a leading cause of heart failure worldwide. Midkine (MDK), a conserved heparin-binding growth factor with antiapoptotic, proangiogenic, anti-infective, and proinflammatory functions, has been implicated in inflammatory and fibrotic diseases. Its specific roles and mechanisms in DCM pathogenesis remain unclear.
MATERIALS AND METHODS: A doxorubicin (DOX)-induced mouse model and DOX-treated HL-1 cardiomyocytes were used to investigate the effects of MDK on DCM progression. Myocardial injury and fibrosis were evaluated using hematoxylin and eosin (HE), Picrosirius Red (PSR), and Masson's trichrome staining. MDK and Neurexin-1 (NRXN1) localization in cardiac tissues was assessed through immunofluorescence. Cell viability, apoptosis, and surface area were measured by Cell Counting Kit-8 (CCK-8), flow cytometry, TUNEL, and Actin-Red staining. mRNA and protein levels were quantified by RT-qPCR and western blotting.
RESULTS: MDK expression was significantly elevated in both DOX-induced DCM and HL-1 cells. Exogenous MDK administration aggravated myocardial injury, interstitial fibrosis, and cardiomyocyte apoptosis in vivo, and reduced cell viability while increasing apoptosis and cell surface in vitro. Mechanistically, MDK markedly enhanced DOX-induced upregulation of NRXN1, IL-1β, IL-6, TNF-α, NLRP3, ANP, BNP, NEU1, cleaved caspase-1/caspase-1, cleaved IL-1β, cleaved caspase-3/caspase-3; while attenuating DOX-induced downregulation of NRG1, NEXN, and SYNE1 in vivo and in vitro.
CONCLUSION: MDK promotes DCM-associated heart failure through NRXN1 upregulation and enhanced inflammatory responses, highlighting itself as a potential therapeutic target for DCM.
MATERIALS AND METHODS: A doxorubicin (DOX)-induced mouse model and DOX-treated HL-1 cardiomyocytes were used to investigate the effects of MDK on DCM progression. Myocardial injury and fibrosis were evaluated using hematoxylin and eosin (HE), Picrosirius Red (PSR), and Masson's trichrome staining. MDK and Neurexin-1 (NRXN1) localization in cardiac tissues was assessed through immunofluorescence. Cell viability, apoptosis, and surface area were measured by Cell Counting Kit-8 (CCK-8), flow cytometry, TUNEL, and Actin-Red staining. mRNA and protein levels were quantified by RT-qPCR and western blotting.
RESULTS: MDK expression was significantly elevated in both DOX-induced DCM and HL-1 cells. Exogenous MDK administration aggravated myocardial injury, interstitial fibrosis, and cardiomyocyte apoptosis in vivo, and reduced cell viability while increasing apoptosis and cell surface in vitro. Mechanistically, MDK markedly enhanced DOX-induced upregulation of NRXN1, IL-1β, IL-6, TNF-α, NLRP3, ANP, BNP, NEU1, cleaved caspase-1/caspase-1, cleaved IL-1β, cleaved caspase-3/caspase-3; while attenuating DOX-induced downregulation of NRG1, NEXN, and SYNE1 in vivo and in vitro.
CONCLUSION: MDK promotes DCM-associated heart failure through NRXN1 upregulation and enhanced inflammatory responses, highlighting itself as a potential therapeutic target for DCM.