线粒体HIGD1A表达受抑加重多柔比星引起的H9c2心肌细胞焦亡OA

AIM:Doxorubicin(DOX)-induced heart failure is a serious complication in tumor chemotherapy,but the underlying mechanisms are not well clarified.This study aimed to investigate whether and how the mitochondrial hypoxia-induced gene domain family member 1A(HIGD1A)plays a role in DOX-induced cardiomyocyte injury especially pyroptosis.METHODS:H9c2 cardiomyocytes were cultured and treated with DOX for 24 h to induce cardiomyocyte inju-ry.The cells were divided into seven groups according to the treatment(s):control,DOX,siNC,Higd1a siRNA(si-Higd1a),siNC+DOX,si Higd1a+DOX,and si Higd1a+DOX+MCC950[a nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inhibitor].DHE staining was performed to measure intracellular reactive oxygen species(ROS),TMRE staining was used to evaluate mitochondrial function,Western blot was employed to detect the expression of pyroptosis-related proteins,and lactate dehydrogenase(LDH)release was detected to evaluate cardiomyocyte injury.RESULTS:DOX markedly repressed the expression of HIGD1A both at the mRNA and the protein levels(P<0.05),and significantly decreased the viability of H9c2 cardiomyocytes(P<0.01),compared to the control group.Silencing of Higd1a by siRNA exacerbated DOX-induced ROS generation,declined mitochondrial membrane potential(P<0.01),in-creased the expressions of pyroptosis markers including NLRP3,gasdermin D cleaved fragment,cleaved caspase-1 and in-terleukin-18(P<0.01),and promoted LDH release(P<0.01).Treatment with MCC950 to inhibit NLRP3 partially re-versed cardiomyocyte pyroptosis caused by Higd1a silencing(P<0.05).CONCLUSION:Repressed HIGD1A expres-sion is responsible for DOX-induced mitochondrial dysfunction and pyroptosis of H9c2 cardiomyocytes.Inhibiting NLRP3 by MCC950 partially reverses DOX-induced HIGD1A downregulation and cardiomyocyte pyroptosis.