Ferroptosis and Autophagy-Related Genes in the Pathogenesis of Ischemic Cardiomyopathy

Abstract

BackgroundObesity plays an important role in type 2 diabetes mellitus (T2DM) and myocardial infarction (MI). Ferroptosis and ferritinophagy are related to metabolic pathways, such as fatty acid metabolism and mitochondrial respiration. We aimed to investigate the ferroptosis- and autophagy-related differentially expressed genes (DEGs) that might be potential targets for MI progression.MethodsGSE116250 was analyzed to obtain DEGs. A Venn diagram was used to obtain the overlapping ferroptosis- and autophagy-related DEGs. The enrichment pathway analysis was performed and the hub genes were obtained. Pivotal miRNAs, transcription factors, and drugs with the hub genes interactions were also predicted. The MI mice model was constructed, and qPCR analysis and single-cell sequencing were used to validate the hub genes.ResultsUtilizing the limma package and the Venn diagram, 26 ferroptosis-related and 29 autophagy-related DEGs were obtained. The list of ferroptosis-related DEGs was analyzed, which were involved in the cellular response to a toxic substance, cellular oxidant detoxification, and the IL-17 signaling pathway. The list of autophagy-related DEGs was involved in the regulation of autophagy, the regulation of JAK-STAT signaling pathway, and the regulation of MAPK cascade. In the protein-protein interaction network, the hub DEGs, such as IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, were obtained. After validation using qPCR analysis in the MI mice model and single-cell sequencing, the 10 hub genes can be the potential targets for MI deterioration.ConclusionThe screened hub genes, IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, may be therapeutic targets for patients with MI and may prevent adverse cardiovascular events.

CCR2 inhibitor strengthens the adiponectin effects against myocardial injury after infarction

“…Macrophages are involved in all the CAD stages, including the inflammation response in atherosclerosis, heart failure, and MI. [31][32][33][34] CD169+ macrophage or its receptor Mertk deficiency impaired the mitochondria elimination in the early infarction period, therefore, cardiomyocytes autophagy was impaired, mitochondria were accumulated, and ventricular functions decreased. 35 In addition, macrophages facilitate cardiac electrical conduction via Cx43 and Cx43 conditional deletion in macrophages and congenital lack of macrophages delays atrioventricular conduction.…”

“…Macrophages are involved in all the CAD stages, including the inflammation response in atherosclerosis, heart failure, and MI 31–34 . CD169+ macrophage or its receptor Mertk deficiency impaired the mitochondria elimination in the early infarction period, therefore, cardiomyocytes autophagy was impaired, mitochondria were accumulated, and ventricular functions decreased 35 .…”

Potential diagnostic biomarkers: 6 cuproptosis- and ferroptosis-related genes linking immune infiltration in acute myocardial infarction

“…DUSP1-mediated dephosphorylation of JNK has been shown to have an antiapoptotic effect in myocardial ischemiareperfusion (I/R) injury and has been identified as an immunerelated diagnostic biomarker for AMI [32,53,54]. CDKN1A, also called p21, inhibits cardiomyocyte proliferation through acetylation modification in MI and has been proposed as a potential therapeutic target for MI [55,56]. TLR4, a key pattern recognition receptor, is expressed on macrophages and cardiomyocytes and its elevated expression in MI exacerbates ischemic injury to cardiomyocytes [57], participating in multiple inflammatory signaling pathways [58][59][60][61].…”

Identification of 6 cuproptosis- and ferroptosis-related genes linking immune infiltration as diagnostic biomarkers for acute myocardial infarction

“…CDKN1A, also called p21, has been shown to inhibit cardiomyocyte proliferation by acetylation modi cation in MI [54]. Meanwhile, Zheng Y et al, [55] found CDKN1A may be potential therapeutic targets for patients with MI. TLR4 is a key molecular pattern recognition receptor that is expressed on the cell membrane surface of macrophages and cardiomyocytes.…”