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Inhibition of HMOX1 alleviates diabetic cardiomyopathy by targeting ferroptosis
Huiping Yang1, Gongyi Xiao2,3, Dinghui Wang1
1Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
Insights
Diabetic cardiomyopathy involves ferroptosis, a cell death pathway. Heme oxygenase-1 (HMOX1) exacerbates this, and targeting it may treat diabetic heart disease.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Cell Death Mechanisms
Background:
- Diabetic cardiomyopathy (DCM) is a significant complication of diabetes mellitus, with its underlying pathology and pathogenesis not fully understood.
- Ferroptosis, a regulated form of cell death, is increasingly implicated in various diseases.
Purpose of the Study:
- To investigate the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy.
- To clarify the effect of heme oxygenase-1 (HMOX1) on ferroptosis in DCM and its therapeutic potential.
Main Methods:
- Established in vivo (high-fat diet/streptozotocin) and in vitro (H9C2 cells) models of DCM.
- Utilized transcriptome sequencing, Western blot, qPCR, and biochemical assays to assess ferroptosis markers and cellular changes.
- Investigated the impact of HMOX1 knockdown and ferrostatin-1 treatment.
Main Results:
- The diabetic microenvironment induced ferroptosis in both in vivo and in vitro models, evidenced by altered expression of key proteins (GPX4, SLC7A11, ferritin, PTGS2, ACSL4) and increased oxidative stress markers (MDA, LDH; decreased GSH).
- Heme oxygenase-1 (HMOX1) expression was elevated in DCM, and its knockdown ameliorated ferroptosis, reduced cardiac fibrosis, and improved cardiac function.
- Ferrostatin-1 (Fer-1) effectively reversed ferroptosis in the in vitro model.
Conclusions:
- Ferroptosis plays a crucial role in the pathogenesis of diabetic cardiomyopathy.
- Heme oxygenase-1 (HMOX1) contributes to DCM by promoting ferroptosis, suggesting it as a potential therapeutic target for managing diabetic heart disease.
Abstract:
Diabetic cardiomyopathy (DCM) is an important complication of chronic diabetes mellitus. However, its pathologic process and pathogenesis have not been fully elucidated. This study aims to investigate the role of ferroptosis in DCM and clarify the effect of heme oxygenase-1 (HMOX1) on DCM by targeting ferroptosis. In vivo, an animal model of DCM is established by subjecting mice to a high-fat diet (HFD) combined with low-dose streptozotocin (STZ) injection. We induce an in vitro DCM model by exposing H9C2 cells to high glucose and palmitic acid. Transcriptome sequencing reveals that the differentially expressed genes (DEGs) are enriched primarily in fatty acid metabolism and mitochondrial fatty acid β-oxidation, which are closely related to ferroptosis. The experimental results show that the diabetic microenvironment induces ferroptosis both in vivo and in vitro. Western blot analysis reveals the decreased expressions of the antioxidant proteins GPX4, SLC7A11 and ferritin in the DCM group. However, qPCR demonstrates the elevated expressions of the ferroptosis markers PTGS2 and ACSL4. Biochemical indicators further support the occurrence of ferroptosis, with increased levels of malondialdehyde (MDA) and lactate dehydrogenase (LDH), along with decreased level of glutathione (GSH). In vitro, intervention with high glucose and palmitic acid in H9C2 cells results in ferroptosis, which is reversed by ferrostatin-1 (Fer-1). Results show the elevated expression of HMOX1 in DCM. Moreover, knockdown of HMOX1 ameliorates ferroptosis, thereby alleviating diabetic cardiomyopathy by reducing cardiac fibrosis and improving cardiac function. Our study elucidates the role of HMXO1 in DCM pathogenesis and provides a potential therapeutic strategy for clinical treatment.
