Short-chain fatty acids combined with intronic DNA methylation of HIF3A: Potential predictors for diabetic cardiomyopathy

Background: Hyperglycemia can induce the heart to enter an oxygen-restricted environment, which results in diabetic cardiomyopathy (DCM). Microbiota-derived short-chain fatty acids (SCFAs) affect O₂ consumption and play crucial roles in modulating metabolic and cardiovascular health. The epigenetic regulation of the hypoxia-inducible factor 3A (HIF3A) gene is implicated in oxidative metabolism in the pathogenesis of diabetes. Identifying the associations between plasma SCFA levels and intronic DNA methylation of HIF3A may reveal useful predictors or provide insights into the disease processes of DCM. Methods: In this cross-sectional study, we analyzed plasma SCFA levels, HIF3A expression, and CpG methylation of HIF3A intron 1 in peripheral blood from patients with type 2 diabetes presenting with (n = 92) and without (n = 105) cardiomyopathy. Results: Plasma butyric acid levels and HIF3A mRNA expression in peripheral blood were decreased in DCM patients, whereas 3 CpGs in HIF3A intron 1 (CpG 6, CpG 7 and CpG 11) were highly methylated in DCM patients. Interestingly, butyric acid levels positively correlated with HIF3A levels, while a negative association was identified between butyric acid levels and the methylation rates of HIF3A intron 1 at CpG 6. Butyric acid levels also correlated with several clinical/echocardiographic factors in DCM patients. Additionally, the combination of plasma butyric acid levels and HIF3A intron 1 methylation at CpG 6 discriminated DCM patients from type2 diabetes mellitus (T2DM) patients. Conclusions: The novel associations between plasma butyric acid levels and HIF3A intron 1 methylation at CpG 6 may highlight an underlying mechanism by which the “microbial-myocardial” axis and host–microbe interactions may participate in the pathogenesis of DCM.