Aquaporin 1 deficiency drives diabetic cardiomyopathy via mediating myocardial edema

BACKGROUND: Myocardial edema is a prevalent pathological phenomenon in cardiac diseases and is implicated in the pathogenesis of numerous cardiovascular disorders. Nevertheless, the characteristics and specific mechanisms of diabetic myocardial edema remain inadequately understood. METHODS: We developed mouse models of diabetic cardiomyopathy and a myocardial cell model subjected to high glucose (HG) conditions. Single-cell RNA sequencing (ScRNA-seq) was utilized to investigate the transcriptional mechanisms associated with increased myocardial edema, with functional and mechanistic validation performed at both the animal and cellular levels. RESULTS: Our study identified that myocardial edema manifests early in the progression of diabetic cardiomyopathy in diabetic mice, following a pattern of initial increase followed by a decrease as the disease advances. Through single-cell sequencing, we observed a significant overexpression of the classic aquaporin 1 (Aqp1), known for its association with edema, specifically in the C0 subtype of cardiomyocytes, with an overall increase in diabetic cardiomyopathy. Aqp1 was markedly upregulated in the C0 subtype (|logFC| ≥ 1, p-value < 0.05), and functional enrichment analysis linked it to signaling pathways and apoptotic processes pertinent to diabetic complications. Inhibition of AQP1 protein expression specifically in myocardial cells intensified myocardial cell edema, consequently leading to increased apoptosis of these cells (p < 0.05). Notably, our study also discovered that, within the diabetic myocardium, Aqp1 gene expression levels in myocardial cells were significantly elevated (p < 0.05), whereas AQP1 protein expression levels were markedly reduced (p < 0.05). This gene-protein expression mismatch suggests that AQP1 might undergo accelerated post-translational degradation, potentially mediated by ROS-induced oxidative stress or the ubiquitin-proteasome pathway. CONCLUSION: Myocardial edema is likely to manifest in the early phases of diabetic cardiomyopathy, characterized by an initial increase followed by a subsequent reduction. In the context of diabetic cardiomyopathy, the Aqp1 gene, associated with edema, is markedly upregulated. Concurrently, the AQP1 protein is subject to continuous degradation as a result of ROS accumulation. This process exacerbates myocardial cell edema and further elevates myocardial cell apoptosis, thereby advancing the progression of diabetic cardiomyopathy.