Ubiquitin-specific protease 38 promotes atrial fibrillation in diabetic mice by stabilizing iron regulatory protein 2.

BACKGROUND: Atrial fibrillation (AF) is a common cardiovascular disease often observed in diabetes mellitus, and there is currently no satisfactory therapeutic option. Ubiquitin-specific protease 38 (USP38) has been implicated in the degradation of numerous substrate proteins in the myocardium. Herein, we aim to investigate the role of USP38 in AF induced by diabetes. METHODS: Cardiac-specific transgenic USP38 mice and cardiac-specific knockout USP38 mice were constructed, and streptozotocin was used to establish diabetic mouse model. Functional, electrophysiological, histologic, biochemical studies were performed. RESULTS: The expression of USP38 was upregulated in atrial tissues of diabetic mice and HL-1 cells exposed to high glucose. USP38 overexpression increased susceptibility to AF, accompanied by aberrant expression of calcium-handling protein, heightened iron load and oxidation stress in diabetic mice. Conversely, USP38 deficiency reduced vulnerability to AF by hampering ferroptosis. Mechanistically, USP38 bound to iron regulatory protein 2 (IRP2), stabilizing it and remove K48-linked polyubiquitination chains, thereby increasing intracellular iron overload, lipid peroxidation, and ultimately contributing to ferroptosis. In addition, reduced iron overload by deferoxamine treatment alleviated oxidation stress and decreased vulnerability to AF in diabetic mice. CONCLUSION: Overall, our findings reveal the detrimental role of USP38 in diabetes-related AF, manifested by increased level of iron overload and oxidation stress.

Anxiety disorder and cardiovascular disease: a two-sample Mendelian randomization study.

AIMS: Cardiovascular disease is the leading cause of death worldwide. Anxiety disorders are common psychiatric conditions associated with cardiovascular outcomes. This two-sample Mendelian randomization (MR) study investigated the causal relationship between anxiety disorders and coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). METHODS: Single nucleotide polymorphisms (SNPs) associated with anxiety disorders (16 730 cases; 101 021 controls) were obtained from the UK Biobank genome-wide association study (GWAS). Cardiovascular outcome data were derived from the FinnGen study (CHD: 21 012 cases and 197 780 controls; MI: 12 801 cases and 187 840 controls; HF: 23 397 cases and 194 811 controls; and AF: 22 068 cases and 116 926 controls). Inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode analyses examined causality. RESULTS: IVW analysis demonstrated significant causal relationships between anxiety disorders and increased risk of CHD [odds ratio (OR): 4.496; 95% confidence interval (CI): 1.777-11.378; P = 0.002], MI (OR: 5.042; 95% CI: 1.451-17.518; P = 0.011), and HF (OR: 3.255; 95% CI: 1.461-7.252; P = 0.004). No relationship was observed with AF (OR: 1.775; 95% CI: 0.612-5.146; P = 0.29). Other methods showed non-significant associations. Two-way analysis indicated no reverse causality. CONCLUSIONS: Anxiety disorders were causally associated with greater risk of CHD, MI, and HF but not AF among individuals of European descent. Further research on mediating mechanisms and in diverse populations is warranted.