Budde, T. | bioRxiv Science

bioRxiv2024

TMPRSS6 cleaves KCNE1 and causes arrhythmias in iron overload disease

Iron storage disease is associated with cardiovascular manifestations, including various forms of cardiac arrhythmias of unknown origin. In this study, cardiac arrhythmias associated with iron overload were investigated in human iPSC-derived cardiomyocytes (hiPSC-CM) and hiPSC-derived sinus node-like pacemaker cells. Among other effects, iron overload leads to an increase in the plasma membrane-anchored protease TMPRSS6. TMPRSS6 cleaves the auxiliary subunit KCNE1 N-terminally and thus modulates the function of both the IKs (KCNQ1/KCNE1 current) and the If (HCN4/KCNE1) ion channels. Furthermore, TMPRSS6 induces a reduction of electric field potential (EFP) count and increased duration in hiPSC-derived ventricular-like cells and in hiPSC-derived pacemaker-like cells. In accordance with these in vitro generated results, TMPRSS6-mediated interactions show pro-arrhythmic effects in silico. Therefore, the TMPRSS6 - KCNE1-KCNQ1 and TMPRSS6 - KCNE1-HCN4 cascades may represent new clinically relevant pro-arrhythmic mechanisms in iron overload diseases.

physiology↗

bioRxiv2022

The effects of oral supplementation of Japanese sake yeast on anxiety, depressive-like symptoms, oxidative stress, and BDNF changes in chronically stressed adolescent rats

Chronic stress during the pre-pubertal period has adverse effects in developing neuropsychiatric disorders such as depression and anxiety. The administration of supplements with antioxidant properties may alleviate depression and anxiety behavior. This study investigated the effects of oral supplementation of Japanese sake yeast on anxiety, depressive-like symptoms, oxidative stress, and changes in brain-derived neurotropic factor (BDNF) in adolescence rats subjected to chronic stress. In order to assess the effects of chronic stress, adolescent rats were grouped into one non-stressed control group (non-stress) and four different experimental groups. The other animals were subjected to stress and orally received normal saline (Control-stress), 15 mg/kg yeast (Stress-15), 30 mg/kg yeast (Stress-30) and 45 mg/kg yeast (Stress-45). Anxiety and depression-like behavior, BDNF levels, and oxidative stress markers were evaluated. The rats exposed to stress exhibited anxiogenic and depression-like behavior as well as lower levels of BDNF and higher levels of oxidative markers compared with non-stressed rats (P<0.05). However, the oral supplementation of sake yeast decreased anxiogenic and depression-like behavior and oxidative indices, and also increased BDNF levels compared to stressed rats treated with saline in a dose-dependent manner (P<0.05). In sum, stress caused anxiety and depression behavior, increased oxidative indices, and reduced BDNF levels while sake yeast alleviated adverse effects of stress on anxiety and depression behaviors, decreased oxidative markers, and increased BDNF levels.

neuroscience↗