Currently, electronics and iontronics in abiotic-biotic systems can only use electrons and single-species ions as unitary signal carriers. Thus, a mechanism of gating transmission for multiple biosignals in such devices is needed to match and modulate complex aqueous-phase biological systems. Here we report the use of cascade-heterogated biphasic gel iontronics to achieve diverse electronic-to-multi-ionic signal transmission. The cascade-heterogated property determined the transfer free energy barriers experienced by ions and ionic hydration-dehydration states under an electric potential field, fundamentally enhancing the distinction of cross-interface transmission between different ions by several orders of magnitude. Such heterogated or chemical-heterogated iontronics with programmable features can be coupled with multi-ion cross-interface mobilities for hierarchical and selective cross-stage signal transmission. We expect that such iontronics would be ideal candidates for a variety of biotechnology applications.

It has been recognized that myocardial apoptosis is one major factor in the development of heart dysfunction and autophagy has been shown to influence the apoptosis. In previous studies, we reported that anti-β₁-adrenergic receptor autoantibodies (β₁-AABs) decreased myocardial autophagy, but the role of decreased autophagy in cardiomyocyte apoptosis remains unclear. In the present study, we used a β₁-AAB-immunized rat model to investigate the role of decreased autophagy in cardiomyocyte apoptosis. We reported that the level of autophagic flux increased early and then decreased in an actively β₁-AAB-immunized rat model. Rapamycin, an mTOR inhibitor, restored myocardial apoptosis in the presence of β₁-AABs. Further, we found that the early increase of autophagy was an adaptive stress response that is possibly unrelated to β₁-AR, and the activation of the β₁-AR and PKA contributed to late decreased autophagy. Then, after upregulating or inhibiting autophagy with rapamycin, Atg5 overexpression adenovirus or 3-methyladenine in cultured primary neonatal rat cardiomyocytes, we found that autophagy decline promoted myocardial apoptosis effectively through the mitochondrial apoptotic pathway. In conclusion, the reduction of apoptosis through the proper regulation of autophagy may be important for treating patients with β₁-AAB-positive heart dysfunction.

Background: Angiotensin II type 1 receptor ( AT ₁ R) autoantibody ( AT 1‐ AA ) was first identified as a causative factor in preeclampsia. Unlike physiological ligand angiotensin II (Ang II ), AT 1‐ AA can induce vasoconstriction in a sustained manner, causing a series of adverse effects, such as vascular injury and poor placental perfusion. However, its underlying mechanisms remain unclear. Here, from the perspective of AT ₁ R internalization, the present study investigated the molecular mechanism of sustained vasoconstriction induced by AT ₁ R autoantibody. Methods and Results: In the current study, we used the vascular‐ring technique to determine that AT 1‐ AA ‐positive IgG, which was obtained from the sera of preeclamptic patients, induced long‐term vasoconstriction in endothelium‐intact or endothelium‐denuded rat thoracic arteries. The effect was caused by prolonged activation of AT ₁ R downstream signals in vascular smooth muscle cells, including Ca ²⁺ , protein kinase C, and extracellular signal‐regulated kinase 1 and 2. Then, using subcellular protein fractionation, cell surface protein biotinylation, and total internal reflection fluorescence, we found that AT 1‐ AA ‐positive IgG resulted in significantly less AT ₁ R internalization than in the Ang II treatment group. Moreover, through use of fluorescent tracing and bioluminescence resonance energy transfer, we found that AT 1‐ AA ‐positive IgG cannot induce the recruitment of β‐arrestin1/2, which mediated receptor internalization. Then, the effect of sustained AT ₁ R activation induced by AT 1‐ AA ‐positive IgG was rescued by overexpression of β‐arrestin2. Conclusions: These data suggested that limited AT ₁ R internalization resulting from the inhibition of β‐arrestin1/2 recruitment played an important role in sustained vasoconstriction induced by AT 1‐ AA ‐positive IgG, which may set the stage for avoiding AT ₁ R overactivation in the management of preeclampsia.

G protein-coupled receptors (GPCRs) are the largest family of membrane proteins in the human body and are responsible for accurately transmitting extracellular information to cells. Arrestin is an important member of the GPCR signaling pathway. The main function of arrestin is to assist receptor desensitization, endocytosis and signal transduction. In these processes, the recognition and binding of arrestin to phosphorylated GPCRs is fundamental. However, the mechanism by which arrestin recognizes phosphorylated GPCRs is not fully understood. The GPCR phosphorylation recognition “bar code model” and “flute” model describe the basic process of receptor phosphorylation recognition in terms of receptor phosphorylation sites, arrestin structural changes and downstream signaling. These two models suggest that GPCR phosphorylation recognition is a process involving multiple factors. This process can be described by a “QR code” model in which ligands, GPCRs, G protein-coupled receptor kinase, arrestin, and phosphorylation sites work together to determine the biological functions of phosphorylated receptors. Graphical Abstract

Heart failure is the terminal stage of many cardiac diseases, in which β₁-adrenoceptor (β₁-AR) autoantibody (β₁-AA) has a causative role. By continuously activating β₁-AR, β₁-AA can induce cytotoxicity, leading to cardiomyocyte apoptosis and heart dysfunction. However, the mechanism underlying the persistent activation of β₁-AR by β₁-AA is not fully understood. Receptor endocytosis has a critical role in terminating signals over time. β₂-adrenoceptor (β₂-AR) is involved in the regulation of β₁-AR signaling. This research aimed to clarify the mechanism of the β₁-AA-induced sustained activation of β₁-AR and explore the role of the β₂-AR/Gi-signaling pathway in this process. The beating frequency of neonatal rat cardiomyocytes, cyclic adenosine monophosphate content, and intracellular Ca²⁺ levels were examined to detect the activation of β₁-AA. Total internal reflection fluorescence microscopy was used to detect the endocytosis of β₁-AR. ICI118551 was used to assess β₂-AR/Gi function in β₁-AR sustained activation induced by β₁-AA in vitro and in vivo. Monoclonal β₁-AA derived from a mouse hybridoma could continuously activate β₁-AR. β₁-AA-restricted β₁-AR endocytosis, which was reversed by overexpressing the endocytosis scaffold protein β-arrestin1/2, resulting in the cessation of β₁-AR signaling. β₂-AR could promote β₁-AR endocytosis, as demonstrated by overexpressing/interfering with β₂-AR in HL-1 cells, whereas β₁-AA inhibited the binding of β₂-AR to β₁-AR, as determined by surface plasmon resonance. ICI118551 biasedly activated the β₂-AR/Gi/G protein-coupled receptor kinase 2 (GRK2) pathway, leading to the arrest of limited endocytosis and continuous activation of β₁-AR by β₁-AA in vitro. In vivo, ICI118551 treatment attenuated myocardial fiber rupture and left ventricular dysfunction in β₁-AA-positive mice. This study showed that β₁-AA continuously activated β₁-AR by inhibiting receptor endocytosis. Biased activation of the β₂-AR/Gi/GRK2 signaling pathway could promote β₁-AR endocytosis restricted by β₁-AA, terminate signal transduction, and alleviate heart damage.

Vascular remodeling can be caused by angiotensin II type 1 receptor (AT₁R) autoantibody (AT1-AA), although the related mechanism remains unknown. Angiotensin II type 2 receptor (AT₂R) plays multiple roles in vascular remodeling through cross-talk with AT₁R in the cytoplasm. Here, we aimed to explore the role and mechanism of AT₂R in AT1-AA-induced vascular smooth muscle cell (VSMC) migration, which is a key event in vascular remodeling. In vitro and in vivo, we found that AT₂R can promote VSMC migration in AT1-AA-induced vascular remodeling. Moreover, AT₂R expression was upregulated via Klf-5/IRF-1-mediated transcriptional and circErbB4/miR-29a-5p-mediated posttranscriptional mechanisms in response to AT1-AA. Our data provide a molecular basis for AT1-AA-induced AT₂R expression by transcription factors, namely, a circular RNA and a microRNA, and showed that AT₂R participated in AT1-AA-induced VSMC migration during the development of vascular remodeling. AT₂R may be a potential target for the treatment of AT1-AA-induced vascular diseases.