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  • Under some pathological conditions AT

    2024-04-17

    Under some pathological conditions, AT1R internalization is decreased when agonist exposure is prolonged. This weakens or removes the AT1R desensitization effect and leads to AT1R and downstream signal overactivation. AT1R overactivation can result in continued biological effects such as sustained vasoconstriction [36] and vascular remodeling [37], which eventually promotes the development of various cardiovascular diseases. If the pathological mechanism behind the reduction of AT1R internalization can be illuminated and prevented, AT1R overactivation could be reversed to avoid a series of adverse events.
    Reducing AT1R internalization is closely related to the occurrence and development of many cardiovascular diseases, and its main manifestation is abnormal receptor activation and non-desensitization. Abnormal activation of the β-adrenergic receptor in patients with idiopathic dilated cardiomyopathy is caused by autoantibody-induced reduced receptor internalization [38]. As another prototypical G-protein coupled receptor, AT1R is activated abnormally by autoantibodies in some hypertensive disorders, such as preeclampsia, malignant hypertension, and essential BIBR 1532 [39]. Similar to β-adrenergic receptor, it is possible that the abnormal activation of AT1R may be related to reduced receptor internalization. It is similarly that autoantibodies against AT1R and β-adrenergic receptor, some other GPCR autoantibodies are closely related to cardiovascular disease; these autoantibodies might activate the corresponding receptor in a sustained manner without desensitization [40,41]. However, it is currently unknown whether reduced internalization is a common mechanism induced by autoantibodies.
    With deeper research into AT1R internalization, researchers identified two small molecule proteins that bind to the carboxylterminus of AT1R: AT1R-related protein (ATRAP) and AT1R-related protein 1 (ARAP1). These proteins play an important role in AT1R trafficking [88,89]. ATRAP can promote AT1R internalization; thus, ATRAP has a protective role in some diseases and it can effectively suppress abnormal activation of the AT1R signaling pathway and negatively regulate the functions mediated by AT1R activation. ATRAP overexpression significantly decreased the density of AT1R on the plasma membrane and also inhibited signal transduction upon Ang II treatment [88]. Ohsawa et al. found that knocking out ATRAP could abnormally activate AT1R on renal tubules to accelerate the development of hypertension [90]. A study by Oppermann et al. also partially supported the idea that ATRAP knockout mice exhibited elevated in arterial blood pressure and blood volume. Specifically, they found an increased AT1R density in the renal cortical cell membrane, suggesting that ATRAP knockout can inhibit AT1R internalization and induce AT1R overactivation leading to increased blood pressure in mice [91]. In contrast, ARAP1 promotes AT1R recycling to increase the density on the plasma membrane and help recover receptor signaling functions [89], In other words, it decreases AT1R internalization. Overexpressing ARAP1 in the kidney led to the development of the hypertension and renal hypertrophy, presumably by reducing AT1R internalization [92]. In conclusion, upregulating ATPAR, downregulating ARAP1, or increasing the rate of ATPAR and ARAP1 reduces AT1R internalization and thereby promotes the occurrence and development of AT1R-induced cardiovascular diseases.
    Summary and prospect AT1R internalization not only affects the density of the receptor on the plasma membrane, but also the intensity of signal transduction. Reducing internalization can cause abnormal activation of AT1R, thus promoting the development of some cardiovascular diseases such as hypertension. Therefore, it is important to study the mechanisms of reducing AT1R internalization. This study analyzes the possible mechanisms behind decreased internalization based on the different steps of AT1R internalization, including that binding to AT1R, AT1R phosphorylation, AT1R endocytosis, and AT1R recycling, as well as the expression of ATRAP and ARAP1. If the reduced internalization can be prevented or increased, the adverse effects induced by the sustained activation of AT1R would be reduced. For example, the Ang II analogs, TRV027, specifically biased activates AT1R-β-arrestin signaling without stimulating G proteins, and it has some beneficial cardiovascular effects [93]. Some novel drugs are likely to selectively promote receptor internalization and therefore have enhanced therapeutic potential for cardiovascular diseases [93,94].