Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
INCT Nanobiofarmacêutica, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Am J Physiol Cell Physiol. 2024 Oct 1;327(4):C1143-C1149. doi: 10.1152/ajpcell.00049.2024. Epub 2024 Aug 19.
The renin-angiotensin system (RAS) is composed of a series of peptides, receptors, and enzymes that play a pivotal role in maintaining cardiovascular homeostasis. Among the most important players in this system are the angiotensin-II and angiotensin-(1-7) peptides. Our group has recently demonstrated that alamandine (ALA), a peptide with structural and functional similarities to angiotensin-(1-7), interacts with cardiomyocytes, enhancing contractility via the Mas-related G protein-coupled receptor member D (MrgD). It is currently unknown whether this modulation varies along the distinct phases of the day. To address this issue, we assessed the ALA-induced contractility response of cardiomyocytes from mice at four Zeitgeber times (ZTs). At ZT2 (light phase), ALA enhanced cardiomyocyte shortening in an MrgD receptor-dependent manner, which was associated with nitric oxide (NO) production. At ZT14 (dark phase), ALA induced a negative modulation on the cardiomyocyte contraction. β-Alanine, an MrgD agonist, reproduced the time-of-day effects of ALA on myocyte shortening. -nitro-l-arginine methyl ester, an NO synthase inhibitor, blocked the increase in fractional shortening induced by ALA at ZT2. No effect of ALA on myocyte shortening was observed at ZT8 and ZT20. Our results show that ALA/MrgD signaling in cardiomyocytes is subject to temporal modulation. This finding has significant implications for pharmacological approaches that combine chronotherapy for cardiac conditions triggered by disruption of circadian rhythms and hormonal signaling. Alamandine, a member of the renin-angiotensin system, serves critical roles in cardioprotection, including the modulation of cardiomyocyte contractility. Whether this effect varies along the day is unknown. Our results provide evidence that alamandine via receptor MrgD exerts opposing actions on cardiomyocyte shortening, enhancing, or reducing contraction depending on the time of day. These findings may have significant implications for the development and effectiveness of future cardiac therapies.
肾素-血管紧张素系统（RAS）由一系列肽、受体和酶组成，在维持心血管稳态中发挥关键作用。在这个系统中，最重要的参与者之一是血管紧张素-II 和血管紧张素-(1-7)肽。我们的研究小组最近表明，与血管紧张素-(1-7)具有结构和功能相似性的肽类物质alamandine（ALA）与心肌细胞相互作用，通过 Mas 相关 G 蛋白偶联受体成员 D（MrgD）增强收缩性。目前尚不清楚这种调节是否会随一天中的不同时间而变化。为了解决这个问题，我们评估了来自在四个 Zeitgeber 时间（ZT）的小鼠的 ALA 诱导的心肌细胞收缩反应。在 ZT2（光照相）时，ALA 以 MrgD 受体依赖性方式增强心肌细胞缩短，这与一氧化氮（NO）产生有关。在 ZT14（暗相）时，ALA 对心肌细胞收缩产生负调节作用。MrgD 激动剂β-丙氨酸复制了 ALA 对肌细胞缩短的时间效应。一氧化氮合酶抑制剂 -nitro-l-arginine methyl ester 阻断了 ALA 在 ZT2 时引起的分数缩短增加。在 ZT8 和 ZT20 时，未观察到 ALA 对心肌细胞缩短的影响。我们的结果表明，心肌细胞中的 ALA/MrgD 信号受到时间调节。这一发现对于结合昼夜节律和激素信号中断引起的心脏疾病的时间治疗的药理学方法具有重要意义。alamandine 是肾素-血管紧张素系统的成员，在心脏保护中发挥关键作用，包括调节心肌细胞收缩性。这种效应是否随一天中的时间而变化尚不清楚。我们的结果提供了证据，表明 alamandine 通过受体 MrgD 对心肌细胞缩短产生相反的作用，根据一天中的时间增强或减少收缩。这些发现可能对未来心脏治疗的发展和有效性具有重要意义。
