B-arrestin-2 Signaling Is Important to Preserve Cardiac Function During Aging.
B-arrestin-2 Signaling Is Important to Preserve Cardiac Function During Aging.
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DOI：
10.3389/fphys.2021.696852
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发表时间：
2021
影响因子：
4
通讯作者：
Rosas PC
中科院分区：
文献类型：
--
作者：
Capote AE;Batra A;Warren CM;Chowdhury SAK;Wolska BM;Solaro RJ;Rosas PC
这里报道的实验验证了β-arrestin-2是在衰老过程中保存心功能的一个重要因素的假设。我们通过老化β-arrestin-2基因敲除(KO)小鼠和相当于12-16个月的野生型(WT)小鼠来验证这一假设。我们发展这些实验的理论基础是，血管紧张素II受体1型(AT1R)上的血管紧张素II信号既促进G蛋白信号传递，也促进β-arrestin-2信号传递。β-arrestin-2参与GPCRs的脱敏、内化，但也可以作为适应性信号转导的支架，这种信号转导可能独立或平行于G-蛋白信号转导发生。我们以前曾报道，在扩张型心肌病小鼠模型中，作用于AT1R的偏向配体促进β-arrestin-2信号转导，增加心肌收缩能力，减少适应不良。虽然有证据表明血管紧张素II诱导心血管系统的不良适应衰老，但β-arrestin-2信号在衰老中的作用尚未被研究。通过超声心动图，我们发现与对照组相比，老年KO小鼠的左房和左心室内径增大，收缩性能参数降低，但射血分数保持不变。与同年龄段的WT对照组相比，老年KO组的松弛参数也较低。此外，老年KO小鼠的心功能障碍与肌球蛋白结合蛋白-C和肌球蛋白调节轻链等肌丝蛋白磷酸化的变化有关。我们的证据为β-arrestin-2作为一种重要的信号机制在衰老过程中保护心脏功能提供了新的见解。
Experiments reported here tested the hypothesis that β-arrestin-2 is an important element in the preservation of cardiac function during aging. We tested this hypothesis by aging β-arrestin-2 knock-out (KO) mice, and wild-type equivalent (WT) to 12–16months. We developed the rationale for these experiments on the basis that angiotensin II (ang II) signaling at ang II receptor type 1 (AT1R), which is a G-protein coupled receptor (GPCR) promotes both G-protein signaling as well as β-arrestin-2 signaling. β-arrestin-2 participates in GPCR desensitization, internalization, but also acts as a scaffold for adaptive signal transduction that may occur independently or in parallel to G-protein signaling. We have previously reported that biased ligands acting at the AT1R promote β-arrestin-2 signaling increasing cardiac contractility and reducing maladaptations in a mouse model of dilated cardiomyopathy. Although there is evidence that ang II induces maladaptive senescence in the cardiovascular system, a role for β-arrestin-2 signaling has not been studied in aging. By echocardiography, we found that compared to controls aged KO mice exhibited enlarged left atria and left ventricular diameters as well as depressed contractility parameters with preserved ejection fraction. Aged KO also exhibited depressed relaxation parameters when compared to WT controls at the same age. Moreover, cardiac dysfunction in aged KO mice was correlated with alterations in the phosphorylation of myofilament proteins, such as cardiac myosin binding protein-C, and myosin regulatory light chain. Our evidence provides novel insights into a role for β-arrestin-2 as an important signaling mechanism that preserves cardiac function during aging.
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影响因子：
64.8
作者：
Kho, Changwon;Lee, Ahyoung;Jeong, Dongtak;Oh, Jae Gyun;Chaanine, Antoine H.;Kizana, Eddy;Park, Woo Jin;Hajjar, Roger J.
通讯作者：
Hajjar, Roger J.
影响因子：
20.1
作者：
Lovelock JD;Monasky MM;Jeong EM;Lardin HA;Liu H;Patel BG;Taglieri DM;Gu L;Kumar P;Pokhrel N;Zeng D;Belardinelli L;Sorescu D;Solaro RJ;Dudley SC Jr
通讯作者：
Dudley SC Jr
影响因子：
5.6
作者：
Markandran K;Poh JW;Ferenczi MA;Cheung C
通讯作者：
Cheung C
影响因子：
3.5
作者：
Chakouri, Nourdine;Reboul, Cyril;Cazorla, Olivier
通讯作者：
Cazorla, Olivier
影响因子：
2.9
作者：
FRITZ, JD;SWARTZ, DR;GREASER, ML
通讯作者：
GREASER, ML