A Kinase Interacting Protein 1 (AKIP1) promotes cardiomyocyte elongation and physiological cardiac remodelling.
A Kinase Interacting Protein 1 (AKIP1) promotes cardiomyocyte elongation and physiological cardiac remodelling.
复制标题
DOI：
10.1038/s41598-023-30514-1
复制
发表时间：
2023-03-10
影响因子：
4.6
通讯作者：
Westenbrink, B. Daan
中科院分区：
文献类型：
--
作者：
Nijholt, Kirsten T.;Sanchez-Aguilera, Pablo I.;Booij, Harmen G.;Oberdorf-Maass, Silke U.;Dokter, Martin M.;Wolters, Anouk H. G.;Giepmans, Ben N. G.;van Gilst, Wiek H.;Brown, Joan H.;de Boer, Rudolf A.;Sillje, Herman H. W.;Westenbrink, B. Daan
激酶相互作用蛋白 1 (AKIP1) 是一种信号转导接头，可在体外促进生理性肥大。本研究的目的是确定 AKIP1 是否促进体内生理性心肌细胞肥大。因此，心肌细胞特异性过度表达 AKIP1 (AKIP1-TG) 的成年雄性小鼠和野生型 (WT) 同窝小鼠在有或没有跑轮的情况下单独笼养 4 周。评估运动表现、心脏重量与胫骨长度 (HW/TL)、MRI、组织学和左心室 (LV) 分子标志物。虽然基因型之间的运动参数相当，但与 WT 小鼠相比，AKIP1-TG 小鼠运动引起的心脏肥大有所增强，体重秤 HW/TL 的增加和 MRI 上 LV 质量的增加证明了这一点。 AKIP1 诱导的肥大主要由心肌细胞长度的增加决定，这与 p90 核糖体 S6 激酶 3 (RSK3) 的减少、磷酸酶 2A 催化亚基 (PP2Ac) 的增加和血清反应因子 (SRF) 的去磷酸化有关。通过电子显微镜，我们在心肌细胞核中检测到了 AKIP1 蛋白簇，它可能会影响信号体的形成，并在运动时容易发生转录转换。从机制上讲，AKIP1 促进运动诱导的蛋白激酶 B (Akt) 激活、CCAAT 增强子结合蛋白 Beta (C/EBPβ) 下调以及与富含 Glu/Asp 的羧基末端结构域 4 (CITED4) 相互作用的 Cbp/p300 反式激活因子的去抑制。最后，我们确定 AKIP1 是心肌细胞伸长和生理性心脏重塑的新型调节剂，可激活 RSK3-PP2Ac-SRF 和 Akt-C/EBPβ-CITED4 通路。这些发现表明 AKIP1 可能作为心脏重塑的生理重编程的节点。
A Kinase Interacting Protein 1 (AKIP1) is a signalling adaptor that promotes physiological hypertrophy in vitro. The purpose of this study is to determine if AKIP1 promotes physiological cardiomyocyte hypertrophy in vivo. Therefore, adult male mice with cardiomyocyte-specific overexpression of AKIP1 (AKIP1-TG) and wild type (WT) littermates were caged individually for four weeks in the presence or absence of a running wheel. Exercise performance, heart weight to tibia length (HW/TL), MRI, histology, and left ventricular (LV) molecular markers were evaluated. While exercise parameters were comparable between genotypes, exercise-induced cardiac hypertrophy was augmented in AKIP1-TG vs. WT mice as evidenced by an increase in HW/TL by weighing scale and in LV mass on MRI. AKIP1-induced hypertrophy was predominantly determined by an increase in cardiomyocyte length, which was associated with reductions in p90 ribosomal S6 kinase 3 (RSK3), increments of phosphatase 2A catalytic subunit (PP2Ac) and dephosphorylation of serum response factor (SRF). With electron microscopy, we detected clusters of AKIP1 protein in the cardiomyocyte nucleus, which can potentially influence signalosome formation and predispose a switch in transcription upon exercise. Mechanistically, AKIP1 promoted exercise-induced activation of protein kinase B (Akt), downregulation of CCAAT Enhancer Binding Protein Beta (C/EBPβ) and de-repression of Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 4 (CITED4). Concludingly, we identified AKIP1 as a novel regulator of cardiomyocyte elongation and physiological cardiac remodelling with activation of the RSK3-PP2Ac-SRF and Akt-C/EBPβ-CITED4 pathway. These findings suggest that AKIP1 may serve as a nodal point for physiological reprogramming of cardiac remodelling.
登录
查看更多内容
影响因子：
20.1
作者：
Li J;Kritzer MD;Michel JJ;Le A;Thakur H;Gayanilo M;Passariello CL;Negro A;Danial JB;Oskouei B;Sanders M;Hare JM;Hanauer A;Dodge-Kafka K;Kapiloff MS
通讯作者：
Kapiloff MS
影响因子：
8
作者：
Bezzerides, Vassilios J.;Platt, Colin;Rosenzweig, Anthony
通讯作者：
Rosenzweig, Anthony
影响因子：
5
作者：
Ryall, Karen A.;Bezzerides, Vassilios J.;Rosenzweig, Anthony;Saucerman, Jeffrey J.
通讯作者：
Saucerman, Jeffrey J.
DOI：
10.1590/s0100-879x2011007500112
发表时间：
2011-09-01
影响因子：
2.3
作者：
Fernandes, T.;Soci, U.P.R.;Oliveira, E.M.
通讯作者：
Oliveira, E.M.
影响因子：
64.5
作者：
Boström P;Mann N;Wu J;Quintero PA;Plovie ER;Panáková D;Gupta RK;Xiao C;MacRae CA;Rosenzweig A;Spiegelman BM
通讯作者：
Spiegelman BM