G protein-coupled receptor kinase 5 (GRK5) contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure.
G protein-coupled receptor kinase 5 (GRK5) contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure.
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DOI：
10.1093/cvr/cvab044
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发表时间：
2022-01-07
影响因子：
10.8
通讯作者：
Koch WJ
中科院分区：
文献类型：
--
作者：
de Lucia C;Grisanti LA;Borghetti G;Piedepalumbo M;Ibetti J;Lucchese AM;Barr EW;Roy R;Okyere AD;Murphy HC;Gao E;Rengo G;Houser SR;Tilley DG;Koch WJ
心肌梗死(MI)是世界范围内最常见的心力衰竭(HF)原因。G蛋白偶联受体激酶5(GRK5)在衰竭的人心肌中表达上调，并在动物模型中促进非适应性心肌肥厚。然而，GRK5在缺血性心脏病中的作用仍不清楚。在这项研究中，我们评估了心肌GRK5是否在小鼠心肌梗死后发挥关键作用，并检查了特定的心脏免疫和炎症反应。心肌细胞特异性GRK5过表达转基因小鼠(TgGRK5)和非转基因斜发对照(NLC)小鼠以及心肌细胞特异性GRK5基因敲除小鼠(GRK5cKO)和野生型(WT)小鼠受到心肌梗死的影响，并研究其功能和结构的变化以及结果。与NLC心肌梗死后小鼠相比，TgGRK5心肌梗死后小鼠的心功能降低，左心室内径增大，存活率降低。与NLC小鼠相比，TgGRK5组小鼠心肌肥大和纤维化以及胎儿基因表达增加。在TgGRK5小鼠中，GRK5的升高产生了免疫调节剂，导致白细胞增加并持续到受损的心脏，最终导致慢性心脏炎症。我们发现在TgGRK5心肌梗死后4天和8周，促炎症的中性粒细胞和巨噬细胞以及中性粒细胞、巨噬细胞和T淋巴细胞的存在分别增加。相反，与心肌梗死后WT小鼠相比，GRK5cKO小鼠受到保护，免受缺血损伤，并显示出早期免疫细胞(主要是单核细胞)向心脏募集的减少，心脏收缩能力的改善和死亡率的降低。有趣的是，心肌细胞特异性GRK2转基因小鼠与TgGRK5小鼠没有相同的表型，也没有心肌梗死后心脏白细胞迁移和细胞因子或趋化因子产生的增加。我们的研究表明，在小鼠缺血后心力衰竭模型中，心肌细胞GRK5在调节白细胞进入心脏、心功能和存活方面具有关键的和GRK选择性作用，支持抑制GRK5作为心力衰竭的治疗靶点。
Myocardial infarction (MI) is the most common cause of heart failure (HF) worldwide. G protein-coupled receptor kinase 5 (GRK5) is upregulated in failing human myocardium and promotes maladaptive cardiac hypertrophy in animal models. However, the role of GRK5 in ischemic heart disease is still unknown. In this study, we evaluated whether myocardial GRK5 plays a critical role post-MI in mice and included the examination of specific cardiac immune and inflammatory responses. Cardiomyocyte-specific GRK5 overexpressing transgenic mice (TgGRK5) and non-transgenic littermate control (NLC) mice as well as cardiomyocyte-specific GRK5 knockout mice (GRK5cKO) and wild type (WT) were subjected to MI and, functional as well as structural changes together with outcomes were studied. TgGRK5 post-MI mice showed decreased cardiac function, augmented left ventricular dimension and decreased survival rate compared to NLC post-MI mice. Cardiac hypertrophy and fibrosis as well as fetal gene expression were increased post-MI in TgGRK5 compared to NLC mice. In TgGRK5 mice, GRK5 elevation produced immuno-regulators that contributed to the elevated and long-lasting leukocyte recruitment into the injured heart and ultimately to chronic cardiac inflammation. We found an increased presence of pro-inflammatory neutrophils and macrophages as well as neutrophils, macrophages and T-lymphocytes at 4-days and 8-weeks respectively post-MI in TgGRK5 hearts. Conversely, GRK5cKO mice were protected from ischemic injury and showed reduced early immune cell recruitment (predominantly monocytes) to the heart, improved contractility and reduced mortality compared to WT post-MI mice. Interestingly, cardiomyocyte-specific GRK2 transgenic mice did not share the same phenotype of TgGRK5 mice and did not have increased cardiac leukocyte migration and cytokine or chemokine production post-MI. Our study shows that myocyte GRK5 has a crucial and GRK-selective role on the regulation of leucocyte infiltration into the heart, cardiac function and survival in a murine model of post-ischemic HF, supporting GRK5 inhibition as a therapeutic target for HF.
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影响因子：
16.6
作者：
Accornero F;Schips TG;Petrosino JM;Gu SQ;Kanisicak O;van Berlo JH;Molkentin JD
通讯作者：
Molkentin JD
DOI：
10.1093/gerona/gly139
发表时间：
2019-03-14
期刊：
The journals of gerontology. Series A, Biological sciences and medical sciences
影响因子：
--
作者：
de Lucia C;Wallner M;Eaton DM;Zhao H;Houser SR;Koch WJ
通讯作者：
Koch WJ
GRK5介导的病理心肥大的加剧涉及促进核NFAT活性。
影响因子：
20.1
作者：
Hullmann JE;Grisanti LA;Makarewich CA;Gao E;Gold JI;Chuprun JK;Tilley DG;Houser SR;Koch WJ
通讯作者：
Koch WJ
心肌梗塞和心力衰竭中的基质金属蛋白酶。
DOI：
10.1016/bs.pmbts.2017.02.001
发表时间：
2017
影响因子：
--
作者：
DeLeon-Pennell KY;Meschiari CA;Jung M;Lindsey ML
通讯作者：
Lindsey ML
影响因子：
5.5
作者：
Fatini, Cinzia;Sticchi, Elena;Gensini, Gian Franco
通讯作者：
Gensini, Gian Franco