Determining the absolute requirement of G protein-coupled receptor kinase 5 for pathological cardiac hypertrophy: short communication.
Determining the absolute requirement of G protein-coupled receptor kinase 5 for pathological cardiac hypertrophy: short communication.
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DOI：
10.1161/circresaha.112.273367
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发表时间：
2012-09-28
影响因子：
20.1
通讯作者：
Koch WJ
中科院分区：
文献类型：
--
作者：
Gold JI;Gao E;Shang X;Premont RT;Koch WJ
心力衰竭(HF)通常是适应性不良心肌肥厚的终末期。一个促成因素是肥大基因表达程序的激活，该程序由组蛋白脱乙酰基酶(HDAC)磷酸化抑制转录抑制所控制。心脏特异性过表达G蛋白偶联受体激酶5(GRK5)是一种具有HDAC5活性的核蛋白，可促进体内心脏对压力超负荷的耐受，然而，其在适应性和非适应性肥厚中的内源性需求尚不清楚。我们使用整体或心肌细胞特异性GRK5基因缺失的小鼠模型来确定慢性肥厚刺激后内源性GRK5对心肌肥厚和心衰发生的绝对需求。GRK5基因完全缺失的小鼠造成横动脉缩窄(TAC)。在12周时，这些小鼠表现出减弱的肥大、重塑和肥大基因转录，同时心脏功能得到保护。GRK5的全球缺失也减少了由于慢性苯肾上腺素注射而导致的肥大和相关基因的表达。然后，我们产生了有条件的心脏特异性GRK5缺失的小鼠，也显示了类似的对TAC后病理性心肌肥厚和心衰的保护作用。这些结果将心肌细胞GRK5定义为心室压力超负荷后病理性心脏生长的关键调节因子，支持其作为内源性(病理)-生理性HDAC激酶的作用。此外，这些结果将GRK5定义为一个潜在的治疗靶点，以限制肥厚性应激后心衰的发展。
Heart failure (HF) is often the end-phase of maladaptive cardiac hypertrophy. A contributing factor is activation of a hypertrophic gene expression program controlled by decreased class II histone deacetylase (HDAC) transcriptional repression via HDAC phosphorylation. Cardiac-specific overexpression of G protein-coupled receptor kinase-5 (GRK5), has previously been shown to possess nuclear activity as a HDAC5 kinase, promoting an intolerance to in vivo ventricular pressure-overload, however, its endogenous requirement in adaptive and maladaptive hypertrophy remains unknown. We used mouse models with global or cardiomyocyte-specific GRK5 gene deletion to determine the absolute requirement of endogenous GRK5 for cardiac hypertrophy and HF development following chronic hypertrophic stimuli. Mice with global deletion of GRK5 were subjected to transverse aortic constriction (TAC). At 12 weeks, these mice showed attenuated hypertrophy, remodeling, and hypertrophic gene transcription along with preserved cardiac function. Global GRK5 deletion also diminished hypertrophy and related gene expression due to chronic phenylephrine infusion. We then generated mice with conditional, cardiac-specific deletion of GRK5 that also demonstrated similar protection from pathological cardiac hypertrophy and HF following TAC. These results define myocyte GRK5 as a critical regulator of pathological cardiac growth following ventricular pressure-overload, supporting its role as an endogenous (patho)-physiological HDAC kinase. Further, these results define GRK5 as a potential therapeutic target to limit HF development after hypertrophic stress.