Department of Physiology, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, PO Box 70576, Johnson City, TN 37614, USA.
Mol Cell Biochem. 2011 Jul;353(1-2):13-22. doi: 10.1007/s11010-011-0769-6. Epub 2011 Mar 15.
β-Adrenergic receptor (β-AR) stimulation induces cardiac myocyte apoptosis and plays an important role in myocardial remodeling. Here we investigated expression of various apoptosis-related genes affected by β-AR stimulation, and examined first time the role of ataxia telangiectasia mutated kinase (ATM) in cardiac myocyte apoptosis and myocardial remodeling following β-AR stimulation. cDNA array analysis of 96 apoptosis-related genes indicated that β-AR stimulation increases expression of ATM in the heart. In vitro, RT-PCR confirmed increased ATM expression in adult cardiac myocytes in response to β-AR stimulation. Analysis of left ventricular structural and functional remodeling of the heart in wild-type (WT) and ATM heterozygous knockout mice (hKO) 28 days after ISO-infusion showed increased heart weight to body weight ratio in both groups. M-mode echocardiography showed increased percent fractional shortening (%FS) and ejection fraction (EF%) in both groups 28 days post ISO-infusion. Interestingly, the increase in %FS and EF% was significantly lower in the hKO-ISO group. Cardiac fibrosis and myocyte apoptosis were higher in hKO mice at baseline and ISO-infusion increased fibrosis and apoptosis to a greater extent in hKO-ISO hearts. ISO-infusion increased phosphorylation of p53 (Serine-15) and expression of p53 and Bax to a similar extent in both groups. hKO-Sham and hKO-ISO hearts exhibited reduced intact β1 integrin levels. MMP-2 protein levels were significantly higher, while TIMP-2 protein levels were lower in hKO-ISO hearts. MMP-9 protein levels were increased in WT-ISO, not in hKO hearts. In conclusion, ATM plays a protective role in cardiac remodeling in response to β-AR stimulation.
β-肾上腺素能受体（β-AR）刺激诱导心肌细胞凋亡，并在心肌重构中起重要作用。在这里，我们研究了受β-AR 刺激影响的各种凋亡相关基因的表达，并首次研究了共济失调毛细血管扩张突变激酶（ATM）在β-AR 刺激后心肌细胞凋亡和心肌重构中的作用。96 种凋亡相关基因的 cDNA 阵列分析表明，β-AR 刺激增加了心脏中 ATM 的表达。在体外，RT-PCR 证实β-AR 刺激可增加成年心肌细胞中 ATM 的表达。在 ISO 输注后 28 天，对野生型（WT）和 ATM 杂合敲除小鼠（hKO）的左心室结构和功能重构分析表明，两组的心脏重量与体重比均增加。M 型超声心动图显示两组 ISO 输注后 28 天的百分分数缩短（%FS）和射血分数（EF%）均增加。有趣的是，hKO-ISO 组的%FS 和 EF%增加幅度明显较低。hKO 小鼠的基线和 ISO 输注时的心肌纤维化和细胞凋亡均较高，hKO-ISO 心脏的纤维化和凋亡增加幅度更大。ISO 输注可使 p53（丝氨酸 15）磷酸化和 p53 和 Bax 的表达在两组中增加到相似的程度。hKO-Sham 和 hKO-ISO 心脏的完整β1 整合素水平降低。hKO-ISO 心脏的 MMP-2 蛋白水平显著升高，而 TIMP-2 蛋白水平较低。MMP-9 蛋白水平在 WT-ISO 中增加，但在 hKO 心脏中没有增加。总之，ATM 在 β-AR 刺激引起的心脏重构中发挥保护作用。
