Loss of PTEN attenuates the development of pathological hypertrophy and heart failure in response to biomechanical stress
Loss of PTEN attenuates the development of pathological hypertrophy and heart failure in response to biomechanical stress
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DOI：
10.1093/cvr/cvn041
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发表时间：
2008-06-01
影响因子：
10.8
通讯作者：
Penninger, Josef M.
中科院分区：
文献类型：
--
作者：
Oudit, Gavin Y.;Kassiri, Zamaneh;Penninger, Josef M.
目的：对生物力学应激的适应不良反应是心脏病的一种基本反应。10号染色体上缺失的3 '-脂质磷酸酶、磷酸酶和张力蛋白同源物（PTEN）的缺失与Akt/蛋白激酶B和糖原合成酶激酶-β的磷酸化增加相关。我们假设，这些关键的变化将停止发展的病理性肥大和心力衰竭的进展，在响应于pressure overload.Methods和结果在小鼠中，肌肉特异性敲除的PTEN，mckCRE-PTENflox/flox（PTEN KO），导致基础肥大和轻度减少左心室（W）收缩功能。交配小鼠进行主动脉结扎（AB）或假手术。与mckCRE-PTEN+/+对照小鼠相比，PTEN KO小鼠中的压力超负荷导致病理性肥大减少，间质纤维化减少，细胞凋亡减少，LV功能明显保留。丝裂原活化蛋白激酶（MAPK）信号的蛋白质印迹分析显示，细胞外信号调节激酶（ERK）1和ERK 2的磷酸化与显着减少的磷酸化的jun N-末端激酶（JNK）1和JNK 2，和p38在PTEN基因敲除小鼠进行AB。PTEN的缺失与促血管生成因子、血管内皮生长因子-A和血管生成素-2的表达增加相关，并与压力超负荷时心肌毛细血管密度的保持相关。此外，带状PTEN KO小鼠保持了已知在心力衰竭中失调的几个关键代谢基因的表达。与此相反，降压剂量的G蛋白偶联受体（GPCR）激动剂血管紧张素II（Ang II）导致增加的病理性肥大和MAPK激活在PTEN KO mice.Conclusion的损失PTEN防止发展适应不良的心室重构与保存血管生成和代谢基因表达的压力超负荷，但不响应于GPCR激动剂，Ang II。抑制心脏中的PTEN信号传导可能代表了一种减缓心力衰竭对病理生物力学应激反应的进展的新方法。
Aims The maladaptive response to biomechanical stress is a fundamental response in heart disease. Loss of the 3'-lipid phosphatase, phosphatase and tensin homolog deleted on chromosome ten (PTEN), is associated with increased phosphorylation of Akt/protein kinase B and glycogen synthase kinase-beta. We hypothesize that these key changes will halt the development of pathological hypertrophy and the progression to heart failure in response to pressure overload.Methods and results In mice, muscle-specific knockout of PTEN, mckCRE-PTENflox/flox (PTEN KO), resulted in basal hypertrophy and mild reduction in left ventricular (W) systolic function. Mate mice were subjected to aortic banding (AB) or sham operation. In contrast to mckCRE-PTEN+/+ control mice, pressure overload in PTEN KO mice resulted in reduced pathological hypertrophy, less interstitial fibrosis, and reduced apoptosis with a marked preservation of LV function. Western blot analysis of mitogen-activated protein kinase (MAPK) signalling showed equivalent phosphorytation of extracellular signal-regulated kinase (ERK)1 and ERK2 with markedly reduced phosphorylation of jun N-terminal kinase (JNK)1 and JNK2, and p38 in PTEN KO mice subjected to AB. Loss of PTEN was associated with increased expression of the proangiogenic factors, vascular endothelial growth factor-A and angiopoietin-2, with preservation of the myocardial capillary density in response to pressure overload. Moreover, banded PTEN KO mice maintained the expression of several key metabolic genes that are known to be dysregulated in heart failure. In contrast, a subpressor dose of the G protein-coupled receptor (GPCR) agonist angiotensin II (Ang II) Leads to increased pathological hypertrophy and MAPK activation in PTEN KO mice.Conclusion Loss of PTEN prevents the development of maladaptive ventricular remodelling with preservation of angiogenesis and metabolic gene expression in response to pressure overload but not in response to the GPCR agonist, Ang II. Inhibition of PTEN signalling in the heart may represent a novel approach to slow the progression of heart failure in response to pathological biomechanical stress.