Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, CA, USA.
Circ Res. 2013 Apr 26;112(9):1244-52. doi: 10.1161/CIRCRESAHA.113.301084. Epub 2013 Mar 13.
Cardiac hypertrophy results from the complex interplay of differentially regulated cascades based on the phosphorylation status of involved signaling molecules. Although numerous critical regulatory kinases and phosphatases have been identified in the myocardium, the intracellular mechanism for temporal regulation of signaling duration and intensity remains obscure. In the nonmyocyte context, control of folding, activity, and stability of proteins is mediated by the prolyl isomerase Pin1, but the role of Pin1 in the heart is unknown.
To establish the role of Pin1 in the heart.
Here, we show that either genetic deletion or cardiac overexpression of Pin1 blunts hypertrophic responses induced by transaortic constriction and consequent cardiac failure in vivo. Mechanistically, we find that Pin1 directly binds to Akt, mitogen activated protein kinase (MEK), and Raf-1 in cultured cardiomyocytes after hypertrophic stimulation. Furthermore, loss of Pin1 leads to diminished hypertrophic signaling of Akt and MEK, whereas overexpression of Pin1 increases Raf-1 phosphorylation on the autoinhibitory site Ser259, leading to reduced MEK activation.
Collectively, these data support a role for Pin1 as a central modulator of the intensity and duration of 2 major hypertrophic signaling pathways, thereby providing a novel target for regulation and control of cardiac hypertrophy.
心脏肥大是由涉及信号分子磷酸化状态的不同调节级联的复杂相互作用引起的。尽管已经在心肌中鉴定出许多关键的调节激酶和磷酸酶，但信号持续时间和强度的细胞内调节机制仍不清楚。在非心肌细胞中，蛋白质的折叠、活性和稳定性的控制是由脯氨酰异构酶 Pin1 介导的，但 Pin1 在心脏中的作用尚不清楚。
确定 Pin1 在心脏中的作用。
在这里，我们表明 Pin1 的基因缺失或心脏过表达均可减弱体内主动脉缩窄诱导的和随后的心力衰竭引起的心肌肥厚反应。在机制上，我们发现 Pin1 在培养的心肌细胞中，在受到肥厚刺激后，直接与 Akt、丝裂原激活蛋白激酶 (MEK) 和 Raf-1 结合。此外，Pin1 的缺失导致 Akt 和 MEK 的肥厚信号减弱，而过表达 Pin1 则增加 Raf-1 在自动抑制位点 Ser259 上的磷酸化，从而减少 MEK 的激活。
总之，这些数据支持 Pin1 作为 2 种主要肥厚信号通路的强度和持续时间的中心调节剂的作用，从而为心脏肥厚的调节和控制提供了一个新的靶点。
