HSF1的磷酸化經ERK/GSK3路徑抑制RNF126以維持IGF-IIR表現促進高血壓所引起的心肌細胞肥大及凋亡

• Main Authors: Fa-Lun Lee, 李法倫
• Other Authors: Shu-Fen Peng
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/73608506640669288415

碩士 === 中國醫藥大學 === 生物科技學系碩士班 === 104 === Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure (HF). Our previous finding showed that extracellular signal-regulated kinases (ERK) inhibitor effective suppressed cardiomyocyte hypertrophy and apoptosis via inhibiting Angiotensin II (Ang II)-induced insulin-like growth factor II receptor (IGF-IIR) expression. As well, we discovered Ang II-induced heat shock transcription factor I phosphorylation (pHSF1) accumulated in cytosol, which is positive correlated with cardiomyocyte hypertrophy and apoptosis. However, the detailed mechanism by which ERK affects HSF-I phosphorylation to regulate IGF-IIR in heart cell remains elusive. In this study, we found that Ang II activated its downstream kinase ERK to increase IGF-IIR expression through its receptor, Angiotensin II type I receptor (AT1R). ERK activation subsequently phosphorylates HSF1 on serine 307 and leads to secondary phosphorylation by glycogen synthase kinase III (GSK3) on serine 303 in cardiac myoblast. Unexpectedly, we observed that Ang II-induced IGF-IIR expression was increased by ERK/GSK3 activation not though the DNA transcription, but via repressing IGF-IIR protein degradation. When the proteasome activity was inhibited, lots of ubiquitin-bound IGF-IIR complex was accumulated in cardiac myoblast, which is similar with the effect of Ang II. And we found that the E3 ubiquitin ligase of IGF-IIR, RING finger protein CXXVI (RNF126), was inhibited by p-HSF1 S303 to continually cause cardiomyocyte injury in hypertensive model. Afterwards, we confirmed direct effect of ERK/GSK3 inhibitor and compared with the widely used hypertension-Angiotensin II receptor blockers (ARBs) in vivo during 12 weeks Intraperitoneal(IP) injection into Wistar-Kyoto rats (WKY) and Spontaneously Hypertensive rat(SHR). Then we analyzed the cardiac function by echocardiography, observed the image of TUNEL, IHC, H&E staining on tissue sections, and isolated the left ventricular heart tissue to compare the target protein expression. Finally, we concluded that ERK/GSK3-activated pHSF1 at serine 303 and 307 repress the protein degradation of IGF-IIR by RNF126 decrease was accelerating cardiomyocyte hypertrophy and apoptosis during hypertension-induced HF. These findings provided us HSF1-influenced associated protein have therapeutic value in developing treatments for cardiac disease.