| 摘要: | 異常的高血壓通常會造成心臟肥大和心肌細胞凋亡，促進心臟衰竭的進展。臨床上高血壓患者通常表現較高的血管收縮素 II (Angiotensin II , Ang II)。我們的研究已經建立了Ang II 誘導心臟細胞凋亡的機制，Ang II 透過調節JNK-SIRT1-HSF1 訊息路徑活化類胰島素生長因子II (Insulin-like growth factor II receptor, IGF-IIR) 進而造成心肌細胞凋亡。IGF-IIR 活化觸發心臟衰竭時心肌細胞凋亡的訊息傳導路徑。數千年以來中草藥被用作為一種治療心臟病的療法。桔梗 (PG) 的萃取物和純化物具有神經保護、抗菌、抗發炎、抗癌、抗過敏和降低膽固醇等性能。在此項研究中，我們發現結梗具有保護心臟之作用，實驗結果顯示桔梗的萃取物顯著抑制Ang II 誘導的IGF-IIR 訊號傳導途徑以防止心肌細胞凋亡。 桔梗萃取物藉由減弱Ang II 調控的JNK 活化而造成SIRT1 (為熱休克轉錄因子1 之去乙醯基酵素)降解作用，來抑制IGF-IIR 活性。透過維SIRT1 穩定性來增強熱休克轉錄因子1 (Heat shock factor 1, HSF1)對IGF-IIR 的轉錄抑制作用，保護心肌細胞免於凋亡作用。此外；動物實驗結果顯示，餵食桔梗顯著降低自發性高血壓大鼠 (Spontaneously hypertensive rat, SHR) 心肌細胞凋亡。因此，桔梗可能被認為是治療高血壓所引起的心臟疾病之有效治療方法。
PART II
高血壓是一種進行性的疾病，左心室代償性增厚以?持足夠的心?出量，這將會導致心肌細胞纖?化 (fibrosis)，血管新生不足，心肌重塑 (myocardial remodeling)；甚至會造成心肌細胞凋亡(apoptosis) 和心臟衰竭等。這過程中涉及一種可能的機制：Ang II透過調節JNK-SIRT1-HSF1 訊息傳遞路徑，進而活化IGF-IIR 導致心肌?胞凋亡。在本研究中，我們證明桔梗皂? (Platycodin D, PD)能夠抑制IGF-IIR 轉錄 (transcription) 和轉譯 (translation) 作用，並且不會造成細胞毒性。研究結果顯示：PD 可以調控與高血壓?導之?胞凋亡作用相關的IGF-IIR 蛋白表現。最重要的是：PD減少Ang II ?導的p-HSF1 和p-JNK 蛋白表現；並增加SIRT1 蛋白表現。此外；PD 抑制細胞凋亡作用如：降低Ang II ?導的半胱天冬?-3 (caspases 3) 蛋白活性和減少IGF-IIR 轉位至?胞膜作用等。這些?果表明，PD 可作為一種功能性化合物，保護心肌?胞免於高血壓所造成之?胞凋亡
It has been widely accepted that abnormal hypertension leads to cardiac hypertrophy and apoptosis which contributes to the progress of heart failure.
Elevated levels of the vessel contractor protein Ang II are commonly observed in hypertensive patients. Our studies have built up a detailed mechanism of angiotensin II (Ang II). Ang II induced cardiac apoptosis through activation of IGF-IIR by JNK-SIRT1-HSF1 regulation. IGF-IIR activation triggered intracellular signaling cascades that contributed to cardiomyocyte apoptosis during heart failure. Traditional Chinese Medicine (TCM) has been used as a prescription of heart disease therapy for thousands of years. The extracts and purified of PG may exhibit neuroprotective, anti-microbial, anti-inflammatory, anti-cancer, anti-allergy and cholesterol-lowering properties. In this study, we demonstrated the cardioprotective role of PG in cardiomyocytes. Our data indicated that the crude extract of PG significantly suppressed the Ang II-induced IGF-IIR signaling pathway to preventcardiomyocyte apoptosis. PG extract inhibited IGF-IIR activity by alleviating Ang II-mediated JNK activation and SIRT1 degradation. Sustaining the SIRT1 stability by PG enhanced HSF1-mediated IGF-IIR suppression, which protected cardiomyocyte from apoptosis.
Moreover, administration of PG significantly reduced the cardiac apoptosis in the hearts of SHRs. Therefore, PG may be considered as an effective treatment for hypertension-induced cardiac diseases
PART II
Hypertension is a progressive condition. The compensatory left ventricular hypertrophy maintains cardiac output. It leads to myocardial remodeling characterized by fibrosis, insufficient vascularization, even
apoptosis and heart failure. This condition involves a possible mechanism of Ang II-induced cardiac apoptosis through the activation of IGF-IIR by JNK-SIRT1-HSF1 regulation. In this study, we demonstrate that PD is capable of inhibiting IGF-IIR transcription and translation without cytotoxicity. These findings suggest that PD has an effect on IGF-IIR expression that is related to hypertension-induced apoptosis. Most
important of all, PD reduces p-HSF1 and p-JNK expression induced by Ang II. SIRT1 expression is also upregulated by PD compared with the Ang II group. PD suppresses apoptosis, as indicated by reductions in Ang II-induced caspase-3 activity and IGF-IIR translocation to the cell membrane. These results indicate that PD may be a functional compound to protect cardiomyoblasts from apoptosis occurring in response to
hypertension. |
