TM-1-1 和 TM-1-1-DP 對於成年大鼠初代心肌細胞之心臟保護及抗氧化力

簡介：TM-1-1 (NTU-A) 和 TM-1-1-DP (NTU-A-DP) 是由aporphine alkaloid 類合成而來的兩個衍生物。在過去的研究中，TM-1-1 (NTU-A) 和 TM-1-1-DP (NTU-A-DP)已在缺血再灌流的動物實驗中發現許多的心臟保護作用。這些保護作用包括：減少梗塞面積、減少發炎物質的釋放以及活化具有心臟保護功效的eNOS和ERK等蛋白。且具有兩個磷酸根的TM-1-1-DP (NTU-A-DP) 又比 TM-1-1 (NTU-A) 擁有更好的水溶性與安全性。然而，他們的分子保護機制以及彼此間的差異尚未釐清。方法與材料：我們使用成年SD大鼠的初代心室細胞作為主要的細胞模式，來排除其他非心肌細胞的干擾與模擬生理狀態。我們也使用氯化亞鈷與過氧化氫等化學物質在細胞模式上模擬缺血時的細胞缺氧狀態以及再灌流之氧化壓力。實驗結果與討論：我們首先發現 TM-1-1 (NTU-A) 和 TM-1-1-DP (NTU-A-DP)對初代心室細胞有促進eNOS和ERK活化的初步效果。TM-1-1 (NTU-A) 和 TM-1-1-DP (NTU-A-DP)也有潛力透過5-HT2B receptor相關路徑提升因過氧化氫而降低的細胞存活率。雖然同樣是提升細胞存活率，我們發現TM-1-1 (NTU-A) 和 TM-1-1-DP (NTU-A-DP)是透過不一樣的路徑：TM-1-1 (NTU-A) 可以透過5-HT2B receptor的活化而降低caspase 3 的活性與增加細胞的存活率；TM-1-1-DP (NTU-A-DP)則可能透過 PI3K/AKT/eNOS的訊息傳遞路徑增加細胞的存活率。然而，一些與5-HT2B receptor不相關或與NO訊息傳遞不相關的路徑以及其他細節還需要後續更深入的探討。

關鍵字

Thaliporphine衍生物；初代成年大鼠心室細胞；過氧化氫所引發的氧化壓力； eNOS ； L-NAME ； 5-HT2B receptor ； SB-215505

並列摘要

M 1-1 (NTU-A) and TM 1-1-DP (NTU-A-DP) are two synthetic derivatives of aporphine alkaloid. They had been found to afford various cardioprotective effects on ischemia-reperfusion model in vivo including a reduction of infarct size, inflammatory cytokines and an activation of cardioprotective proteins such as eNOS and ERK with better water solubility and safety for the later compound. However, the molecular mechanisms of their beneficial effects and differences haven’t been fully investigated. In order to elucidate their possible protective pathways on myocyes, we isolated primary cardiomyocytes to exclude interferences from non-myocytes and tried to gain better access to physiological or pathological condition in vivo. In the present study, primary ventricular cardiomyocytes were isolated from adult male Sprague-Dawley rats as a main cell model in vitro. Besides, hydrogen peroxide was administered to mimic the oxidative stress produced during reperfusion, which imposed a major injury to ischemia-reperfused hearts. Here, we found a preliminary effect of NTU-A and NTU-A-DP to induce eNOS and ERK activations in cultured ventricular cardiomyocytes, which had been proven in vivo. NTU-A and NTU-A-DP also showed a potential to maintain cell viability after H2O2-induced oxidative stress via the activation of 5-HT2B receptor-related pathway. Moreover, NTU-A can reduce caspase 3 activity and increase cell viability via the activation of 5-HT2B receptor; and NTU-A-DP may increase cell survival by stimulation of PI3K/AKT/eNOS signaling pathway via the activation of 5-HT2B receptor. Whereas, the involvement of 5-HT2B receptor-independent, NO-independent pathways and other details require further investigation.

並列關鍵字

Thaliporphine derivatives ； Primary adult rat ventricular cardiomyocytes ； hydrogen peroxide-induced oxidative stress ； eNOS ； L-NAME ； 5-HT2B receptor ； SB-215505

參考文獻

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2 Kloner R. A. & Whittaker P. Deleterious effects of oxygen radicals in ischemia/reperfusion. Resolved and unresolved issues. Circulation80, 1115-1127, doi:10.1161/01.cir.80.5.1115 (1989).

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5 M. J. Su & Lee. Thaliporphine, a positive inotropic agent with a negative chronotropoc action. Eur. J. Pharmacol.254, 141-150 (1994).

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TM-1-1 和 TM-1-1-DP 對於成年大鼠初代心肌細胞之心臟保護及抗氧化力

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