砷化物是環境中常見類金屬，其在醫藥的用途上扮演著多面性的角色。一方面，它是一個很強的助致癌物，並且與某些血管疾病的發生有關連；另一方面，砷化物具有對抗急性前骨髓細胞白血病的能力，因此在醫療的應用上也具有開發的潛力。
　　烏腳病是一種在1960-70期間發生在台灣西南沿海一帶的地方性血管疾病，根據文獻顯示，深井水中所含的砷化物，可能在烏腳病的發生過程中扮演重要的角色。為了探討三價砷化物的攝取與烏腳病發生的關聯性，我們研究三價砷化物對培養中的大血管與微血管內皮細胞在細胞表現血纖維蛋白溶解能力與抗凝活性上的影響。結果發現經由砷化物處理後的人類微血管內皮細胞(HMEC-1)，其胞內表現的組織型血纖維蛋白溶解原活化因子(tissue-type plasminogen activator)之mRNA含量下降、血纖維蛋白溶解酶原活化因子抑制子(plasminogen activator inhibitors)的mRNA含量及活性上升，同時三價砷化物也會抑制人類微血管內皮細胞的凝血酶調節素(thrombomodulin; TM)之mRNA表現，並且降低TM抗原的表現量。然而，砷化物的處理卻對人類臍靜脈內皮細胞(HUVECs)的血纖維蛋白溶解能力沒有明顯的影響。這結果顯示三價砷化物很明顯的降低人類微血管內皮細胞的血纖維蛋白溶解能力，對人類臍靜脈內皮細胞的影響則較不明顯，而這可能與烏腳病具有較低之血纖維蛋白溶解能力具有相關性。
　　感染性病原菌，例如皰疹病毒，會促進動脈粥狀化病變的進展。在先前的實驗中，我們從牛頸動脈內皮細胞的持續培養中分離出一隻牛皰疹病毒第四型(BHV-4)，我們也發現牛頸動脈內皮細胞適合此病毒的感染。因為三價砷化物可能會影響內皮細胞的生理特性，因此我們認為砷化物會影響牛皰疹病毒在牛頸動脈內皮細胞中的複製。當牛皰疹病毒感染牛頸動脈內皮細胞後，會刺激細胞使得mitogen-activated protein kinase (MAPK)中的extracellular signal-regulated kinase (ERK)產生兩個週期的活化作用。如果以MEK的專一性抑制劑U0126或低濃度三價砷化物處理牛皰疹病毒感染的牛頸動脈內皮細胞，則會以濃度相關的形式阻斷ERK的活化，並且會使培養的病毒之病毒DNA合成及病毒複製受到抑制。進一步的研究顯示病毒的前早期基因-2 (IE-2)，此前早期基因是病毒DNA複製時必須的基因，很明顯地受到U0126及砷化物處理的壓抑。這些結果指出在牛頸動脈內皮細胞中複製繁殖的皰疹病毒，U0126及砷化物可以透過抑制ERK活化，而抑制病毒的IE-2蛋白合成，及病毒的複製。
　　另一方面，以較高濃度的砷化物處理，會誘導細胞產生熱休克蛋白70(HSP70)，同時干擾細胞生長週期的進行，導致細胞在S及G2/M週期累積。在此情況下，牛皰疹病毒第四型的感染力，包括IE-2的表現，DNA複製及病毒的產量均明顯受抑制，在相同處理之牛頸動脈內皮細胞的細胞存活率並不受砷化物處理的的影響。如果以actinomycin D處理細胞，則會抑制HSP70的誘發並且會使砷化物的抗病毒活性下降，這顯示砷化物處理牛頸動脈內皮細胞後所誘導產生的壓力性反應，可透過誘導熱休克蛋白70的生合成，及干擾細胞生長週期的進行，而抑制牛皰疹病毒第四型的複製。我們的研究發現，依於砷化物所使用的濃度與細胞型態，砷化物可經由產生不同的機轉而抑制牛皰疹病毒第四型的複製，這些結果或許可以提供新的方向用以治療與皰疹病毒相關的感染。
　　總之，砷化物對內皮細胞有多面性的影響，具有成為病毒抑制藥物的潛力；然而，在長期的砷化物暴露下，可能對內皮細胞的生物功能產生反向的影響, 例如造成血纖維蛋白溶解能力的降低。

　　Arsenic is a semimetal commonly found in environment and has pleiotropic effects in medicinal use. It has a potent cocarcinogenic activity and is implicated in vascular diseases. On the other hand, it exhibits therapeutic effect against acute promelocytic leukemica.
　　The field studies implicated that arsenic in the drinking water from artesian wells was significantly correlated with the development of the Blackfoot disease, an endemic peripheral vascular atherosclerosis disease that occurred in the southwest coast of Taiwan. In order to investigate the relationship of arsenite uptake and vascular disease, the effects of arsenite on the fibrinolytic and anticoagulant activities of cultured endothelial cells obtained from large and micro blood vessels were analyzed. Incubation with arsenite decreased t-PA mRNA level, and increased PAI-1 mRNA level and PAI activity in human microvascular endothelial cells (HMEC-1), but not in human umbilical vein endothelial cells (HUVECs). The thrombomodulin (TM) mRNA expression and antigen level in HMEC-1 were also inhibited by arsenite treatment. The results demonstrated HMEC-1 is more sensitive to arsenite than HUVECs in inhibition of fibrinolytic activity and may be responsible for the reduced fibrinolysis activity in Blackfoot disease.
　　Many recent reports suggested that infection of pathogen such as herpesviridae might promote the atherosclerotic cascade. In the previous studies, we isolated a bovine herpesvirus-4 (BHV-4) from the culture of bovine arterial endothelial (BAE) cells, and demonstrated that BAE cells were susceptible to the infection of the virus. Since arsenite may affect the physiological properties of endothelial cells, we propose arsenite would affect the BHV-4 replication in BAE cells. Infection of BHV-4 induced a biphasic activation of one of the cellular mitogen-activated protein kinase (MAPK) downstream targets, extracellular signal-regulated kinase (ERK). Treatment with either U0126, a potent inhibitor of MAPK/ERK kinase (MEK) or arsenite, results in a dose-dependent inhibition of ERK activation, viral DNA synthesis and viral replication in the culture. Further investigations revealed that transcription of viral immediate-early gene 2 (IE-2), which is required for viral DNA replication, was significantly suppressed by both U0126 and arsenite. These results imply that inhibition of ERK activation by U0126 or arsenite can effectively inhibit viral IE-2 protein synthesis and viral replication.
　　On the other hand, pretreatment with high dosage of arsenite would induce heat shock protein 70 (HSP70) expression and cause interruption of cell cycle leading to accumulation of cells in the S and G2/M phases. BHV-4 infectivity, including IE-2 expression, DNA replication and viral yield, were significantly reduced in nontoxic concentrations of arsenite, in which cellular DNA synthesis or cell viability were not significantly affected under resting and confluent conditions. Actinomycin D inhibited the induction of HSP70 and reduced arsenite antiviral activity. The results indicated that stress responses induced by arsenite in BAE cells resulted in the induction of HSP70 and interference of cell cycle progression leading to the inhibition of BHV-4. In conclusion, our findings indicate that arsenite inhibits BHV-4 replication via different mechanisms depending on the doses of arsenite and cell types, which may provide a new direction in treatment of herpesvirus-related infection.
　　In summary, arsenic has pleiotropic effect on endothelial cells. It has the potential to be a viral suppressing agent. However, long term exposure of arsenite may have an adverse effect on the biological functions of endothelial cells, such as decrease in fibrinolytic activity.

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