高血壓是一種慢性病，亦是現在最普遍的文明病。雖然已有一些化學合成降血壓藥物被開發出來，但通常伴隨一些副作用。一般認為從天然物中得到的血管收縮素轉化酶抑制(ACEI)胜肽相較於化學合成的藥物就有較低的副作用。龍膽石斑 (Epinephelus lanceolatus)，為世界上最大的石斑魚種，屬暖水性魚類，分佈範圍廣泛，其生長快速及高單價讓牠迅速成為台灣海水養殖的優勢種。在魚皮表面遍佈粘液，其成分會因魚種差異而有所不同。許多文獻已有研究與報告，魚的表皮粘液的組成和特徵對於免疫能力非常重要，例如活性胜肽、抗菌蛋白、凝集素、溶菌酶及蛋白酶等。本研究為利用4種酵素 (pepsin、trypsin、chymotrypsin及thermolysin) 水解龍膽石斑上皮黏液16小時，並由其一水解物中篩選並製備具抑制ACE活性之短鏈胜肽。研究結果顯示，thermolysin水解物對ACE具有最佳抑制活性，其IC50為32.24±2.75μg/mL，並利用逆相高效能液相層析儀將此水解物進行成分分群，其中以第五分群具有最佳抑制ACE活性，並在此分液中篩選出LR-6及LE-5胜肽，合成後測定其抑制活性之IC50分別為737.5±84.72μM及29.92±4.5μM，其抑制劑型態分別為真實抑制劑型及藥物前驅物型。此研究成果可為龍膽石斑養殖業開發可能之生技產品，增加產業競爭力且提高產業產品的附加價值。

Hypertension is a very common chronic disease nowadays. Although some chemically synthesized antihypertensive drugs have been developed, they are usually accompanied by side effects. Side effect of hypotensive active peptides is generally considered that are lower than that of synthetic one. Giant grouper (Epinephelus lanceolatus) is the largest grouper that belongs to warm-water species. It became a dominant species in Taiwan marine agriculture because of its fast growth rate and high price. Mucus composition varies throughout the epithelial surface and among fish species. The composition and characteristics of skin mucus is very important for the maintenance of its immune functions such as bioactive peptides, antibacterial proteins, lectins, lysozymes and proteases. The objectives of this study were to screen ACE inhibitory short-chain peptide from one of giant grouper epidermis mucus protein hydrolysate using different proteases (pepsin, trypsin, chymotrypsin and thermolysin) to hydrolysis for 16 hrs. The results indicated that thermolysin hydrolysate had the highest ACE inhibitory activity with the IC50 value of 32.24±2.75μg/mL. Fractionation of thermolytic hydrolysate was performed by reversed-phase high performance liquid chromatography (RP-HPLC). Fraction 5 showed the highest ACE inhibitory activity. LR-6 and LE-5 was chosen among all identified peptides from fraction 5, it has an IC50 value of 737.5±84.72μM and 29.92±4.5μM, the type of inhibitor is true inhibitor and prodrug, respectively. According to the results, development of biotech products of the peptide have improved the industrial competitiveness and economic value of the industrial products.

丁予安。1999。臨床高血壓。藝軒圖書出版社。新北市。112頁。
中央研究院數位文化中心&中央研究院生物多樣性研究中心。台灣魚類資料庫。
王俊雄、紀櫻珍、吳振龍、施奕仲、薛亞聖。2007。高血壓病患疾病管理之臨床應用。北市醫學雜誌 4卷2期。103-115頁。
行政院農業委員會漁業署。2017。民國106年 (2017) 漁業統計年報。
行政院衛生福利部。2017。105年國人死因統計結果。
施雅惠。2016。利用蛋白質體分析方法自決明子水解物中篩選出具降血壓活性之胜肽。碩士論文。屏東：國立屏東科技大學。
陳紫英。2015。行政院農業委員會水產試驗所。第112期。
劉江明、張桂香。2010。高血壓中醫奇方。吳氏圖書有限公司。
衛生福利部食品藥物管理署。2015。醫療器材使用安全記者會宣導資料。
衛生福利部國民健康署。2018。慢性病防治。
衛生福利部統計處。2017。民國106年死因統計年報。
Atlas S. A. (2007). The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition. Supplement to Journal of Managed Care Pharmacy 13(8): S9-S20.
Bansil R., & Turner B. (2018). The biology of mucus: Composition, synthesis and organization. Advanced Drug Delivery Reviews 124: 3-15.
Bhagani S., Kapil V., & Lobo M. D. (2018). Hypertension. Pathogenesis, Risk factors and prevention. 509-515.
Bougatef A., Arroume N. N., Plé R. R., Leroy Y., Guillochon D., Barkia A., & Naris M. (2008). Angiotensin I-converting enzyme (ACE) inhibitory activities of sardinelle (Sardinella aurita) by-products protein hydrolysates obtained by treatment with microbial and visceral fish serine proteases. Food Chemistry 111: 350-356.
Byun H. G., & Kim S. K. (2001). Purification and characterization of angiotensin I converting enzyme (ACE) inhibitory peptides from Alaska pollack (Theragra chalcogramma) skin. Process Biochemistry 36: 1155-1162.
Chiang C. E., Wang T. D., Ueng K. C., Lin T. H., Yeh H. I., Chen C. Y., Wu Y. J., Tsai W. C., Chao T. H., Chen C. H., Chu P. H., Chao C. L., Liu P. Y., Sung S. H., Cheng H. M., Wang K. L., Li Y. H., Chiang F. T., Chen J. H., Chen W. J., Yeh S. J., & Lin S. J. (2015). 2015 Guidelines of the Taiwan Society of Cardiology and the Taiwan Hypertension Society for the Management of Hypertension. Journal of the Chinese Medical Association. 1-47.
Chobanian A. V., Bakris G. L., Black H. R., Cushman W. C., Green L. A., Izzo J. L., Jones D. W., Materson B. J., Oparil S., Wright J. T., & Roccella E. J. (2003). Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure 42: 1206-1252.
Cushman D. W., & Cheung H. S. (1971). Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lung. Biochemical Pharmacology 20: 1637–1648.
Davis L. L. (2018). Hypertension: How Low to Go When Treating Older Adults. The journal for nurse pracitioners 15: 1-6.
Elavarasan K., Shamasundar B. A., Badii F., & Howell N. (2016). Angiotensin I-converting enzyme (ACE) inhibitory activity and structural properties of oven- and freeze-dried protein hydrolysate from fresh water fish (Cirrhinus mrigala). Food Chemistry 206: 210-216.
Emdin M., Fatini C., Mirizzi G., Poletti R., Borrelli C. Prontera C., Latini R., Passino C., Clerico A., & Vergaro G. (2015). Biomarkers of activation of renin-angiotensin-aldosterone system in heart failure: how useful, how feasible?. Clinica Chimica Acta 443: 85-93.
Fahmi A., Morimura S., Guob H.C., Shigematsu T., Kida K., & Uemurac Y. (2004). Production of angiotensin I converting enzyme inhibitory peptides from sea bream scales Process Biochemistry 39: 1195–1200.
Harris T., Cook E. F., Kannel W., Schatzkin A., & Goldman L. (1985). Blood pressure experience and risk of cardiovascular disease in the elderly. American heart association. 7:118–124.
Helal F., & Lane M. E. (2014). Transdermal delivery of Angiotensin Converting Enzyme inhibitors. European Journal of Pharmaceutics and Biopharmaceutics 88: 1-7.
Hseu J. R., Hwang P. P., & Ting Y. Y. (2004). Morphometric model and laboratory analysis of intracohort cannibalism in giant grouper Epinephelus lanceolatus fry. Ficheries Science 70: 482–486.
Je J. Y., Park Y., Jung W. K., Park P. J., & Kim S. K. (2005). Isolation of angiotensin I converting enzyme (ACE) inhibitor from fermented oyster sauce, Crassostrea gigas. Food Chemistry 90: 809-814.
Kaya A., Tatlisu M. A., Kaya T. K., Yildirimturk M., Gungor B., Karatas B., Yazici S., Keskin M., Avsar S., & Murat A. (2016). Pharmacology in Emergency Medicine 50: 108-115.
Kearney P. M., Whelton M. Reynolds K., Muntner P., Whelton P. P. K., & He J. (2005). Global burden of hypertension: analysis of worldwide data. The Lancet 356 (9455) 217-113.
Lammi C., Aiello G., Boschin G., & Arnoldi A. (2019). Multifunctional peptides for the prevention of cardiovascular disease: A new concept in the area of bioactive food-derived peptides. Journal of Functional Foods 55: 135-145.
Lang T., Klasson S., Larsson E., Johansson M. E. V., Hansson G. C., &　 Samuelsson　T. (2016). Searching the Evolutionary Origin of Epithelial Mucus Protein Components - Mucins and FCGBP. Advance Access publication 33: 1921-1936.
Lin K., Zhang L. W., Han X., Xin L., Meng Z. X., Gong P. M., & Cheng D. Y. (2018). Yak milk casein as potential precursor of angiotensin I-converting enzyme inhibitory peptides based on in silico proteolysis. Food Chemistry 254: 340-347.
Meisel H., & FitzGerald R. J. (2003). Biofunctional peptides from milk proteins: Mineral binding and cytomodulatory effects. Current Pharmaceutical design 9: 1289-1295.
Minkiewicz P., Dziuba J., Iwaniak A., Dziuba M., & Darewicz M. (2008). BIOPEP database and other programs for processing bioactive peptide sequences. Journal of AOAC International 91: 965-980.
Nasri, R., Chataigné, G., Bougatef A., Chaâbouni M. K., Dhulster P., & Nasri M. (2013). Novel angiotensin I-converting enzyme inhibitory peptides from enzymatic hydrolysates of goby (Zosterisessor ophiocephalus) muscle proteins. Journal of Proteomics 91: 444-452.
Pan D., Guo H., Zhao B., & Cao J. (2011). The molecular mechanisms of interactions between bioactive peptides and angiotensin-converting enzyme. Bioorganic & Medicinal Chemistry Letters 21: 3898–3904.
Pank M., KirretaO., Paberit N., & Aaviksaar A. (1982). Hydrophobic interaction in thermolysin specificity. Federation of European Biochemical Societies Letters 142 (2) 297-300.
Perumareddi P. (2018) Prevention of hypertension related to cardiovascular disease. Primary care: clinics in office practice.
Salehabadi H., Khajeh K., Dabirmanesh B., BIglar M., & Amanlou M. (2019). Evaluation of angiotensin converting enzyme inhibitors by SPR biosensor and theoretical studies. 120: 117-123.
Dos Santos D.M., de Souza C. B., & Pereira H. J. (2017). Angiotensin converting enzymes in fish venom. Toxicon 131: 63-67.
Sasaki C., Tamura S., Tohse R., Fujito S., Miyu K., Asada C., & Nakamura Y. (2018) Isolation and identification of an angiotensin I-converting enzyme inhibitory peptide from pearl oyster (Pinctada fucata) shell protein hydrolysate. Process Biochemistry 77: 137-142.
Souza M. C. d., Franco C. H. j., Pinheiro C. B., & Diniz R. (2014) Conformational polymorphism of a zinc complex with enalapril antihypertensive drug. Polyhedron 81: 290-297.
Tenorio H. d. A., Costa R. B., Marques M. E. C., Santos C. W. V. d. Gomes F. S., & Pereira H. J. V. (2016) Angiotensins processing activities in the venom and epidermic mucus of Scorpaena plumieri. Toxicon 119: 92-98.
Tu M., Wang C., Chen C., Zhang R., Liu H., Lu W., Jaing L., & Du M. (2018). Identification of a novel ACE-inhibitory peptide from casein and evaluation of the inhibitory mechanisms. Food Chemistry. 256: 98-104.
Whyte S. K. (2007). The innate immune response of finfish e A review of current knowledge. Fish & shellfish immunology 23: 1127-1151.
Wu J., Aluko R. E., & Nakai S. (2006). Structural Requirements of Angiotensin I-Converting Enzyme Inhibitory Peptides: Quantitative Structure-Activity Relationship Study of Di- and Tripeptides. Agricultural and Food chemistry 54: 732-738.
Wzgarda A., Kleszcz R., Prokop M., Regulska K., Regulski M., Paluszczak J., & Stanisz B. J. (2017). Unknown face of known drugs – what else can we expect from angiotensin converting enzyme inhibitors?. European Journal of Pharmacology 797: 9-19.
Zhao H., Li D. Li T., Yang Y., Liu Y., Li J., & Mao J. (2019). Efficacy and safety of acupuncture for hypertension: An overview of systematic reviews. Complementary Therapies in Clinical Practice 32: 185-194.