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研究生: 廖品豪
Pin-Hao Liao
論文名稱: 第一型糖尿病與高血壓引起勃起功能障礙之病理機制與治療策略
The Exploration of Pathophysiologic Mechanisms and Therapeutic Strategy for Type I Diabetes and Hypertension Induced Erectile Dysfunction
指導教授: 鄭劍廷
Chien, Chiang-Ting
學位類別: 碩士
Master
系所名稱: 生命科學系
Department of Life Science
論文出版年: 2015
畢業學年度: 103
語文別: 中文
論文頁數: 128
中文關鍵詞: 高血壓第一型糖尿病勃起功能障礙活性氧細胞凋亡細胞自噬一氧化氮
英文關鍵詞: Hypertension, Type I diabetes, Erectile dysfunction, Reactive oxygen species, Apoptosis, Autophagy, Nitric oxide
DOI URL: https://doi.org/10.6345/NTNU202205346
論文種類: 學術論文
相關次數: 點閱:210下載:5
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  • 研究背景:高血壓與糖尿病為現代人常見之文明病。高血壓與糖尿病造成男性勃起功能障礙可能是因血管、神經與平滑肌病變和內分泌睪固酮失調所致。我們推論其造成勃起功能障礙的病生理機轉為:長期高血壓與高血糖環境可能會增加活性氧產生而(1)引起發炎反應,(2)降低陰莖海綿體之一氧化氮產生與作用,(3)增加活性氧產生會氧化大分子如DNA、脂質與蛋白質造成陰莖海綿體內神經、血管與平滑肌肉細胞進行三種計畫性細胞死亡如細胞自噬、細胞凋亡與發炎性細胞死亡,(4)直接影響勃起功能之海綿體神經發生生理失調與病理結構病變而無法刺激陰莖海綿體之勃起,(5) 影響Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor (Nrf-2)/Heme-oxygenase 1 (HO-1)表現與訊息途徑而造成勃起功能障礙。
    研究方法:本研究利用正常血壓之WKY成年雄鼠與自發性高血壓之成年雄鼠。實驗分成四組:正常血壓WKY組(N=6),糖尿病WKY組 (N=6),高血壓SHR組 (N=6)與糖尿病合併高血壓SHR組 (N=6)。我以腹腔注射鏈佐霉素 (Streptozotocin,65 mg/kg)誘發第一型糖尿病。記錄海綿體內壓觀察代謝症候群老鼠的海綿體勃起功能,以高感度化學發光偵測儀定量血液中活性氧數量觀察氧化壓力變化,以組織免疫染色與西方墨點法觀察三種計畫性細胞死亡包括細胞凋亡、細胞自噬與發炎性細胞凋亡相關蛋白的表現與作用,以及一氧化氮量測儀觀察組織內一氧化氮變化量。我亦探究一氧化氮前驅化學物質與內皮一氧化氮合成酶(Endothelial Nitric Oxide Synthase, eNOS)抑制劑對勃起功能之影響。
    研究目的:為釐清糖尿病與高血壓引起男性勃起功能障礙的病理機轉,並建立找尋新型治療策略的動物生理模式。
    研究結果:結果顯示高血壓組(ΔICP/MAP = 0.22±0.02, N=6)與糖尿病組(ΔICP/MAP = 0.27±0.01, N=6)之陰莖海綿體勃起功能顯著低於控制組(ΔICP/MAP = 0.33±0.01, N=6),且同時罹患高血壓與糖尿病的組別有更低之陰莖海綿體勃起功能(ΔICP/MAP = 0.20±0.02, N=6)。高血壓組(lucigenin ROS = 784±452 counts/120 sec, N=6;luminol ROS = 741±132 counts/120 sec, N=6)與糖尿病組(lucigenin ROS = 643±192 counts/120 sec, N=6;luminol ROS = 393±158 counts/120 sec, N=6)之氧化壓力壓顯著高於控制組(lucigenin ROS = 445±160 counts/120 sec, N=6;luminol ROS = 117±74 counts/120 sec, N=6),且同時罹患高血壓與糖尿病的組別有更高的氧化壓力(lucigenin ROS = 5820±259 counts/120 sec, N=6;luminol ROS = 4550±1537 counts/120 sec, N=6)。靜脈注射左旋精氨酸後各組勃起海綿體內壓與海綿體一氧化氮量皆有提高。控制組在注射人工合成的一氧化氮提供劑CCL5後亦有較高的勃起海綿體內壓。注射內皮一氧化氮合成酶(eNOS) 拮抗劑N-硝基-L-精氨酸甲酯(Nω-Nitro-L-Arginine methyl ester hydrochloride, L-NAME)會明顯降低所有組別之勃起海綿體內壓。與控制組比較,糖尿病會增加發炎指標(Cluster of Differentiation 68 , CD68)、細胞凋亡蛋白cleaved-Caspase-3、細胞自噬蛋白Beclin-1、與保護性蛋白Nrf-2之表現。與控制組比較,高血壓亦增加發炎指標CD68、細胞凋亡蛋白cleaved-Caspase-3、細胞自噬蛋白Beclin-1、與保護性蛋白Nrf-2和HO-1之表現。而糖尿病合併高血壓組別有更高之發炎指標CD68、細胞凋亡蛋白cleaved-Caspase-3、細胞自噬蛋白Beclin-1、與保護性蛋白Nrf-2和HO-1之表現。在陰莖海組織染色也一致性發現糖尿病、高血壓或是糖尿病合併高血壓會造成陰莖內神經、海綿體和血管組織增加白血球浸潤、CD68單核球(Monocyte)數目、肥大細胞(Mast Cell)數目、細胞凋亡與細胞自噬數目與纖維化程度而eNOS表現則降低。
    結論:綜合以上實驗結果,代謝症候群引起勃起功能失常可能是透過氧化壓力、發炎、細胞凋亡與細胞自噬的增加,雖然Nrf-2/HO-1保護機制有略為增加但不能對抗嚴重的傷害程度。給予CCL5及左旋精氨酸可以改善勃起功能。

    Background: Diabetes and hypertension are modern civilization diseases, and they are also the major factors contributing to erectile dysfunction (ED) possibly via vascular, neuronal, smooth muscle cell damage and endocrine testosterone dysregulation. The possible pathophysiologic mechanisms of ED may be ascribed to excess reactive oxygen species (ROS) generation (1) leading to inflammation in the corpus cavernosum, (2) decreasing the production and activity of nitric oxide (NO), (3) oxidizing DNA, lipid and protein in vascular, neuronal and smooth muscle cells of corpus cavernosum leading to three types of programmed cell death, apoptosis, autophagy and pyroptosis, (4) directly impairing cavernous nervous function and structural alteration leading to ED, and (5) affecting of Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor (Nrf-2) and heme oxygenase 1 (HO-1) expression/signaling to leading to ED. The therapeutic potential of NO donors were also evaluated in our ED model.
    Purpose: I explored the pathophysiologic mechanisms and therapeutic effect of NO donors on hypertension and diabetes induced ED in the rats.
    Methods: I used adult male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in this study. I divided these rats into four groups, normal WKY (N=6), diabetic WKY (N=6), normal SHR (N=6) and diabetic SHR (N=6). I induced streptozotocin (65 mg/kg, i.p.) to induce type I diabetes in WKY and SHR rats. I recorded intra-cavernous pressure (ICP) as the index of erectile function by electrical stimulation of cavernosal nerves. I used an ultrasensitive chemiluminescence analyzer to determine blood ROS and oxidative stress. I utilized Western Blotting and the immunohistochemistry to explore the possible proteins involved three types of programmed cell death, apoptosis, autophagy and pyroptosis in the penis tissue. I also used a NO detector to measure NO amount and the effect of NO donor and endothelial nitric oxide synthase (eNOS) inhibitor on hypertension and diabetes induced ED in the rats.
    Results: The ratio of ΔICP/MAP was significantly decreased in normal SHR (ΔICP/MAP = 0.22±0.02, N=6), diabetic WKY (ΔICP/MAP = 0.27±0.01, N=6), and diabetic SHR (ΔICP/MAP = 0.20±0.02, N=6) when compared to normal WKY rats (ΔICP/MAP = 0.33±0.01, N=6). The amount of oxidative stress was significantly increased in normal SHR (lucigenin ROS = 784±452 counts/120 sec, N=6; luminol ROS = 741±132 counts/120 sec, N=6), diabetic WKY (lucigenin ROS = 643±192 counts/120 sec, N=6; luminol ROS = 393±158 counts/120 sec, N=6), and diabetic SHR (lucigenin ROS = 5820±259 counts/120 sec, N=6; luminol ROS = 4550±1537 counts/120 sec, N=6) when compared to the normal WKY (lucigenin ROS = 445±160 counts/120 sec, N=6; luminol ROS = 117±74 counts/10 sec, N=6). Intravenous administration of L-Arginine markedly increased the ICP and NO amount in all four groups. Intravenous synthetic NO donor CCL5 also dose-dependently increased ICP in the ED rats. However, eNOS inhibitor treatment (Nω-Nitro-L-Arginine methyl ester hydrochloride, L-NAME) significantly depressed ICP in all four groups. When compared to normal WKY rats, diabetes increased inflammatory cluster of differentiation 68 (CD68) and mast cells numbers, apoptotic cleaved Caspase-3, autophagic Beclin-1 and protective Nrf-2 expression in the penis. When compared to normal WKY rats, diabetes increased inflammatory cluster of differentiation 68 (CD68), mast cells numbers, apoptotic cleaved Caspase-3, autophagic Beclin-1 and protective Nrf-2 expression in the penis. In comparison with normal WKY, hypertension also enhanced CD68, apoptotic cleaved Caspase-3, autophagic Beclin-1 and Nrf-2/HO-1 expression. In addition, diabetic SHR had a highest CD68, apoptotic cleaved-Caspase-3, autophagic Beclin-1 and Nrf-2/HO-1 expression when compared to normal WKY, diabetic WKY and SHR. The results from immunohistochemistry showed that diabetic WKY, SHR and diabetic SHR consistently displayed higher stains of leukocyte infiltration, CD68, mast cells, cleaved-Caspase-3, Beclin-1, fibrosis and Nrf-2/HO-1 expression and a decreased stain of eNOS in the impaired cavernosal nerves and vessels and corpus cavernosum of the penis.
    Conclusion: Based on these results, diabetes and hypertension led to ED through the increased oxidative stress, inflammation, apoptosis and autophagy and the decreased NO synthesis and production. Although Nrf-2/HO-1 signaling is mildly enhanced after hypertension or diabetes, the upregulation seems to be inadequate to confer protection. The application of CCL5 and L-Arginine can improve the degree of ED.

    中文摘要 4 Abstract 8 縮寫表 14 1-1、研究背景與特色 17 1-2 、代謝症候群造成勃起功能障礙之機制及分類 18 1-2-1、糖尿病與勃起功能障礙 18 1-2-2、高血壓與勃起功能障礙 19 1-2-3、一氧化氮與勃起功能障礙 20 1-2-4、自由基與勃起功能障礙 21 1-3、計劃性細胞死亡與勃起失常之關聯 21 1-3-1、計劃性細胞死亡意義 22 1-3-2、計劃性細胞死亡之分類 22 1-3-3、自由基與計劃性細胞死亡 24 1-4、Nrf-2-Keap1 pathway 25 1-5、左旋精氨酸在勃起過程中的重要性與其潛在治療效果 27 1-6、研究的重要性與目的 28 第二章 研究材料與方法 Materials and Methods 30 2-1、實驗動物分組 31 2-1-1自發性高血壓鼠 (Spontaneously hypertensive rats, SHR) 31 2-1-2正常控制組老鼠 (Wistar-Kyoto rats, WKY) 31 2-2、第一型糖尿病誘發方法 32 2-2-1、糖尿病誘發用藥物:鏈佐霉素Streptozotocin, STZ 32 2-2-2、糖尿病動物誘發方式 32 2-3、陰莖海綿體神經電刺激與海綿體內壓及一氧化氮含量記錄 33 2-3-1、麻醉與插管 33 2-3-2、游離陰莖海綿體神經 34 2-3-3、陰莖海綿體內壓記錄 35 2-3-4、即時陰莖海綿體組織一氧化氮含量變化記錄 35 2-3-5、針對左旋精氨酸治療效果評估之給藥流程 36 2-3-6、針對CCL5治療效果評估之給藥流程 37 2-4、西方墨點轉漬Western Blotting 38 2-5、免疫組織化學染色Immunohistochemistry, IHC 45 2-6、Masson’s Trichrome Stain 48 2-7、TUNEL Assay 49 2-8、離體血液自由基測定 52 第三章 研究結果 Results 55 3-1、STZ誘發第一型糖尿病造成體重下降與高血糖及代謝參數變化 56 3-2、高血壓與第一型糖尿病造成血液自由基增加 57 3-3、高血壓與第一型糖尿病嚴重影響陰莖海綿體勃起內壓 58 3-4、左旋精氨酸與CCL5對由高血壓與第一型糖尿病所引起之勃起失常之治療效果 60 3-5、高血壓與第一型糖尿病嚴重影響陰莖海綿體組織一氧化氮 釋放能力與eNOS表現量 61 3-6、左旋精氨酸改善勃起時陰莖組織一氧化氮釋放能力 62 3-7、高血壓誘發陰莖海綿體組織、血管與神經細胞發炎反應 64 3-8、高血壓與第一型糖尿病誘發陰莖海綿體組織、血管與神經細胞凋亡 65 3-9、高血壓誘發陰莖海綿體組織、血管與神經細胞自噬 65 3-10、高血壓與第一型糖尿病誘發陰莖組織Nrf-2/HO-1保護機制 66 3-11、高血壓與第一型糖尿病導致陰莖海綿體組織與血管週邊纖維化 68 第四章、總結 Conclusion 69 第五章、討論 Discussion 71 圖表 Figures 81 表格 Table 120 參考文獻 123

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