發(fā)布時間：2018-08-28 10:33

【摘要】：研究背景糖尿病心肌病(Diabetic Cardiomyopathy,DC)最初由Rubler于1972年首先描述,定義為無冠狀動脈疾病、高血壓或其他潛在病因的由糖尿病引起的一種特異性心肌病。常表現(xiàn)為心臟順應性降低,舒張期充盈受阻或收縮功能不全。研究發(fā)現(xiàn)高血糖及相關的代謝紊亂可直接損傷心肌,從而導致DC,因此糖尿病心血管并發(fā)癥的患者均可合并DC。臨床上DC擁有很大的發(fā)病人群,對患者造成很大的危害。早期的觀點認為在DC病理生理改變中,心肌破壞的主要形式為心肌細胞壞死,而隨后大量的研究發(fā)現(xiàn),心肌壞死更多發(fā)生在心肌梗塞的急性期等急性病變中,而糖尿病的心肌病理改變是慢性長期的過程,主要表現(xiàn)為心肌間質纖維化、心肌細胞肥大和心肌細胞凋亡,其中心肌細胞凋亡在DC的發(fā)生發(fā)展中占據(jù)主要地位[1,2],故抑制心肌細胞凋亡應是臨床防治糖尿病性心肌病的關鍵。在既往的研究中已發(fā)現(xiàn)上調脂聯(lián)素途徑關鍵蛋白脂聯(lián)素受體連接蛋白1(APPL1)可改善糖尿病性心肌病[3],進一步的研究發(fā)現(xiàn)脂聯(lián)素途徑保護心血管系統(tǒng)作用環(huán)節(jié)在于激活脂聯(lián)素信號途徑中的APPL1-AMPK軸,抑制核因子NF-?B的表達[4,5]。此外,其他實驗室和我們均已發(fā)現(xiàn)脂聯(lián)素信號途徑中的PPARα能抑制NF-?B,直接參與防止糖尿病心肌細胞凋亡[6],而PPARα為AMPK的重要信號下游分子。據(jù)此,我們推測在脂聯(lián)素途徑中可能存在“APPL1-AMPK-PPARα軸”,其在防止糖尿病心肌細胞凋亡方面可能占有重要地位。又有研究發(fā)現(xiàn)胰高血糖素樣肽-1(GLP-1)對心血管系統(tǒng)有一定保護作用,可以減少包括糖尿病心肌細胞的凋亡,并可促進脂聯(lián)素的分泌,且該作用獨立于降糖效應之外[7-9]。因此,現(xiàn)在廣泛認可的觀點是GLP-1具有對糖尿病患者心血管保護作用,其機制可能與激活脂聯(lián)素途徑有關,我們進一步推測GLP-1可能具有減少糖尿病心肌細胞凋亡的作用,其作用機制在于激活心肌細胞脂聯(lián)素信號通路,活化APPL1-AMPK-PPARα軸。為證明我們的設想,本實驗擬從臨床觀察、動物模型和細胞水平進行深入研究。目前,臨床上尚無明確的糖尿病性心肌病的診斷標準,主要以心功能參數(shù)作為參考指標。我們擬首先收集臨床2型糖尿病病例,并與正常體檢人群對照,探索2型糖尿病患者血清脂聯(lián)素水平變化與心功能參數(shù)改變的相關關系。其次擬通過小劑量鏈脲佐菌素(stz)+高脂飲食誘導2型糖尿病大鼠模型,予以glp-1受體激動劑艾塞那肽為干預措施,觀察艾塞那肽對糖尿病心肌細胞凋亡的影響,并觀察艾塞那肽通過調節(jié)脂聯(lián)素途徑關鍵連接蛋白appl1水平影響心肌細胞凋亡的作用。最后,在培養(yǎng)大鼠原代心肌細胞中檢測艾塞那肽對心肌細胞脂聯(lián)素信號途徑的激活作用及對細胞凋亡的影響。目的觀察2型糖尿病血清脂聯(lián)素水平與心臟功能之間的相關關系以及艾塞那肽對心肌細胞凋亡的影響,闡明艾塞那肽通過激活脂聯(lián)素途徑改善糖尿病性心肌病的作用及其機制。方法1.收集2型糖尿病患者及健康體檢者的臨床基本資料,采集患者空腹靜脈血,elisa法檢測血清高分子量脂聯(lián)素水平,增強磁共振測定患者心功能指標;2.構建2型糖尿病sd大鼠模型,高脂飲食喂養(yǎng),分為正常對照組(n組),糖尿病組(d組),糖尿病加胰島素治療組(di組),糖尿病加艾塞那肽治療組(de組),成模后干預12周,取大鼠髂靜脈血,elisa法測定血清胰島素、脂聯(lián)素,多媒體生物信號記錄儀測定血流動力學,tuenl法檢測心肌細胞凋亡變化,取心臟組織行免疫組化及western-blotting檢測信號分子appl1、ampk、pparα、nf-?b表達水平;3.培養(yǎng)原代鼠心肌細胞,分為正常對照組(c組),高糖高脂組(d組),高糖高脂+艾塞那肽組(de組),高糖高脂+艾塞那肽+appl1過表達腺病毒組(oe組),高糖高脂+艾塞那肽+appl1干擾腺病毒組(bl組),elisa法測定細胞培養(yǎng)液中高分子量脂聯(lián)素水平,tuenl法檢測原代心肌細胞凋亡變化,取心肌細胞行western-blotting檢測信號分子appl1、ampk、pparα、nf-?b表達水平。結果本實驗共收集到30例2型糖尿病患者(t2dm組)及30例健康體檢患者(n組),兩組患者一般資料無明顯差異,t2dm組患者糖化血糖水平(hba1c)、空腹血糖水平、homa-ir指數(shù)明顯高于n組患者,c肽水平低于n組患者,而兩組間胰島素水平無明顯統(tǒng)計學差異。t2dm組患者血清hdl水平(1.23±0.40mmol/l)明顯低于n組患者(1.61±0.45mmol/l),tg水平(3.73±3.44mmol/l)明顯高于n組患者(1.56±0.86mmol/l),差異具有統(tǒng)計學意義(p0.05)。二組患者的tc及l(fā)dl水平無差別(p0.05)。t2dm組患者血清高分子量脂聯(lián)素水平(10.83±2.81mg/l)明顯低于n組(14.90±3.26mg/l)(p0.05)。經(jīng)心臟增強磁共振檢測,t2dm組患者心臟左室舒張末期容積(edv)(59.70±7.26ml/m2)及每搏輸出量(sv)(34.77±6.48ml/m2)較n組edv(65.84±9.67ml/m2)及sv(38.40±4.75ml/m2)降低,而收縮末期容積(esv)(29.00±6.60ml/m2)較n組(24.25±5.51ml/m2)明顯增加,差異均有統(tǒng)計學意義(p0.05)。相關分析顯示高分子量脂聯(lián)素水平與糖尿病患者每搏輸出量之間存在一定的正相關關系[r=0.376,p=0.041]。在動物實驗中,di組及de組血糖較d組明顯下降,血清胰島素上升,差異均有統(tǒng)計學意義(p0.05),而di與de兩組間血糖水平無明顯差異。d組及di組血清高分子量脂聯(lián)素水平較n組明顯下降,de組血清高分子量脂聯(lián)素水平較di組明顯上升,差異均有統(tǒng)計學意義(p0.05)。d組心肌細胞凋亡率(55.71%±3.84%)明顯增加,de組大鼠心肌細胞凋亡率(27.43%±3.63%)明顯下降,而與de組比較,di組大鼠心肌細胞凋亡率(43.91%±4.23%)明顯升高。心功能檢測顯示相較于c組,d組大鼠心臟lvsp(105.87±4.08mmhg)及di組大鼠心臟lvsp(107.19±4.09mmhg)明顯降低,而d組大鼠心臟lvedp(17.62±1.74mmhg)及di組大鼠心臟lvedp(17.48±1.49mmhg)明顯增加,差異均具有統(tǒng)計學意義(p0.05)。相較于di組,de組大鼠心臟lvsp(119.11±5.11mmhg)明顯增加,而lvedp(13.64±1.25mmhg)明顯降低,差異具有統(tǒng)計學意義(p0.05)。對心肌細胞信號分子的檢測顯示相較于c組,d組及di組心肌appl1、p-ampk、pparα表達量均明顯降低,但nf-?b表達量較c組明顯升高。de組appl1、p-ampk、pparα表達量分別為0.65±0.02、0.78±0.04、1.72±0.05,較d組及di組明顯增加,de組大鼠心肌nf-?b表達量較d組和di組心肌明顯升高,差異有統(tǒng)計學意義(p0.05)。細胞實驗中,我們發(fā)現(xiàn)心肌細胞具有自分泌脂聯(lián)素的能力,并觀察到de組、oe組、bl組大鼠細胞上清高分子量脂聯(lián)素水平分別為9.40±0.16mg/l、8.70±0.34mg/l、和9.30±0.30mg/l,較d組明顯上升(p0.05),de、oe、bl組細胞上清脂聯(lián)素水平比較差異沒有統(tǒng)計學意義(p0.05)。但細胞凋亡檢測結果提示de組細胞凋亡(20%~29%)較d組(34%~42%)有降低趨勢。oe組中這種趨勢更加明顯(18%~24%),但相反的bl組細胞凋亡率較de組明顯上升(43%~52%),差異均有統(tǒng)計學意義(p0.05)。另外,各組心肌細胞appl1、p-ampk、pparα、nf-?b檢測結果與動物實驗結果具有相同變化趨勢。結論2型糖尿病患者心臟收縮及舒張功能受損與循環(huán)中高分子量脂聯(lián)素水平降低密切相關,運用glp-1受體激動劑艾塞那肽干預糖尿病后通過上調血清和心肌細胞自分泌脂聯(lián)素水平及激活APPL1-AMPK-PPARα軸信號通路,抑制了心肌細胞內(nèi)NF-?B活化和心肌細胞凋亡,改善糖尿病心肌功能。
[Abstract]:Background Diabetic cardiomyopathy (DC), originally described by Rubler in 1972, is defined as a specific cardiomyopathy caused by diabetes without coronary artery disease, hypertension or other underlying causes. It is often characterized by decreased cardiac compliance, diastolic filling impairment or systolic dysfunction. Blood glucose and related metabolic disorders can directly damage the myocardium and lead to DC, so patients with diabetic cardiovascular complications can be combined with DC. Clinically, DC has a large number of patients, causing great harm to patients. A large number of studies have found that myocardial necrosis occurs more in the acute phase of myocardial infarction and other acute lesions, and diabetic myocardial pathological changes are a chronic long-term process, mainly manifested as myocardial interstitial fibrosis, cardiomyocyte hypertrophy and cardiomyocyte apoptosis, in which cardiomyocyte apoptosis plays a major role in the occurrence and development of DC [1,2]. It has been found that up-regulation of adiponectin pathway key protein adiponectin receptor connexin 1 (APPL1) can improve diabetic cardiomyopathy [3]. Further studies have found that adiponectin pathway protects cardiovascular system by activating lipids. The APPL1-AMPK axis in the adiponectin signaling pathway inhibits the expression of nuclear factor NF-? B [4,5]. In addition, other laboratories and we have found that PPARa in the adiponectin signaling pathway inhibits NF-? B and directly participates in the prevention of apoptosis of diabetic cardiomyocytes [6]. PPARa is an important downstream molecule of AMPK signal. There may be an "APPL1-AMPK-PPAR alpha axis" which may play an important role in preventing apoptosis of diabetic cardiomyocytes. Some studies have found that glucagon-like peptide-1 (GLP-1) has a protective effect on cardiovascular system, which can reduce apoptosis of cardiomyocytes including diabetes mellitus and promote adiponectin secretion, and this effect is independent of Therefore, it is widely accepted that GLP-1 has cardiovascular protective effects in diabetic patients. The mechanism may be related to the activation of adiponectin pathway. We further speculate that GLP-1 may reduce the apoptosis of diabetic cardiomyocytes by activating adiponectin signaling pathway. To prove our hypothesis, we intend to conduct in-depth study from clinical observation, animal model and cell level. At present, there is no definite clinical diagnostic criteria for diabetic cardiomyopathy, mainly with cardiac function parameters as reference indicators. We intend to collect clinical type 2 diabetes mellitus cases and with normal. To explore the relationship between serum adiponectin level and cardiac function parameters in type 2 diabetes mellitus (T2DM) patients. Secondly, the model of type 2 diabetes mellitus (DM) rats was induced by low-dose streptozotocin (stz) + high-fat diet, and the intervention of GLP-1 receptor agonist exenatide was given to observe the effect of exenatide on diabetic cardiomyocyte apoptosis. Aim To observe the effect of exenatide on apoptosis of cardiomyocytes by regulating the level of key connexin appl 1 in adiponectin pathway. The relationship between diabetic cardiomyopathy and adiponectin level and cardiac function, and the effect of exenatide on cardiomyocyte apoptosis were studied to elucidate the effect and mechanism of exenatide on diabetic cardiomyopathy by activating adiponectin pathway. Methods Serum high-molecular-weight adiponectin levels were detected and cardiac function indexes were measured by enhanced magnetic resonance imaging (MRI). 2. The model of type 2 diabetes mellitus (DM) rats were established and fed with high-fat diet. The rats were divided into normal control group (n group), diabetic group (d group), diabetic plus insulin group (di group), diabetic plus exenatide group (de group). The levels of serum insulin and adiponectin were measured by elisa, the hemodynamics was measured by multimedia bio-signal recorder, the changes of cardiomyocyte apoptosis were detected by tuenl, and the expressions of appl-1, ampk, PPAR-a and NF-B were detected by immunohistochemistry and western-blotting. 3. Group c, group d, group de, group oe, group bl, group d, group d, group d, group d, group de, group oe, group b, group b, group d, group d, group d, group d, group d, group d, group d, group c, group d, group d, group d, group d, group d, group c, group d, group c, group d, group d, group d, group d, group d, group c, group d, group d, group d, group d, group d, group c, group d, group d, group c, group c, group d, group c, group c, group Western-blotting was used to detect the expression of appl-1, ampk, PPAR-a and nf-b. Results 30 patients with type 2 diabetes mellitus (t2dm group) and 30 healthy people (n group) were collected. There was no significant difference in the general data between the two groups. The levels of hba1c, fasting blood glucose and HOMA-IR index in T2DM group were significantly higher than those in n group. The level of serum HDL (1.23 + 0.40 mmol / l) in T2DM group was significantly lower than that in N group (1.61 + 0.45 mmol / l), and the level of TG (3.73 + 3.44 mmol / l) was significantly higher than that in N group (1.56 + 0.86 mmol / l), the difference was statistically significant (p0.05). Serum high-molecular-weight adiponectin (10.83 (+ 2.81 mg / l)) in T2DM group was significantly lower than that in N group (14.90 (+ 3.26 mg / l) (p0.05). left ventricular end-diastolic volume (edv) (59.70 (+ 7.26 ml / m2) and stroke output (sv) (34.77 (+ 6.48 ml / m2)) in T2DM group were significantly lower than that in N group (65.84 (+ 9.67 ml / m2) and SV (38.4) by cardiac contrast-enhanced magnetic resonance imaging. The end systolic volume (esv) (29.00 + 6.60ml / m2) was significantly higher than that of N group (24.25 + 5.51ml / m2). correlation analysis showed that there was a positive correlation between high molecular weight adiponectin level and stroke output of diabetic patients [r = 0.376, P = 0.041]. The levels of high molecular weight adiponectin in group D and di were significantly lower than those in group n, and the levels of high molecular weight adiponectin in group de were significantly higher than those in group di (p0.05). Myocyte apoptosis rate (55.71% + 3.84%) was significantly increased, myocardial apoptosis rate (27.43% + 3.63%) was significantly decreased in de group, and myocardial apoptosis rate (43.91% + 4.23%) was significantly increased in di group compared with de group. cardiac function test showed that compared with C group, LVSP (105.87 + 4.08mmhg) in D group and LVSP (107.19 + 4.09mmhg) in Di Group rats. LVEDP (17.62 + 1.74 mmhg) in group D and LVEDP (17.48 + 1.49 mmhg) in group Di were significantly increased (p0.05). LVSP (119.11 + 5.11 mmhg) in group de was significantly increased, while LVEDP (13.64 + 1.25 mmhg) in group Di was significantly decreased (p0.05). Compared with group c, the expression of appl-1, p-ampk and PPAR-a in myocardium of group D and di decreased significantly, but the expression of NF-B increased significantly. the expression of appl-1, p-ampk and PPAR-a in myocardium of group de were 0.65 (+) 0.02, 0.78 (+) 0.04, 1.72 (+) 0.05) respectively, which were significantly higher than that of group D and di. the expression of NF-B in myocardium of group de was significantly higher than that of group D and di. The level of high molecular weight adiponectin in the supernatant of de group, OE group and BL group was 9.40 (+ 0.16 mg / l), 8.70 (+ 0.34 mg / l) and 9.30 (+ 0.30 mg / l) respectively, which was significantly higher than that of D group (p0.05), de, OE and BL group (p0.05). There was no significant difference in serum adiponectin levels (p0.05). however, the results of apoptosis detection showed that apoptosis in de group (20% ~ 29%) was lower than that in D group (34% ~ 42%). The results of appl-1, p-ampk, PPAR-alpha and NF-B in cardiomyocytes of group 2 showed the same trend as those of animal experiment. Conclusion The impairment of cardiac systolic and diastolic function in type 2 diabetes mellitus is closely related to the decrease of circulating high molecular weight adiponectin levels. Cell autocrine adiponectin level and activation of APPL1-AMPK-PPARalpha axis signaling pathway inhibited the activation of NF-? B and myocardial cell apoptosis, and improved diabetic myocardial function.
【學位授予單位】：第三軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R587.2

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6 郁U，

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