【正文】 中 文 全 稱AMI Acute myocardial infarction 急性心肌梗死ALD Aldosterone 醛固酮ANG II Angiotensin II 血管緊張素 IIACEI Angiotensinconvertingenzyme inhibitor 血管緊張素轉(zhuǎn)換（酶）抑制劑ARB Angiotensin receptor blocker 血管緊張素受體拮抗劑CF Cardiac function 心功能CHD Coronary heart disease 冠心病CHF Congestive heart failure 慢性心力衰竭DOC Doxycycline 多西環(huán)素ECM Extracellular matrix 細(xì)胞外基質(zhì)HF Heart failure 心力衰竭M(jìn)I Myocardial infarction 心肌梗死 VR Ventricular remodeling 心室重構(gòu) LVR Left ventricular remodeling 左心室重構(gòu) MF Myocardial fibrosis 心肌纖維化MMP2 Matrix metalloproteinase 2 基質(zhì)金屬蛋白酶 2MMP9 Matrix metalloproteinase 9 基質(zhì)金屬蛋白酶 9LAD Left anterior descending coronary 冠狀動(dòng)脈左前降支LVAW Left ventricular anterior wall 左心室前壁LVPW Left ventricular posterior wall 左心室后壁安 徽 醫(yī) 科 大 學(xué) 碩 士 學(xué) 位 論 文6LVSD Left ventricular end systolic diameter 左室收縮末期內(nèi)徑LVEDD Left ventricular enddiastolic dimension 左室舒張末內(nèi)徑LVFS Left ventricular fractional shortening 左室短軸縮短率LVEF Left ventricular ejection fraction 左心室射血分?jǐn)?shù)RAAS Reninangiotensinaldosterone system 腎素血管緊張素 醛固酮系統(tǒng) 安 徽 醫(yī) 科 大 學(xué) 碩 士 學(xué) 位 論 文7中文摘要多西環(huán)素抑制基質(zhì)金屬蛋白酶對(duì)心肌梗死大鼠左室重構(gòu)和心功能的影響研究目的 觀察多西環(huán)素（Doxycycline）對(duì)心肌梗死（Myocardial infarction， MI）后大鼠心肌基質(zhì)金屬蛋白酶2（MMP2）和基質(zhì)金屬蛋白酶9（MMP9）活性的影響及其對(duì)大鼠心肌梗死后心衰（ Heart failure，HF）和左心室重構(gòu)(Left ventricular remodeling，LVR)的保護(hù)作用。術(shù)后 2 周后 SD 雄性大鼠全身麻醉?xiàng)l件下心臟彩超評(píng)價(jià) SD 雄性大鼠心功能，心臟彩超檢查結(jié)束后處死大鼠開(kāi)胸右室采血后取出大鼠心臟，用 PBS 緩沖液沖洗干凈，并除去附著的脂肪，稱出全心重量（HW） 。研究結(jié)果 MI 2 周后與模型組相比，心臟彩超提示：多西環(huán)素組左室前壁（Left ventricular anterior wall，LVAW）厚度明顯增加（P） ，左室舒張末期內(nèi)徑(Left ventricular enddiastolic dimension，LVDD)縮?。≒） ，左室短軸縮短率( Left ventricular fractional shortening， LVFS)顯著增加，左心室射血分?jǐn)?shù)（Left ventricular ejection fraction，LVEF）增高。關(guān)鍵詞：心肌梗死 左室重構(gòu) 基質(zhì)金屬蛋白酶 多西環(huán)素 心肌纖維化 AbstractDoxycycline Attenuate Left Ventricular Remodeling and Improve Left Ventricular Function through Inhibiting Matrix metalloproteinases inPost Myocardial Infarcted RatsObjectives To observe the effects of doxycycline on the activity of matrix metalloproteinase2 (MMP2) and MMP9, left ventricular remodeling and left ventricular function in the post myocardial infarction (MI) rats. Methods Total 50 male SD rats intraperitoneal injected with sodium pentobarbital (70 ) anesthesia, after anesthesia, all of them with electrophysiology instrument monitoring ECG, endotracheal intubation and connected to a breathing machine (Respiratory rate of 45 times per minute, tidal volume of 30 ml each time),34 of them made into models of MI by ligation of anterior descending coronary artery．Except the two died, 32 successful modeling,and then randomly divided into two groups：Model group, Doxycycline (DOC) group, with 16 rats each group．Remaining 16 rats undergoing thoracic surgery without ligaturing anterior descending coronary artery called shamoperated group. Three days later，rats in DOC group were intraperitoneally injected with doxycycline (15 ,bid for 5 days), model group were injected with saline solution ( bid *5 days). Rats in shamoperated group were injected with saline solution ( bid *5 days). Cardiac function were evaluated by echocardiography 2 weeks post MI,After echocardiography examination the rats were all killed,and then open chest removed their heart tissue. Cardiac tissue went through the PBS buffer rinse and removing adhered fat. We calculated heart weight to body weight ratio, 安 徽 醫(yī) 科 大 學(xué) 碩 士 學(xué) 位 論 文10expressed with HW / BW . Cardiac tissue was fixed after the myocardial tissue embedded in paraffin, made of the 5μm thick slices,size of MI were analyzed by Masson staining method . Each group were taken six rat myocardium frozen tissue homogenate placed in Lysis buffer, centrifuged at 12022 rpm for 15 minutes and MMP2, MMP9 activity were analyzed by gelatin enzymatic analysis. Results, Compared with the model group, the left ventricular (LV) wall thickness increased significantly in DOC group, acpanied with the improvement of LV fractional shortening and LV ejection fraction (P, respectively), while the LV enddiastolic diameter was significantly reduced (P). Compared with Shamoperated group,the HW/BW in Model group and Doxycycline group were increased , especially Model group were significantly increased ,(P)。心肌梗死導(dǎo)致嚴(yán)重的心肌損傷，心肌損傷后基因組表達(dá)改變引起的分子、細(xì)胞和間質(zhì)的改變，分子改變表現(xiàn)為炎癥因子、基質(zhì)金屬蛋白酶和生長(zhǎng)因子等的表達(dá)增加，細(xì)胞的改變包括心肌細(xì)胞的肥大、壞死、凋亡和成纖維細(xì)胞的增殖等，間質(zhì)的改變表現(xiàn)為細(xì)胞外基質(zhì)的降解及安 徽 醫(yī) 科 大 學(xué) 碩 士 學(xué) 位 論 文12膠原聚集又稱纖維化。建議只有在血流動(dòng)力學(xué)穩(wěn)定后才可以應(yīng)用β1 受體阻滯劑 [2]。AT1 受體存在于心肌細(xì)胞、血管平滑肌細(xì)胞、內(nèi)皮細(xì)胞、血小板、神經(jīng)末梢和傳導(dǎo)系統(tǒng)，介導(dǎo)所有已知的 AngII 的心血管作用，特別是通過(guò)活化細(xì)胞周期蛋白、降低細(xì)胞周期激酶抑制因子而加強(qiáng)血管壁 DNA 的合成 。Tsutsumi 等人通過(guò)實(shí)驗(yàn)證實(shí)選擇性刺激大動(dòng)脈平滑肌細(xì)胞 AT2 能夠增加緩激肽釋放，進(jìn)一步使得 NO 合成增加，引起舒張血管的效應(yīng)，顯示長(zhǎng)期抑制 AT1 表達(dá)、同時(shí)增加 AT2 表達(dá)，對(duì)于控制高血壓病人的血壓水平是有意義的 [8]。目前臨床應(yīng)用較多的是 ACEI、ARB，一項(xiàng)大規(guī)模的臨床實(shí)驗(yàn)顯示：纈沙坦和卡托普利在改善心功能，抑制梗死后 VR 作用類(lèi)似，但是 ACEI 和 ARB 聯(lián)合組并不能減低死亡率，反而臨床上不良事件增加，故臨床上建議單一用藥 [10]。CHF 治療中的“ALD 逃逸現(xiàn)象”：在心衰時(shí)，由于血管緊張素水平增高，刺激ALD 合成分泌增多。 交感迷走神經(jīng)失衡與 VR心臟自主神經(jīng)之間的不平衡，在心力衰竭的發(fā)展中有著重要作用。一項(xiàng)多中心開(kāi)放性研究納入 32 例心功能 IIIV 級(jí)心力衰竭病人，植入迷走神經(jīng)刺激裝置，規(guī)律刺激患者迷走神經(jīng)達(dá)患者最大耐受程度，隨訪一年，發(fā)現(xiàn)患者 6min 步行由刺激前的（ 411177。7）%提高到（29177。典型特征為細(xì)胞縮小，染色質(zhì)凝集，核膜折疊，核仁裂解，繼而細(xì)胞膜出泡（胞？），分割細(xì)胞為多個(gè)凋亡小體，凋亡小體進(jìn)而被具有吞噬功能的細(xì)胞如巨噬細(xì)胞吞噬、降解。在正常發(fā)育過(guò)程中，心肌細(xì)胞凋亡的數(shù)目具有增齡性變化特征 [19]，是維持心臟組織形態(tài)和功能相對(duì)穩(wěn)定的細(xì)胞學(xué)基礎(chǔ)，并且在心臟形態(tài)轉(zhuǎn)型和重塑中發(fā)揮平衡作用 ，表明無(wú)論在正常生理或病理?xiàng)l件下，心肌細(xì)胞均存在著凋亡現(xiàn)象，具有增齡性變化特征，凋亡可導(dǎo)致心肌細(xì)胞大量減少，并對(duì)心功能產(chǎn)生嚴(yán)重影響。他們利用大氣中的放射性污染發(fā)現(xiàn)，在人的生長(zhǎng)過(guò)程中，心肌細(xì)胞確實(shí)能夠在一定程度上進(jìn)行更新。因