无创性肢体缺血预适应对大鼠心脏延迟保护作用的研究
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摘要
目的：研究和观察无创性肢体缺血预适应(NLIP)对心脏缺血再灌损伤后的延迟保护作用。
方法：麻醉大鼠，以改良的自制无创血压测试仪套管套住大鼠左后肢根部，脉搏传感器紧贴在足背动脉上，加压使脉搏消失即为阻断股动脉标志，持续5min，减压，脉搏出现为再灌标志，持续5min，共3个循环。Wistar大鼠，体重240-260g，雄性，随机分为3组。(1)心肌缺血再灌组(I／R组，n=10)：心脏冠状动脉左前降支(LAD)实施30min缺血，120min再灌。(2)心肌缺血预适应组(IP组，n=10)：心脏LAD实施3次缺血5min／再灌5min后立即对心脏LAD实施30min缺血，120min再灌。(3)NLIP组(n=10)：左后肢实施3次缺血5min／再灌5min，每天1次，连续3天，第4天对心脏LAD实施30min缺血，120min再灌。
结果：
1．NLIP对大鼠心肌缺血再灌损伤后生理学的影响：
与I／R组(0.373±0.131mV)比较，IP和NLIP均能降低缺血后ST-段的抬高程度(0.232±0.086和0.161±0.116mV，P＜0.01)。I／R组心律失常出现时间早(2.5±0.9min)，持续时间长(21.3±5.3min)，发生率高，IP和NLIP均能推迟室性心律失常出现时间(11.2±3.4和16.7±3.5min，P＜0.01)，缩短持续时间(10.1±3.1和7.3±1.2min，P＜0.01)，降低发生率。但后两者之间无显著性差异。
2．NLIP对大鼠心肌缺血再灌损伤后心肌梗死面积和形态学的影响：
I／R组心肌梗死面积大(77.4±22.1mg)，梗死区与危险区比值(IS／AAR)高(44.5±8.1％)，HE染色见心肌细胞损伤严重，出现肿胀、核溶解消失、肌束断裂，伴有炎性细胞浸润。与I／R组比较，IP和NLIP组梗死面积显著减小(43.2±15.4和39.5±13.6mg，P＜0.01)，IS／AAR值明显降低(28.6±9.5和25.4±8.7％，P＜0.01)，HE染色见心肌细胞肿胀不明显，无肌束断裂，少量炎性细胞浸润。
3．NLIP对大鼠心肌缺血再灌损伤后生化的影响：
与I／R组(118.2±36.4U／L和2.66±1.00ng／ml)比较，IP和NLIP组CK-MB和cTnI在再灌期升高幅度降低(80.4±33.4和85.1±27.9U／L，P＜0.05；1.31±0.81和1.20±0.79ng／ml，P＜0.01)。与I／R组(300±49NU／ml)比较，IP和NLIP均能显著提高再灌后SOD活性(366±72和388±67NU／ml，P＜0.05和P＜0.01)。
4．NLIP对大鼠心肌缺血再灌损伤后心肌凋亡的影响：
I／R组在缺血区有较高的细胞凋亡率(16.21±2.12％)，其对应基因Bcl-2／Bax值较低(0.66±0.03)；和I／R组比较，IP和NLIP组的细胞凋亡率明显降低(5.30±0.81和4.82±1.15％，P＜0.01)，Bcl-2／Bax值明显升高(1.44±0.08和1.51±0.09，P＜0.01)。TUNEL法和免疫组化法得到结果与上述一致。
5．NLIP对大鼠心肌缺血再灌损伤后MMP-2、MMP-9及其抑制物TIMP-1的影响：
I／R组的缺血区内MMP-2(21.33±2.34％)和MMP-9(16.41±2.92％)的表达增加，TIMP-1的表达却明显减弱(10.79±1.15％)；与I／R组比较，IP和NLIP组的缺血区内MMP-2(12.35±1.10和12.55±1.08％，P＜0.01)和MMP-9(9.31±1.08和8.76±1.12％，P＜0.01)的表达有所减少，TIMP-1的表达有所增加(15.11±2.58和16.59±2.98％，P＜0.01)。免疫组化染色结果显示，阳性颗粒主要分布于心肌细胞的胞浆和血管内皮细胞的胞浆内，有时在间质细胞的胞浆中也可见到。RT-PCR结果和免疫组化结果一致。
6．NLIP对大鼠心肌缺血再灌损伤后纤溶因子的影响：
各组血浆中t-PA活性在缺血再灌期间呈进行性下降趋势，而PAI-1活性呈进行性升高趋势，再灌后，与I／R组t-PA(1.01±0.33U／ml)和PAI-1(27.11±0.63AU／ml)比较，IP和NLIP均能显著对抗t-PA活性的降低(1.98±0.46和1.89±0.44U／ml，P＜0.01)和PAI-1活性的升高(25.42±0.56和22.01±0.45AU／ml，P＜0.01)。
结论：
1．NLIP能明显降低心肌缺血再灌损伤所致缺血期ST-段抬高幅度，推迟由心肌缺血造成的室性心律失常出现时间，缩短持续时间，能够保护缺血再灌损伤心肌，且能达到心肌早期缺血预适应的程度。
2．NLIP能降低缺血再灌损伤所致心肌梗死面积，改善损伤的心肌细胞形态学改变。
3．NLIP能减少心肌缺血再灌损伤时心肌酶的漏出并且提高SOD的活性而保护心肌细胞。
4．NLIP能抑制缺血再灌损伤心肌细胞凋亡的发生，改善其可能的调控基因Bcl-2、Bax异常表达。
5．NLIP能降低缺血再灌损伤心肌MMPs的表达，增加TIMP-1的表达而减少缺血再灌对心脏基质的损伤，保护心脏正常结构。
6．NLIP能改善缺血再灌损伤所致体内纤溶／抗纤溶系统的紊乱，这可能是其保护心脏作用机制之一。
Objective: To study on the delayed protective effect of noninvasive limb ischemic preconditioning against myocardial injury in rats.
Method: After rat anesthetized with chloral hydrate, the left hind limb was trapped with canula of modified noninvasive sphygmomanometer. After that, to stick pulse transduce to arteria dorsalis pedis. Asphygmia indicated blockade of arteria femoralis, which lasted 5 min, while pulse appearance indicated reperfusion, which last 5 min, the procedure was operated 3 circles. Thirty healthy male Wistar rats (240-260 g) were divided randomly into 3 groups. (1) I/R group, only 30 min ischemia and 120 min reperfusion of LAD was conducted. (2) IP group, 3 circles of 5-min periods of I/R followed by 30 min ischemia and 120 min reperfusion of LAD. (3) NLIP group, 3 circles of 5-min periods of left hind limb I/R, once time every day for 3 days. On the forth day, 30 min ischemia and 120 min reperfusion of LAD was done. shorten IS (43.2±15.4 and 39.5±13.6 mg, P<0.01), decrease IS/AAR (28.6±9.5 and 25.4±8.7%, P<0.01), and myocardial injury was moderate: the swelling was not apparent, no fragmentation, only a little inflammatory cell infiltrated.
3. Influence of NLIP on the biochemistry after IRI
Compared with I/R group (118.2±36.4 U/L and 2.66±1.00 ng/ml), IP and NLIP could decrease CK-MB and cTnI (80.4±33.4 and 85.1±27.9 U/L, P<0.05; 1.31±0.81 and 1.20±0.79 ng/ml, P<0.01). Meanwhile, compared with I/R group (300±49 NU/ml), IP and NLIP could elevate SOD activity(366±72 and 388±67 NU/ml, P<0.05 and P<0.01).
4. Influence of NLIP on apoptosis of myocardium after IRI
The apoptosis rate in ischemic myocardium of I/R group was very high (6.21±2.12%), but Bcl-2/Bax was very low (0.66±0.03). Compared with I/R group, the apoptosis rate was decreased significantly (5.30±0.81and 4.82±1.15%, P<0.01), but Bcl-2/Bax was very high (1.44±0.08 and 1.51±0.09,P<0.01). Results of TUNEL and immunohistochemistry were in coincidence with above.
5. Influence of NLIP on MMPs after IRI
Expression of MMP-2 (21.33±2.34%) and MMP-9 (16.41±2.92%) was high, and TIMP-1 (10.79±1.15%) was low in ischemic myocardium of I/R group. Compared with I/R group, expression of MMP-2 (12.35±1.10 and 12.55±1.08%, P<0.01) and MMP-9 (9.31±1.08 and 8.76±1.12%, P<0.01) was decreased and expression of TIMP-1 (15.11±2.58 and 16.59±2.98%,P<0.01) was increased in IP and NLIP group. Positive particle distributed in the endochylema of myocardial cell and vascular endothelial cell, sometimes in the interstitial cell. Results of RT-PCR were in coincidence with immunohistochemistry.
6. Influence of NLIP on blood fibrinolysis factor after IRI
The activity of t-PA descended in progress during ischemia and reperfusion, but the activity of PAI-1 advanced in progress in every group. After reperfusion, the activity of t-PA and PAI-1 was 1.01±0.33 U/ml and 27.11±0.63 AU/ml respectively. Compared with I/R group, IP and NLIP could prevent t-PA activity (1.98±0.46 and 1.89±0.44 U/ml, P<0.01) from decreasing and PAI-1 (25.42±0.56 and 22.01±0.45 AU/ml, P<0.01) from increasing.
Conclusion:
1. NLIP could protect heart against IRI via reducing ST-segment, delaying onset, shortening duration and decreasing incidence rate of VA, which is nearly to the level of early cardiac ischemic preconditioning.
2. NLIP could decrease IS and improve morphological changes caused by IRI.
3. NLIP could protect cardiac cell against IRI through reducing the leakage of cardiac muscle enzyme, elevating SOD activity.
4. NLIP could prevent myocardium from apoptosis caused by IRI and improve anomaly expression of the controlling gene of Bcl-2 and Bax.
5. NLIP could decrease the expression of MMPs, increase the expression of TIMP caused by IRI, which prevented cardiac matrix from degrading and maintain myocardial normal structure.
6. NLIP could improve the system of fibrinolysis and anti-fibrinolysis, which maybe the one of mechanisms of protection.
方法：麻醉大鼠，以改良的自制无创血压测试仪套管套住大鼠左后肢根部，脉搏传感器紧贴在足背动脉上，加压使脉搏消失即为阻断股动脉标志，持续5min，减压，脉搏出现为再灌标志，持续5min，共3个循环。Wistar大鼠，体重240-260g，雄性，随机分为3组。(1)心肌缺血再灌组(I／R组，n=10)：心脏冠状动脉左前降支(LAD)实施30min缺血，120min再灌。(2)心肌缺血预适应组(IP组，n=10)：心脏LAD实施3次缺血5min／再灌5min后立即对心脏LAD实施30min缺血，120min再灌。(3)NLIP组(n=10)：左后肢实施3次缺血5min／再灌5min，每天1次，连续3天，第4天对心脏LAD实施30min缺血，120min再灌。
结果：
1．NLIP对大鼠心肌缺血再灌损伤后生理学的影响：
与I／R组(0.373±0.131mV)比较，IP和NLIP均能降低缺血后ST-段的抬高程度(0.232±0.086和0.161±0.116mV，P＜0.01)。I／R组心律失常出现时间早(2.5±0.9min)，持续时间长(21.3±5.3min)，发生率高，IP和NLIP均能推迟室性心律失常出现时间(11.2±3.4和16.7±3.5min，P＜0.01)，缩短持续时间(10.1±3.1和7.3±1.2min，P＜0.01)，降低发生率。但后两者之间无显著性差异。
2．NLIP对大鼠心肌缺血再灌损伤后心肌梗死面积和形态学的影响：
I／R组心肌梗死面积大(77.4±22.1mg)，梗死区与危险区比值(IS／AAR)高(44.5±8.1％)，HE染色见心肌细胞损伤严重，出现肿胀、核溶解消失、肌束断裂，伴有炎性细胞浸润。与I／R组比较，IP和NLIP组梗死面积显著减小(43.2±15.4和39.5±13.6mg，P＜0.01)，IS／AAR值明显降低(28.6±9.5和25.4±8.7％，P＜0.01)，HE染色见心肌细胞肿胀不明显，无肌束断裂，少量炎性细胞浸润。
3．NLIP对大鼠心肌缺血再灌损伤后生化的影响：
与I／R组(118.2±36.4U／L和2.66±1.00ng／ml)比较，IP和NLIP组CK-MB和cTnI在再灌期升高幅度降低(80.4±33.4和85.1±27.9U／L，P＜0.05；1.31±0.81和1.20±0.79ng／ml，P＜0.01)。与I／R组(300±49NU／ml)比较，IP和NLIP均能显著提高再灌后SOD活性(366±72和388±67NU／ml，P＜0.05和P＜0.01)。
4．NLIP对大鼠心肌缺血再灌损伤后心肌凋亡的影响：
I／R组在缺血区有较高的细胞凋亡率(16.21±2.12％)，其对应基因Bcl-2／Bax值较低(0.66±0.03)；和I／R组比较，IP和NLIP组的细胞凋亡率明显降低(5.30±0.81和4.82±1.15％，P＜0.01)，Bcl-2／Bax值明显升高(1.44±0.08和1.51±0.09，P＜0.01)。TUNEL法和免疫组化法得到结果与上述一致。
5．NLIP对大鼠心肌缺血再灌损伤后MMP-2、MMP-9及其抑制物TIMP-1的影响：
I／R组的缺血区内MMP-2(21.33±2.34％)和MMP-9(16.41±2.92％)的表达增加，TIMP-1的表达却明显减弱(10.79±1.15％)；与I／R组比较，IP和NLIP组的缺血区内MMP-2(12.35±1.10和12.55±1.08％，P＜0.01)和MMP-9(9.31±1.08和8.76±1.12％，P＜0.01)的表达有所减少，TIMP-1的表达有所增加(15.11±2.58和16.59±2.98％，P＜0.01)。免疫组化染色结果显示，阳性颗粒主要分布于心肌细胞的胞浆和血管内皮细胞的胞浆内，有时在间质细胞的胞浆中也可见到。RT-PCR结果和免疫组化结果一致。
6．NLIP对大鼠心肌缺血再灌损伤后纤溶因子的影响：
各组血浆中t-PA活性在缺血再灌期间呈进行性下降趋势，而PAI-1活性呈进行性升高趋势，再灌后，与I／R组t-PA(1.01±0.33U／ml)和PAI-1(27.11±0.63AU／ml)比较，IP和NLIP均能显著对抗t-PA活性的降低(1.98±0.46和1.89±0.44U／ml，P＜0.01)和PAI-1活性的升高(25.42±0.56和22.01±0.45AU／ml，P＜0.01)。
结论：
1．NLIP能明显降低心肌缺血再灌损伤所致缺血期ST-段抬高幅度，推迟由心肌缺血造成的室性心律失常出现时间，缩短持续时间，能够保护缺血再灌损伤心肌，且能达到心肌早期缺血预适应的程度。
2．NLIP能降低缺血再灌损伤所致心肌梗死面积，改善损伤的心肌细胞形态学改变。
3．NLIP能减少心肌缺血再灌损伤时心肌酶的漏出并且提高SOD的活性而保护心肌细胞。
4．NLIP能抑制缺血再灌损伤心肌细胞凋亡的发生，改善其可能的调控基因Bcl-2、Bax异常表达。
5．NLIP能降低缺血再灌损伤心肌MMPs的表达，增加TIMP-1的表达而减少缺血再灌对心脏基质的损伤，保护心脏正常结构。
6．NLIP能改善缺血再灌损伤所致体内纤溶／抗纤溶系统的紊乱，这可能是其保护心脏作用机制之一。
Objective: To study on the delayed protective effect of noninvasive limb ischemic preconditioning against myocardial injury in rats.
Method: After rat anesthetized with chloral hydrate, the left hind limb was trapped with canula of modified noninvasive sphygmomanometer. After that, to stick pulse transduce to arteria dorsalis pedis. Asphygmia indicated blockade of arteria femoralis, which lasted 5 min, while pulse appearance indicated reperfusion, which last 5 min, the procedure was operated 3 circles. Thirty healthy male Wistar rats (240-260 g) were divided randomly into 3 groups. (1) I/R group, only 30 min ischemia and 120 min reperfusion of LAD was conducted. (2) IP group, 3 circles of 5-min periods of I/R followed by 30 min ischemia and 120 min reperfusion of LAD. (3) NLIP group, 3 circles of 5-min periods of left hind limb I/R, once time every day for 3 days. On the forth day, 30 min ischemia and 120 min reperfusion of LAD was done. shorten IS (43.2±15.4 and 39.5±13.6 mg, P<0.01), decrease IS/AAR (28.6±9.5 and 25.4±8.7%, P<0.01), and myocardial injury was moderate: the swelling was not apparent, no fragmentation, only a little inflammatory cell infiltrated.
3. Influence of NLIP on the biochemistry after IRI
Compared with I/R group (118.2±36.4 U/L and 2.66±1.00 ng/ml), IP and NLIP could decrease CK-MB and cTnI (80.4±33.4 and 85.1±27.9 U/L, P<0.05; 1.31±0.81 and 1.20±0.79 ng/ml, P<0.01). Meanwhile, compared with I/R group (300±49 NU/ml), IP and NLIP could elevate SOD activity(366±72 and 388±67 NU/ml, P<0.05 and P<0.01).
4. Influence of NLIP on apoptosis of myocardium after IRI
The apoptosis rate in ischemic myocardium of I/R group was very high (6.21±2.12%), but Bcl-2/Bax was very low (0.66±0.03). Compared with I/R group, the apoptosis rate was decreased significantly (5.30±0.81and 4.82±1.15%, P<0.01), but Bcl-2/Bax was very high (1.44±0.08 and 1.51±0.09,P<0.01). Results of TUNEL and immunohistochemistry were in coincidence with above.
5. Influence of NLIP on MMPs after IRI
Expression of MMP-2 (21.33±2.34%) and MMP-9 (16.41±2.92%) was high, and TIMP-1 (10.79±1.15%) was low in ischemic myocardium of I/R group. Compared with I/R group, expression of MMP-2 (12.35±1.10 and 12.55±1.08%, P<0.01) and MMP-9 (9.31±1.08 and 8.76±1.12%, P<0.01) was decreased and expression of TIMP-1 (15.11±2.58 and 16.59±2.98%,P<0.01) was increased in IP and NLIP group. Positive particle distributed in the endochylema of myocardial cell and vascular endothelial cell, sometimes in the interstitial cell. Results of RT-PCR were in coincidence with immunohistochemistry.
6. Influence of NLIP on blood fibrinolysis factor after IRI
The activity of t-PA descended in progress during ischemia and reperfusion, but the activity of PAI-1 advanced in progress in every group. After reperfusion, the activity of t-PA and PAI-1 was 1.01±0.33 U/ml and 27.11±0.63 AU/ml respectively. Compared with I/R group, IP and NLIP could prevent t-PA activity (1.98±0.46 and 1.89±0.44 U/ml, P<0.01) from decreasing and PAI-1 (25.42±0.56 and 22.01±0.45 AU/ml, P<0.01) from increasing.
Conclusion:
1. NLIP could protect heart against IRI via reducing ST-segment, delaying onset, shortening duration and decreasing incidence rate of VA, which is nearly to the level of early cardiac ischemic preconditioning.
2. NLIP could decrease IS and improve morphological changes caused by IRI.
3. NLIP could protect cardiac cell against IRI through reducing the leakage of cardiac muscle enzyme, elevating SOD activity.
4. NLIP could prevent myocardium from apoptosis caused by IRI and improve anomaly expression of the controlling gene of Bcl-2 and Bax.
5. NLIP could decrease the expression of MMPs, increase the expression of TIMP caused by IRI, which prevented cardiac matrix from degrading and maintain myocardial normal structure.
6. NLIP could improve the system of fibrinolysis and anti-fibrinolysis, which maybe the one of mechanisms of protection.
引文
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