MAPK家族成员活化表达参与高血压心脏重构的实验研究
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摘要
目的探讨MAPK家族重要成员ERK1/2和P38在高血压心脏重构过程中的作用,及其在高血压心脏不同解剖结构,以及同一解剖结构不同组织学区域中发挥的作用是否相同,从而进一步明确ERK1/2和p38激酶在高血压心脏重构中的作用,从细胞信号转导方面探讨高血压所致的心脏重构的分子机制。
方法动物分组:①高血压组:4周龄组(简称SHR4),16周龄组(简称SHR16),24周龄(简称SHR24)组各10只;②WKY大鼠作为对照组:4周龄组(简称WKY4),16周龄组(简称WKY16),24周龄组(简称WKY24)各10只;③干预组:24周龄高血压大鼠干预组PD98059和干预组SD203580各10只。利用HE染色,光镜测微尺测量4、16、24周龄SHR心脏重构改变,免疫组织化学和Western blot方法,动态观察SHR心脏不同解剖部位PCNA、磷酸化和总ERK1/2和P38的表达变化。
结果1、随着周龄的增加WKY大鼠和SHR的心脏/体重比值逐渐增加,SHR16、24的心脏/体重比值明显高于SHR4(P<0.05),SHR16、24的心脏/体重比值明显高于WKY16、24大鼠(P<0.05)。2、SHR相对左心室壁厚度,随着周龄的增加逐渐增加,以左心肌膜内层和中层厚度增加明显,SHR24相对左心室壁厚度明显高于WKY24大鼠(P<0.05)。与SHR比较,PD98059、SD203580组明显降低左心肌膜内层和中层室壁厚度。3、随周龄的增加PCNA表达降低(P<0.05),SHR16 PCNA表达高于WKY16大鼠(P<0.05)。心脏不同部位PCNA表达不同。4、总ERK1/2在不同周龄SHR,以及SHR和WKY大鼠之间心脏表达无显著性差异,但在左心室和室间隔的表达明显高于右心室的表达(P<0.05)。在左心室和室间隔磷酸化ERK1/2在SHR的表达随周龄的增加表达逐渐增加,SHR16、24表达阳性率明显高于WKY16、24周龄大鼠(P<0.05)。PD98059组磷酸化ERK1/2表达明显降低(P<0.05)。5、总P38表达在各观察组之间无显著性差异。左心肌膜内层的表达高于室间隔和右心室的表达(P<0.05)。在左心室磷酸化P38在SHR的表达随周龄的增加表达逐渐增加,SHR16、24明显高于相应WKY大鼠(P<0.05)。SD203580组,磷酸化P38表达低于对照组(P<0.05)。6、高血压心脏中PCNA、ERK1/2和P38存在正相关关系。
结论
(1)自发性高血压大鼠随周龄的增加,心脏/体重比增加,相对左心室壁厚度逐渐增加,相对室间隔和右心室厚度、相对左右心腔径未发生改变,主要表现为向心性重构和向心性肥厚。PD98059和SD203580分别阻断ERK1/2和P38后,能够明显减少相对左心室壁厚度,一定程度上减缓高血压心脏重构。
(2)随着大鼠周龄的增加,心肌细胞的增殖活性越来越低;高血压状态下,心肌细胞增殖活性的明显增高,可能参与了高血压心肌肥大,心肌细胞表型改变,最终引起心脏重构的发生。
(3) ERK1/2可能参与了高血压心脏重构,主要是通过ERK1/2活性增加参与心脏重构,而并不是通过蛋白总量增加。高血压心脏重构过程中,ERK1/2在不同组织学部位发挥的作用不一定相同。
(4)在大鼠自发性高血压状态下,P38活性增加参与了心肌细胞肥大,左室肥厚,心脏重构。
(5)高血压状态下,ERK1/2和P38可能相辅相成,相互促进,共同促使PCNA高表达,引起心肌细胞肥大,增殖活性增强,最终导致心脏重构。
Objective We studied the role of important member of MAPK family member ERK1/2 and P38 in the process of hypertensive cardiac remodeling ,including different anatomical structures and different histological region of the same anatomical structure ,which further clarified the role of ERK1/2 and p38 in hypertensive cardiac remodeling, and explored the molecular mechanism of hypertensive cardiac remodeling from the cell signal transduction .
Methods (1)30 Spontaneously Hypertensive Rats (SHR) were divided into three groups, which were 4-week-old group,16-week-old group,24- week-old group;(2) 30 Wistar-Kyoto rats as the control group with the normal blood pressure;(3) 20 Spontaneously Hypertensive Rats:PD98059 prevented SHR24 groups and SD203580 prevented SHR24 groups. Light microscope micrometer was used to measure remodeling changes of SHR4、16、24 with HE staining , Immunohistochemistry, Weatern blotting techniques methods were used to observe the expression of PCNA、ERK1/2、P38、P-ERK1/2、P- P38 of myocardial cells in different anatomical parts .
Results 1. Either SHR or WKY ,the ratio of heart weight to body weight was significantly higher with increased week age . SHR24 was significantly higher than SHR4 (P <0.05), SHR16, 24 was significantly higher than WKY16、24(P <0.05). 2. SHR relative left ventricular wall thickness was significantly increased with increased week age, the inner and middle of left myocardium was obvious. SHR24 relative left ventricular wall was significantly higher than SHR4(P <0.05), The inner and middle of left myocardium thickness of PD98059 group and SD203580 group was significantly lower than SHR24 (P <0.05). 3 PCNA expression significantly decrease with increased week age(P <0.05), SHR16 was higher than WKY16 (P <0.05). Different parts with different PCNA expression. (3) Non-phosphorylated ERK1/2 with the same week in different rats, and between WKY and SHR was no significant difference. But the expression of left myocardium was significantly higher than the right myocardium(P <0.05). The expression of P-ERK1/2 in the left myocardium and the left side of septum was significantly higher with increased week age. The expression of SHR16,、24 was significantly higher than WKY16, 24(P<0.05).The expression of P-ERK1/2 of PD98059 group was significantly lower than SHR(P<0.05).(4)The expression of non-phosphorylated P38 of all observation groups was no significant difference. The expression of the inner layer of left myocardium was significantly higher than the left side of septum and right myocardium(P <0.05) . The expression of P-P38 of myocardial cell in the left myocardium was significantly higher with increased week age.SHR16, 24 was significantly higher than WKY16, 24 group (P <0.05).The expression of P-P38 of SD203580 group was significantly lower than SHR (P <0.05).7 There was an positive correlation between PCNA、ERK1/2 and P38 .
Conclusion
(1) The ratio of heart weight to body weight and relative left ventricular wall thickness of spontaneously hypertensive rats increased gradually with week-old. The relative thickness of interventricular septum and right ventricle, and the relative left and right heart chamber diameter did not change, leading to concentric remodeling and concentric hypertrophy. We found that after the use of ERK-specific inhibitor PD98059 and the P38-specific inhibitor SD203580 respectively, the relative left ventricular wall thickness can be significantly reduced,. and hypertensive cardiac remodeling can be slow down to some extent .
(2)Myocardial cells proliferation getting lower and lower with increased week age. In the state of spontaneous hypertension of the rats, higher proliferative activity of myocardial cells may involved in hypertensive cardiac hypertrophy, myocardial cell phenotypes, ultimately lead to the occurrence of cardiac remodeling.
(3)The activation but not by increasing the total protein of ERK1/2 participating the cardiac remodeling of hypertension, Different parts with different role of P-ERK1/2.
(4) During the development of spontaneously hypertensive rats , the activation of P38 expression. participating myocardial cells hypertrophy, left ventricular hypertrophy and cardiac remodeling.
(5) ERK1/2 and P38 may promote each other, and promote high expression of PCNA, induced myocardial cells hypertrophy, proliferation activity increased and leading to cardiac remodeling.
方法动物分组:①高血压组:4周龄组(简称SHR4),16周龄组(简称SHR16),24周龄(简称SHR24)组各10只;②WKY大鼠作为对照组:4周龄组(简称WKY4),16周龄组(简称WKY16),24周龄组(简称WKY24)各10只;③干预组:24周龄高血压大鼠干预组PD98059和干预组SD203580各10只。利用HE染色,光镜测微尺测量4、16、24周龄SHR心脏重构改变,免疫组织化学和Western blot方法,动态观察SHR心脏不同解剖部位PCNA、磷酸化和总ERK1/2和P38的表达变化。
结果1、随着周龄的增加WKY大鼠和SHR的心脏/体重比值逐渐增加,SHR16、24的心脏/体重比值明显高于SHR4(P<0.05),SHR16、24的心脏/体重比值明显高于WKY16、24大鼠(P<0.05)。2、SHR相对左心室壁厚度,随着周龄的增加逐渐增加,以左心肌膜内层和中层厚度增加明显,SHR24相对左心室壁厚度明显高于WKY24大鼠(P<0.05)。与SHR比较,PD98059、SD203580组明显降低左心肌膜内层和中层室壁厚度。3、随周龄的增加PCNA表达降低(P<0.05),SHR16 PCNA表达高于WKY16大鼠(P<0.05)。心脏不同部位PCNA表达不同。4、总ERK1/2在不同周龄SHR,以及SHR和WKY大鼠之间心脏表达无显著性差异,但在左心室和室间隔的表达明显高于右心室的表达(P<0.05)。在左心室和室间隔磷酸化ERK1/2在SHR的表达随周龄的增加表达逐渐增加,SHR16、24表达阳性率明显高于WKY16、24周龄大鼠(P<0.05)。PD98059组磷酸化ERK1/2表达明显降低(P<0.05)。5、总P38表达在各观察组之间无显著性差异。左心肌膜内层的表达高于室间隔和右心室的表达(P<0.05)。在左心室磷酸化P38在SHR的表达随周龄的增加表达逐渐增加,SHR16、24明显高于相应WKY大鼠(P<0.05)。SD203580组,磷酸化P38表达低于对照组(P<0.05)。6、高血压心脏中PCNA、ERK1/2和P38存在正相关关系。
结论
(1)自发性高血压大鼠随周龄的增加,心脏/体重比增加,相对左心室壁厚度逐渐增加,相对室间隔和右心室厚度、相对左右心腔径未发生改变,主要表现为向心性重构和向心性肥厚。PD98059和SD203580分别阻断ERK1/2和P38后,能够明显减少相对左心室壁厚度,一定程度上减缓高血压心脏重构。
(2)随着大鼠周龄的增加,心肌细胞的增殖活性越来越低;高血压状态下,心肌细胞增殖活性的明显增高,可能参与了高血压心肌肥大,心肌细胞表型改变,最终引起心脏重构的发生。
(3) ERK1/2可能参与了高血压心脏重构,主要是通过ERK1/2活性增加参与心脏重构,而并不是通过蛋白总量增加。高血压心脏重构过程中,ERK1/2在不同组织学部位发挥的作用不一定相同。
(4)在大鼠自发性高血压状态下,P38活性增加参与了心肌细胞肥大,左室肥厚,心脏重构。
(5)高血压状态下,ERK1/2和P38可能相辅相成,相互促进,共同促使PCNA高表达,引起心肌细胞肥大,增殖活性增强,最终导致心脏重构。
Objective We studied the role of important member of MAPK family member ERK1/2 and P38 in the process of hypertensive cardiac remodeling ,including different anatomical structures and different histological region of the same anatomical structure ,which further clarified the role of ERK1/2 and p38 in hypertensive cardiac remodeling, and explored the molecular mechanism of hypertensive cardiac remodeling from the cell signal transduction .
Methods (1)30 Spontaneously Hypertensive Rats (SHR) were divided into three groups, which were 4-week-old group,16-week-old group,24- week-old group;(2) 30 Wistar-Kyoto rats as the control group with the normal blood pressure;(3) 20 Spontaneously Hypertensive Rats:PD98059 prevented SHR24 groups and SD203580 prevented SHR24 groups. Light microscope micrometer was used to measure remodeling changes of SHR4、16、24 with HE staining , Immunohistochemistry, Weatern blotting techniques methods were used to observe the expression of PCNA、ERK1/2、P38、P-ERK1/2、P- P38 of myocardial cells in different anatomical parts .
Results 1. Either SHR or WKY ,the ratio of heart weight to body weight was significantly higher with increased week age . SHR24 was significantly higher than SHR4 (P <0.05), SHR16, 24 was significantly higher than WKY16、24(P <0.05). 2. SHR relative left ventricular wall thickness was significantly increased with increased week age, the inner and middle of left myocardium was obvious. SHR24 relative left ventricular wall was significantly higher than SHR4(P <0.05), The inner and middle of left myocardium thickness of PD98059 group and SD203580 group was significantly lower than SHR24 (P <0.05). 3 PCNA expression significantly decrease with increased week age(P <0.05), SHR16 was higher than WKY16 (P <0.05). Different parts with different PCNA expression. (3) Non-phosphorylated ERK1/2 with the same week in different rats, and between WKY and SHR was no significant difference. But the expression of left myocardium was significantly higher than the right myocardium(P <0.05). The expression of P-ERK1/2 in the left myocardium and the left side of septum was significantly higher with increased week age. The expression of SHR16,、24 was significantly higher than WKY16, 24(P<0.05).The expression of P-ERK1/2 of PD98059 group was significantly lower than SHR(P<0.05).(4)The expression of non-phosphorylated P38 of all observation groups was no significant difference. The expression of the inner layer of left myocardium was significantly higher than the left side of septum and right myocardium(P <0.05) . The expression of P-P38 of myocardial cell in the left myocardium was significantly higher with increased week age.SHR16, 24 was significantly higher than WKY16, 24 group (P <0.05).The expression of P-P38 of SD203580 group was significantly lower than SHR (P <0.05).7 There was an positive correlation between PCNA、ERK1/2 and P38 .
Conclusion
(1) The ratio of heart weight to body weight and relative left ventricular wall thickness of spontaneously hypertensive rats increased gradually with week-old. The relative thickness of interventricular septum and right ventricle, and the relative left and right heart chamber diameter did not change, leading to concentric remodeling and concentric hypertrophy. We found that after the use of ERK-specific inhibitor PD98059 and the P38-specific inhibitor SD203580 respectively, the relative left ventricular wall thickness can be significantly reduced,. and hypertensive cardiac remodeling can be slow down to some extent .
(2)Myocardial cells proliferation getting lower and lower with increased week age. In the state of spontaneous hypertension of the rats, higher proliferative activity of myocardial cells may involved in hypertensive cardiac hypertrophy, myocardial cell phenotypes, ultimately lead to the occurrence of cardiac remodeling.
(3)The activation but not by increasing the total protein of ERK1/2 participating the cardiac remodeling of hypertension, Different parts with different role of P-ERK1/2.
(4) During the development of spontaneously hypertensive rats , the activation of P38 expression. participating myocardial cells hypertrophy, left ventricular hypertrophy and cardiac remodeling.
(5) ERK1/2 and P38 may promote each other, and promote high expression of PCNA, induced myocardial cells hypertrophy, proliferation activity increased and leading to cardiac remodeling.
引文
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