MMPs 2 and 9 are essential for coronary collateral growth and are prominently regulated by p38 MAPK.
MMPs 2 and 9 are essential for coronary collateral growth and are prominently regulated by p38 MAPK.
复制标题
DOI：
10.1016/j.yjmcc.2011.08.012
复制
发表时间：
2011-12
影响因子：
5
通讯作者：
Rocic P
中科院分区：
文献类型：
--
作者：
Dodd T;Jadhav R;Wiggins L;Stewart J;Smith E;Russell JC;Rocic P
短暂性、重复性缺血(RI)刺激正常健康(SD)大鼠冠脉侧支生长(CCG)，这需要p38MAPK的激活。相反，RI不能在代谢综合征(JCR)大鼠中诱导CCG，这与p38 MAPK激活不足有关。P38 MAPK激活在CCG中的功能后果尚不清楚。理论上，有效的侧枝生长需要细胞外基质重塑；然而，缺乏对导致这种降解的蛋白水解酶的直接评估和鉴定。在本研究中，我们研究了p38MAPK在基质金属蛋白酶2和9(MMPs 2和9)调节中的作用及其对CCG的需求。大鼠接受RI方案(8次LAD阻断，每次40秒，每20分钟，8小时循环，持续0、3、6或9天)。Western印迹法检测缺血区、侧支依赖区(CZ)和正常区(NZ)中基质金属蛋白酶的表达，酶谱法检测基质金属蛋白酶的活性。再灌流后3d，SD大鼠CZ中MMP2和MMP9的表达和活性均显著增加(~3.5倍)。体内抑制p38MAPK可完全阻断RI诱导的MMP2和MMP9的表达和激活。基质金属蛋白酶的激活与基底膜和血管弹力层成分的降解增加有关：弹性蛋白(~3倍)、层粘连蛋白(~3倍)和IV型胶原(~2倍)。这一作用可被MMP2和MMP9抑制所阻断，MMP2和MMP9抑制MMP2和MMP9也可阻断RI诱导的CCG。相反，在JCR大鼠，RI不诱导MMP2或9的表达或激活，也没有相关的弹性蛋白、层粘连蛋白或IV型胶原的降解。综上所述，MMP2和MMP9的激活是CCG所必需的，并且部分是由p38MAPK介导的。此外，代谢综合征中CCG受损的部分原因可能是缺乏p38MAPK依赖的MMP2和9的激活，从而导致细胞外基质降解减少。
Transient, repetitive ischemia (RI) stimulates coronary collateral growth (CCG) in normal, healthy (SD) rats, which requires p38 MAPK activation. In contrast, RI does not induce CCG in the metabolic syndrome (JCR) rats, which is associated with lack of p38 MAPK activation. The functional consequences of p38 MAPK activation in CCG remain unknown. Theoretically, effective collateral growth would require extracellular matrix remodeling; however, direct assessment as well as identification of proteases responsible for this degradation are lacking. In this study, we investigated the role of p38 MAPK in the regulation of matrix metalloproteinases 2 and 9 (MMPs 2 and 9) and their requirement for CCG in SD vs. JCR rats. The rats underwent the RI protocol (8 LAD occlusions, 40 sec each, every 20 min, in 8 hr cycles for 0, 3, 6, or 9 days). MMP expression was measured in the ischemic, collateral-dependent zone (CZ) and the normal zone (NZ) by Western blot, and MMP activity by zymography. Expression and activation of MMP 2 and 9 were significantly increased (~3.5 fold) on day 3 of RI in the CZ of SD rats. In vivo p38 MAPK inhibition completely blocked RI-induced MMP 2 and 9 expression and activation. MMP activation correlated with increased degradation of components of the basement membrane and the vascular elastic laminae: elastin (~3 fold), laminin (~3 fold) and type IV collagen (~2 fold). This was blocked by MMP 2 and 9 inhibition, which also abolished RI-induced CCG. In contrast, in JCR rats, RI did not induce expression or activation of MMP 2 or 9 and there was no associated degradation of elastin, laminin or type IV collagen. In conclusion, MMP 2 and 9 activation is essential for CCG and is mediated, in part, by p38 MAPK. Furthermore, compromised CCG in the metabolic syndrome may be partially due to the lack of p38 MAPK-dependent activation of MMP 2 and 9 and resultant decreased extracellular matrix degradation.
登录
查看更多内容
影响因子：
64.5
作者：
Hiraoka, N;Allen, E;Weiss, SJ
通讯作者：
Weiss, SJ
DOI：
10.1152/ajpheart.00478.2002
发表时间：
2003-01-01
影响因子：
4.8
作者：
Cai, WJ;Koltai, S;Schaper, J
通讯作者：
Schaper, J
影响因子：
4.8
作者：
Issbrücker, K;Marti, HH;Clauss, M
通讯作者：
Clauss, M
影响因子：
3.5
作者：
KUSUKAWA, J;SASAGURI, Y;MORIMATSU, M
通讯作者：
MORIMATSU, M
影响因子：
5.3
作者：
Gu, ZZ;Cui, J;Lipton, SA
通讯作者：
Lipton, SA