Cardiac kallikrein-kinin system is upregulated in chronic volume overload and mediates an inflammatory induced collagen loss.
Cardiac kallikrein-kinin system is upregulated in chronic volume overload and mediates an inflammatory induced collagen loss.
复制标题
DOI：
10.1371/journal.pone.0040110
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Dell'Italia LJ
中科院分区：
文献类型：
--
作者：
Wei CC;Chen Y;Powell LC;Zheng J;Shi K;Bradley WE;Powell PC;Ahmad S;Ferrario CM;Dell'Italia LJ
单纯性二尖瓣或主动脉瓣返流的“单纯容量超负荷”的临床问题目前还没有文献记载的药物治疗来减轻胶原丢失和由此导致的左心室(LV)扩张和衰竭。在这里，我们确定了一个与激肽释放酶-激动素系统上调有关的潜在机制，该机制与大鼠主动脉腔内瘘(ACF)的容量超负荷有关。对年龄匹配的假手术组、4wk和15wk ACF大鼠进行左心室间质液(ISF)采集、血流动力学和超声心动图检查。ACF大鼠左室扩张，左室舒张末压增加2倍，左心室ISF缓激肽、心肌激肽释放酶和缓激肽2型受体(BK2R)基因表达增加。ACF后4wk和15wk，肥大细胞数量增加，间质胶原减少，而左心室血管紧张素转换酶和糜酶活性升高。用激肽释放酶抑制剂抑肽酶治疗ACF 4wk时，保留了间质胶原，阻止了肥大细胞的增加，并改善了左心室收缩功能。为了确定ISF缓激肽与肥大细胞介导的胶原丢失之间的因果关系，直接在体内注射缓激肽24小时可使肥大细胞数量增加2倍，间质胶原减少30%，而BK2R拮抗剂可阻止这一变化。为了进一步将心肌牵张与细胞激肽释放酶-激肽释放酶系统的上调联系起来，24小时的周期性牵张使成年心肌细胞和成纤维细胞激肽释放酶、BK2R基因表达增加，缓激肽释放酶蛋白和明胶酶活性增加，这些都被激肽释放酶抑制剂抑肽酶所抑制。单纯的容量超负荷与激肽释放酶-激动素系统和ISF缓激肽系统的上调有关，后者介导肥大细胞的渗透、细胞外基质丢失和左心功能障碍--所有这些都可以通过激肽释放酶抑制而得到改善。目前的研究为未来治疗主动脉和二尖瓣反流容量超负荷的潜在药物治疗提供了重要的新见解。
The clinical problem of a “pure volume overload” as in isolated mitral or aortic regurgitation currently has no documented medical therapy that attenuates collagen loss and the resultant left ventricular (LV) dilatation and failure. Here, we identify a potential mechanism related to upregulation of the kallikrein-kinin system in the volume overload of aortocaval fistula (ACF) in the rat. LV interstitial fluid (ISF) collection, hemodynamics, and echocardiography were performed in age-matched shams and 4 and 15 wk ACF rats. ACF rats had LV dilatation and a 2-fold increase in LV end-diastolic pressure, along with increases in LV ISF bradykinin, myocardial kallikrein and bradykinin type-2 receptor (BK2R) mRNA expression. Mast cell numbers were increased and interstitial collagen was decreased at 4 and 15 wk ACF, despite increases in LV ACE and chymase activities. Treatment with the kallikrein inhibitor aprotinin preserved interstitial collagen, prevented the increase in mast cells, and improved LV systolic function at 4 wk ACF. To establish a cause and effect between ISF bradykinin and mast cell-mediated collagen loss, direct LV interstitial bradykinin infusion in vivo for 24 hrs produced a 2-fold increase in mast cell numbers and a 30% decrease in interstitial collagen, which were prevented by BK2R antagonist. To further connect myocardial stretch with cellular kallikrein-kinin system upregulation, 24 hrs cyclic stretch of adult cardiomyocytes and fibroblasts produced increased kallikrein, BK2R mRNA expressions, bradykinin protein and gelatinase activity, which were all decreased by the kallikrein inhibitor-aprotinin. A pure volume overload is associated with upregulation of the kallikrein-kinin system and ISF bradykinin, which mediates mast cell infiltration, extracellular matrix loss, and LV dysfunction–all of which are improved by kallikrein inhibition. The current investigation provides important new insights into future potential medical therapies for the volume overload of aortic and mitral regurgitation.
登录
查看更多内容
影响因子：
24
作者：
Lopez, Begona;Gonzalez, Arantxa;Diez, Javier
通讯作者：
Diez, Javier
DOI：
10.1016/0304-4165(88)90033-5
发表时间：
1988-03-17
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
CHAO, J;SWAIN, C;CHAO, L
通讯作者：
CHAO, L
影响因子：
10.8
作者：
Li, Huey-Jiun;Yin, Hang;Chao, Julie
通讯作者：
Chao, Julie
DOI：
10.1097/01.asn.0000136132.20189.95
发表时间：
2004-09-01
影响因子：
13.6
作者：
Okada, H;Watanabe, Y;Suzuki, H
通讯作者：
Suzuki, H
DOI：
10.1152/ajpheart.01129.2002
发表时间：
2003-10-01
影响因子：
4.8
作者：
Bledsoe, G;Chao, L;Chao, J
通讯作者：
Chao, J