Role of iNOS and peroxynitrite-matrix metalloproteinase-2 signaling in myocardial late preconditioning in rats
Role of iNOS and peroxynitrite-matrix metalloproteinase-2 signaling in myocardial late preconditioning in rats
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DOI：
10.1152/ajpheart.00052.2010
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发表时间：
2010-08-01
影响因子：
4.8
通讯作者：
Ferdinandy, Peter
中科院分区：
文献类型：
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作者：
Bencsik, Peter;Kupai, Krisztina;Ferdinandy, Peter
Bencsik P，Kupai K，Giricz Z，Gorbe A，Pipis J，Murlasits Z，Kocsis GF，Varga-Orvos Z，Puskas LG，Csonka C，Csont T，Ferdinandy P.大鼠心肌晚期预适应中iNOS和过氧亚硝酸盐基质金属蛋白酶-2信号传导的作用。美国生理学杂志心脏循环生理学299：H512-H518，2010年。首次发表于2010年6月11日; doi：10.1152/ajpheart.00052.2010.-我们以前已经表明，抑制心肌一氧化氮（NO）和过氧亚硝基基质金属蛋白酶（MMP）信号的早期预处理（PC）参与其心脏保护作用。因此，在本研究中，我们研究了NO和过氧亚硝基-MMP信号转导在晚期PC发展中的作用。在麻醉大鼠体内，通过连续5个循环的4 min冠状动脉阻断和4 min再灌注来进行PC。24小时后，心脏进行30分钟的冠状动脉闭塞，然后再灌注180分钟，以测量梗死面积。在单独的实验中，分别在PC方案之前和之后3、6、12或24小时对心脏组织进行采样以测量生化参数。与假手术对照组相比，晚期PC组24 h时梗死面积明显减小，心肌诱导型NO合酶（iNOS）活性和基因表达显著增加，SOD活性显著降低。晚PC增加心脏超氧化物水平显着在24小时，但是，它没有改变心脏NO水平。心脏过氧亚硝酸盐水平显着降低。与假手术组相比，晚期PC组在24 h时的下游细胞过氧亚硝基阴离子、MMP-2和MMP-9活性降低。为了验证PC诱导的MMPs抑制是否在梗死面积减小中具有因果作用，在单独的实验中，我们测量了通过伊洛马司他药理学抑制MMPs后的梗死面积，发现与溶媒治疗组相比梗死面积显著减小。总之，这是第一次证明心脏过氧化亚硝酸盐-MMP信号传导的抑制有助于晚期PC的心脏保护作用，并且MMPs的药理学抑制能够减少体内梗死面积。此外，iNOS的表达增加可能在晚期PC的发展中发挥作用;然而，iNOS活性增加不会导致晚期PC中NO产生增加。
Bencsik P, Kupai K, Giricz Z, Gorbe A, Pipis J, Murlasits Z, Kocsis GF, Varga-Orvos Z, Puskas LG, Csonka C, Csont T, Ferdinandy P. Role of iNOS and peroxynitrite-matrix metal-loproteinase-2 signaling in myocardial late preconditioning in rats. Am J Physiol Heart Circ Physiol 299: H512-H518, 2010. First published June 11, 2010; doi:10.1152/ajpheart.00052.2010.-We have previously shown that the inhibition of myocardial nitric oxide (NO) and peroxynitrite-matrix metalloproteinase (MMP) signaling by early preconditioning (PC) is involved in its cardioprotective effect. Therefore, in the present study, we investigated the role of NO and peroxynitrite-MMP signaling in the development of late PC. PC was performed by five consecutive cycles of 4-min coronary occlusion and 4-min reperfusion in anesthetized rats in vivo. Twenty-four hours later, hearts were subjected to a 30-min coronary occlusion followed by 180-min reperfusion to measure infarct size. In separate experiments, heart tissue was sampled to measure biochemical parameters before and 3, 6, 12, or 24 h after the PC protocol, respectively. Late PC decreased infarct size, increased cardiac inducible NO synthase (iNOS) activity and gene expression, and decreased SOD activity at 24 h significantly compared with sham-operated controls. Late PC increased cardiac superoxide levels significantly at 24 h; however, it did not change cardiac NO levels. Cardiac peroxynitrite levels were significantly decreased. Downstream cellular targets of peroxynitrite, MMP-2 and MMP-9 activities were decreased in the late PC group at 24 h compared with the sham-operated group. To verify if PC-induced inhibition of MMPs had a causative role in the reduction of infarct size, in separate experiments, we measured infarct size after the pharmacological inhibition of MMPs by ilomastat and found a significant reduction of infarct size compared with the vehicle-treated group. In conclusion, this is the first demonstration that the inhibition of cardiac peroxynitrite-MMP signaling contributes to cardioprotection by late PC and that pharmacological inhibition of MMPs is able to reduce infarct size in vivo. Furthermore, increased expression of iNOS may play a role in the development of late PC; however, increased iNOS activity does not lead to increased NO production in late PC.