Manning Janet R, Carpenter Gregory, Porter Darius R, House Stacey L, Pietras Daniel A, Doetschman Thomas, Schultz Jo el J
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Growth Factors. 2012 Apr;30(2):124-39. doi: 10.3109/08977194.2012.656759. Epub 2012 Feb 6.
Fibroblast growth factor-2 (FGF2) protects the heart from ischemia-reperfusion (I-R) injury via a vast network of protein kinases. In the heart, downstream effectors of these FGF2-triggered signals have not yet been identified. It is hypothesized that nitric oxide (NO) signaling and ATP-sensitive potassium (K(ATP)) channel activity are key effectors of protein kinases activated by FGF2-mediated cardioprotection. Hearts with a cardiac-specific overexpression of FGF2 (FGF2 Tg) were subjected to I-R injury in the absence or the presence of selective inhibitors of NO synthase (NOS) isoforms or sarcolemmal (sarcK(ATP)) and mitochondrial (mitoK(ATP)) K(ATP) channels. Multiple NOS isoforms are necessary for FGF2-mediated cardioprotection, and nitrite levels are significantly reduced in FGF2 Tg hearts upon inhibition of protein kinase C or mitogen-activated protein kinases. Likewise, sarcK(ATP) and mitoK(ATP) channels are important for cardioprotection elicited by endogenous FGF2. These findings suggest that FGF2-induced cardioprotection occurs via protein kinase-NOS pathways as well as K(ATP) channel activity.
成纤维细胞生长因子-2（FGF2）通过庞大的蛋白激酶网络保护心脏免受缺血再灌注（I-R）损伤。在心脏中，这些FGF2触发信号的下游效应器尚未被确定。据推测，一氧化氮（NO）信号传导和ATP敏感性钾（K(ATP)）通道活性是由FGF2介导的心脏保护作用所激活的蛋白激酶的关键效应器。对心脏特异性过表达FGF2（FGF2转基因）的心脏在不存在或存在NO合酶（NOS）亚型或肌膜（sarcK(ATP)）和线粒体（mitoK(ATP)）K(ATP)通道的选择性抑制剂的情况下进行I-R损伤。多种NOS亚型对于FGF2介导的心脏保护作用是必需的，并且在抑制蛋白激酶C或丝裂原活化蛋白激酶后，FGF2转基因心脏中的亚硝酸盐水平显著降低。同样，sarcK(ATP)和mitoK(ATP)通道对于内源性FGF2引起的心脏保护作用也很重要。这些发现表明，FGF2诱导的心脏保护作用通过蛋白激酶-NOS途径以及K(ATP)通道活性发生。
