Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, ML 0575, Cincinnati, OH 45267, USA.
J Mol Cell Cardiol. 2010 Jun;48(6):1245-54. doi: 10.1016/j.yjmcc.2010.01.014. Epub 2010 Jan 29.
Fibroblast growth factor 2 (FGF2) consists of multiple protein isoforms (low [LMW] and high molecular weight [HMW]), which are localized to different cellular compartments, indicating unique biological activity. We previously showed that the LMW isoform is important in protecting the heart from myocardial dysfunction associated with ischemia-reperfusion (I/R) injury, but the roles of the HMW isoforms remain unknown. To elucidate the role of HMW isoforms in I/R and cardioprotection, hearts from novel mouse models, in which the murine FGF2 HMWs are knocked out (HMWKO) or the human FGF2 24 kDa HMW isoform is overexpressed (HMW Tg) and their wildtype (Wt) or non-transgenic (NTg) cohorts were subjected to an ex vivo work-performing heart model of I/R. There was a significant improvement in post-ischemic recovery of cardiac function in HMWKO hearts (76+/-5%, p<0.05) compared to Wt hearts (55+/-5%), with a corresponding decrease in HMW Tg function (line 20: 38+/-6% and line 28: 33+/-4%, p<0.05) compared to non-transgenic hearts (68+/-9%). FGF2 LMW isoform was secreted from Wt and HMWKO hearts during I/R, and a FGF receptor (FGFR) inhibitor, PD173074 caused a decrease in cardiac function when administered in I/R in Wt and FGF2 HMWKO hearts (p<0.05), indicating that FGFR is involved in FGF2 LMW isoform's biological effect in ischemia-reperfusion injury. Moreover, overexpression of HMW isoform reduced FGFR1 phosphorylation/activation with no further decrease in the phosphorylation state in the presence of the FGFR inhibitor. Overall, our data indicate that HMW isoforms have a detrimental role in the development of post-ischemic myocardial dysfunction.
成纤维细胞生长因子 2（FGF2）由多种蛋白质同工型（低分子量[LMW]和高分子量[HMW]）组成，这些同工型定位于不同的细胞区室，表明具有独特的生物学活性。我们之前的研究表明，LMW 同工型在保护心脏免受与缺血再灌注（I/R）损伤相关的心肌功能障碍方面很重要，但 HMW 同工型的作用仍不清楚。为了阐明 HMW 同工型在 I/R 和心脏保护中的作用，我们使用了新型小鼠模型，其中敲除了鼠 FGF2 HMW（HMWKO）或过表达了人 FGF2 24 kDa HMW 同工型（HMW Tg），并对其野生型（Wt）或非转基因（NTg）对照品进行了体外工作心脏 I/R 模型。与 Wt 心脏（55+/-5%）相比，HMWKO 心脏的缺血后心脏功能恢复有显著改善（76+/-5%，p<0.05），而 HMW Tg 心脏的功能则相应降低（第 20 行：38+/-6%和第 28 行：33+/-4%，p<0.05）与非转基因心脏（68+/-9%）相比。在 I/R 期间，Wt 和 HMWKO 心脏都分泌了 FGF2 LMW 同工型，并且在 Wt 和 FGF2 HMWKO 心脏中给予 FGFR 抑制剂 PD173074 可在 I/R 中降低心脏功能（p<0.05），这表明 FGFR 参与了 FGF2 LMW 同工型在缺血再灌注损伤中的生物学作用。此外，HMW 同工型的过表达降低了 FGFR1 的磷酸化/激活，而在 FGFR 抑制剂存在的情况下，磷酸化状态没有进一步降低。总的来说，我们的数据表明 HMW 同工型在缺血后心肌功能障碍的发展中具有有害作用。
