Department of Cardiology, University Medical Center Groningen, University of Groningen, Experimental Cardiology Section HPC AB 43, PO Box 30.001, Groningen 9700 RB, The Netherlands.
Department of Cardiology, University Medical Center Groningen, University of Groningen, Experimental Cardiology Section HPC AB 43, PO Box 30.001, Groningen 9700 RB, The Netherlands Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Cardiovasc Res. 2016 Aug 1;111(3):217-26. doi: 10.1093/cvr/cvw161. Epub 2016 Jun 14.
A kinase interacting protein 1 (AKIP1) stimulates physiological growth in cultured cardiomyocytes and attenuates ischaemia/reperfusion (I/R) injury in ex vivo perfused hearts. We aimed to determine whether AKIP1 modulates the cardiac response to acute and chronic cardiac stresses in vivo.
Transgenic mice with cardiac-specific overexpression of AKIP1 (AKIP1-TG) were created. AKIP1-TG mice and their wild-type (WT) littermates displayed similar cardiac structure and function. Likewise, cardiac remodelling in response to transverse aortic constriction or permanent coronary artery ligation was identical in AKIP1-TG and WT littermates, as evidenced by serial cardiac magnetic resonance imaging and pressure-volume loop analysis. Histological indices of remodelling, including cardiomyocyte cross-sectional diameter, capillary density, and left ventricular fibrosis were also similar in AKIP1-TG mice and WT littermates. When subjected to 45 min of ischaemia followed by 24 h of reperfusion, AKIP1-TG mice displayed a significant two-fold reduction in myocardial infarct size and reductions in cardiac apoptosis. In contrast to previous reports, AKIP1 did not co-immunoprecipitate with or regulate the activity of the signalling molecules NF-κB, protein kinase A, or AKT. AKIP1 was, however, enriched in cardiac mitochondria and co-immunoprecipitated with a key component of the mitochondrial permeability transition (MPT) pore, ATP synthase. Finally, mitochondria isolated from AKIP1-TG hearts displayed markedly reduced calcium-induced swelling, indicative of reduced MPT pore formation.
In contrast to in vitro studies, AKIP1 overexpression does not influence cardiac remodelling in response to chronic cardiac stress. AKIP1 does, however, reduce myocardial I/R injury through stabilization of the MPT pore. These findings suggest that AKIP1 deserves further investigation as a putative treatment target for cardioprotection from I/R injury during acute myocardial infarction.
激酶相互作用蛋白 1（AKIP1）刺激培养的心肌细胞的生理生长，并减轻离体灌注心脏的缺血/再灌注（I/R）损伤。我们旨在确定 AKIP1 是否调节体内急性和慢性心脏应激的心脏反应。
创建了心脏特异性过表达 AKIP1 的转基因小鼠（AKIP1-TG）。AKIP1-TG 小鼠及其野生型（WT）同窝仔显示出相似的心脏结构和功能。同样，AKIP1-TG 和 WT 同窝仔对主动脉缩窄或永久性冠状动脉结扎的心脏重塑反应也相同，这一点通过连续心脏磁共振成像和压力-容积环分析得到证明。重塑的组织学指标，包括心肌细胞横截面积、毛细血管密度和左心室纤维化，在 AKIP1-TG 小鼠和 WT 同窝仔中也相似。在经历 45 分钟缺血后再灌注 24 小时时，AKIP1-TG 小鼠的心肌梗死面积显著减少了两倍，并且心脏细胞凋亡减少。与之前的报道相反，AKIP1 不与信号分子 NF-κB、蛋白激酶 A 或 AKT 共免疫沉淀或调节其活性。然而，AKIP1 在心脏线粒体中富集，并与线粒体通透性转换（MPT）孔的关键组成部分 ATP 合酶共免疫沉淀。最后，从 AKIP1-TG 心脏分离的线粒体显示出明显减少的钙诱导肿胀，表明 MPT 孔形成减少。
与体外研究相反，AKIP1 过表达不会影响慢性心脏应激下的心脏重塑。然而，AKIP1 通过稳定 MPT 孔减少心肌 I/R 损伤。这些发现表明，AKIP1 值得进一步研究，作为急性心肌梗死期间 I/R 损伤的心脏保护的潜在治疗靶点。
