Wongrakpanich Amaraporn, Morris Angie S, Geary Sean M, Joiner Mei-Ling A, Salem Aliasger K
Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States; Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States.
Int J Pharm. 2017 Mar 30;520(1-2):275-283. doi: 10.1016/j.ijpharm.2017.01.061. Epub 2017 Feb 3.
An excess of calcium (Ca) influx into mitochondria during mitochondrial re-energization is one of the causes of myocardial cell death during ischemic/reperfusion injury. This overload of Ca triggers the mitochondrial permeability transition pore (mPTP) opening which leads to programmed cell death. During the ischemic/reperfusion stage, the activated Ca/calmodulin-dependent protein kinase II (CaMKII) enzyme is responsible for Ca influx. To reduce CaMKII-related cell death, sub-micron particles composed of poly(lactic-co-glycolic acid) (PLGA), loaded with a CaMKII inhibitor peptide were fabricated. The CaMKII inhibitor peptide-loaded (CIP) particles were coated with a mitochondria targeting moiety, triphenylphosphonium cation (TPP), which allowed the particles to accumulate and release the peptide inside mitochondria to inhibit CaMKII activity. The fluorescently labeled TPP-CIP was taken up by mitochondria and successfully reduced reactive oxygen species (ROS) caused by Isoprenaline (ISO) in a differentiated rat cardiomyocyte-like cell line. When cells were treated with TPP-CIP prior to ISO exposure, they maintained mitochondrial membrane potential. The TPP-CIP protected cells from ISO-induced ROS production and decreased mitochondrial membrane potential. Thus, TPP-CIP has the potential to be used in protection against ischemia/reperfusion injury.
线粒体重新供能期间，过量的钙（Ca）流入线粒体是缺血/再灌注损伤期间心肌细胞死亡的原因之一。这种钙超载会触发线粒体通透性转换孔（mPTP）开放，进而导致程序性细胞死亡。在缺血/再灌注阶段，活化的钙/钙调蛋白依赖性蛋白激酶II（CaMKII）负责钙的流入。为了减少与CaMKII相关的细胞死亡，制备了负载CaMKII抑制肽的聚乳酸-羟基乙酸共聚物（PLGA）亚微米颗粒。负载CaMKII抑制肽（CIP）的颗粒用线粒体靶向部分三苯基膦阳离子（TPP）包被，使颗粒能够在线粒体内积累并释放肽以抑制CaMKII活性。荧光标记的TPP-CIP被线粒体摄取，并成功降低了分化的大鼠心肌样细胞系中异丙肾上腺素（ISO）引起的活性氧（ROS）。在ISO暴露之前用TPP-CIP处理细胞时，它们维持了线粒体膜电位。TPP-CIP保护细胞免受ISO诱导的ROS产生，并降低线粒体膜电位。因此，TPP-CIP有潜力用于预防缺血/再灌注损伤。
