Docosahexaenoic Acid, Mitochondrial Dysfunction and Cardiac Reperfusion Injury

描述（由申请人提供）：越来越多的证据表明，由缺血和再灌注引起的不可逆心肌损伤触发线粒体通透性转换孔（MPTP）的开放，从而减少ATP的产生并从线粒体基质释放促凋亡蛋白。药理学抑制MPTP开放被认为是防止I/R诱导的梗死发展的有效手段。我们最近发现，在早期心力衰竭大鼠模型中，用临床相关剂量的I-3多不饱和脂肪酸（PUFA）二十二碳六烯酸（DHA）治疗可显著改变线粒体磷脂组成，延迟Ca 2+诱导的MPTP开放，并预防心功能障碍和心肌细胞凋亡。在这里，我们将讨论DHA对MPTP产生深远影响的潜在机制，并确定它是否会导致缺血/再灌注的小心肌梗死。MPTP跨越线粒体内膜和外膜，用DHA治疗可能会以阻止MPTP开放的方式改变这两种膜的特定成分。几乎没有人知道心脏线粒体内外膜磷脂成分的差异。我们认为，DHA治疗将主要增加内膜中的心磷脂，但将增加DHA和消耗线粒体内膜和外膜中的促炎性I-6 PUFA花生四烯酸。此外，DHA治疗应该延迟Ca 2+和ROS诱导的MPTP开放，并导致更少的心肌细胞凋亡和更小的心肌梗死后I/R在体内。实验将在老年犬中进行，因为它们提供了具有非常类似人类的心脏磷脂组成的临床相关实验模型。我们的目标是确定是否与临床相关剂量的DHA治疗改变线粒体膜结构和功能的方式，防止MPTP开放和凋亡，收缩功能障碍和梗死发展缺血/再灌注。具体目标是：1）确定用DHA处理对线粒体磷脂组成和MPTP开放的影响;和2）确定用DHA处理是否减少缺血诱导的心功能障碍、心肌细胞凋亡和心肌梗死发展。

DESCRIPTION (provided by applicant): There is growing evidence that irreversible myocardial injury caused by ischemia and reperfusion triggers opening of the mitochondrial permeability transition pore (MPTP), which decreases of ATP production and releases pro-apoptotic proteins from the mitochondrial matrix. Pharmacological inhibition of MPTP opening is considered an effective means to prevent I/R induced infarct development. We recently discovered that treatment with a clinically relevant dose of the I-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) dramatically alters mitochondrial phospholipid composition, delays Ca2+induced MPTP opening, and prevents cardiac dysfunction and cardiomyocyte apoptosis in rat models of early stage heart failure. Here we will address the underlying mechanisms responsible for the profound effects of DHA on MPTP, and determine if it results in a small myocardial infarction with ischemia/reperfusion. The MPTP spans the inner and outer mitochondrial membranes, and treatment with DHA may alter specific components of the two membranes in a manner that prevents MPTP opening. Almost nothing is known about differences in phospholipid composition between the inner and outer mitochondrial membrane in the heart. We propose that treatment with DHA will mainly increase cardiolipin in the inner membrane, but will increase DHA and deplete the pro-inflammatory I-6 PUFA arachidonic acid in both inner and outer mitochondrial membranes. Further, DHA treatment should delay Ca2+ and ROS-induced MPTP opening, and result in less cardiomyocyte apoptosis and a smaller myocardial infarction following I/R in vivo. Experiments will be performed in older dogs because they provide a clinically relevant experimental model that has a very human-like cardiac phospholipid composition. Our goal is to determine if treatment with a clinically relevant dose of DHA alters mitochondrial membrane structure and function in a manner that prevents MPTP opening and apoptosis, contractile dysfunction and infarct development with ischemia/reperfusion. The specific aims are to: 1) Determine the effects of treatment with DHA on mitochondrial phospholipid composition and MPTP opening; and 2) Determine if treatment with DHA decreases ischemia- induced cardiac dysfunction, cardiomyocyte apoptosis and myocardial infarct development.