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.
Permanent injury to the myocardium following a heart attack remains a major clinical problem. This work will investigate the effects of dietary supplementation with the I-3 polyunsaturated fatty acid docosahexaenoic acid on the ability of the heart to withstand a heart attack without being injured. Novel cellular mechanisms are investigated, and the results can be rapidly translated into clinical studies.
|Asemu, Girma; O'Connell, Kelly A; Cox, James W et al. (2013) Enhanced resistance to permeability transition in interfibrillar cardiac mitochondria in dogs: effects of aging and long-term aldosterone infusion. Am J Physiol Heart Circ Physiol 304:H514-28|
|Dabkowski, Erinne R; O'Connell, Kelly A; Xu, Wenhong et al. (2013) Docosahexaenoic acid supplementation alters key properties of cardiac mitochondria and modestly attenuates development of left ventricular dysfunction in pressure overload-induced heart failure. Cardiovasc Drugs Ther 27:499-510|