Abstract 17047: Role of Mitochondrial Function and Mitochondrial DNA Integrity in Coronary Metabolic Dilation
Alterations in mitochondrial function are observed in a variety of animal models with impaired cardiac pump function. Often these models have coronary insufficiency and show blunted metabolic regulation of coronary blood flow, that is the connection of flow to metabolism or work. Whether mitochondrial dysfunction is the cause of, or the effect of, impaired coronary flow regulation is unknown. Accordingly, we hypothesized that mitochondrial dysfunction directly impairs coronary metabolic dilation. To test this hypothesis, we studied control rats and those in which mitochondrial dysfunction was induced by administration of a cell permeable recombinant protein containing exonuclease III and a mitochondrial localization sequence (mt-tat-ExoIII). Treatment with mt-tat-ExoIII fragments mitochondrial DNA impairing energy production and increasing mitochondrial ROS generation. Rats were treated (or sham treated: controls) for 3 days with 80 μg of mt-tat-ExoIII per day. After the treatment protocol, we measured myocardial blood flow (MBF) during alterations in cardiac work (CW). CW was approximated (during sevoflurane anesthesia) from the double product of mean arterial pressure (measured by a Millar transducer in the aorta) x heart rate (derived from the aortic pressure trace). CW was altered by i.v. norepinephrine (NE). MBF was measured by contrast echocardiography (ml/min per g) under baseline conditions (hexamethonium, to prevent reflex changes during NE) and during NE infusion. In controls (figure below), NE at doses of 5 and 10 μg/kg/min produced a 56±3 % and 122±3% increase in MBF respectively. In contrast, in the mito-tat-ExoIII rats, NE at 5 and 10 μg/kg/min produced a much smaller increase in flow, 22±2% and 22±2% respectively, despite higher levels of CW. Based on these results, we conclude that mitochondrial dysfunction, induced by mitochondrial DNA fragmentation, is causally involved in impaired metabolic regulation of coronary blood flow.
- © 2010 by American Heart Association, Inc.