Biomedical subjects

Andrew J Murray

Publications and source records attributed to Andrew J Murray.

4 recordsLinked to original sources

PubMed2006

Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart.

OBJECTIVES: Cardiac fatty acid uptake occurs predominantly via sarcolemmal transporter proteins; fatty acid translocase (FAT/CD36), plasma membrane fatty acid binding protein (FABPpm) and fatty acid transporter proteins (FATP) 1 and 6. We hypothesised that levels of the fatty acid transporters would be reduced in the chronically infarcted rat heart, in parallel with reduced dependence on fatty acid utilisation. METHODS AND RESULTS: In vivo left ventricular ejection fractions, measured using echocardiography, were 36% lower in rats six months after coronary artery ligation than in sham-operated control rats. In isolated, perfused, infarcted hearts, 3H-palmitate oxidation was 30% lower, and correlated with in vivo ejection fractions. As myocardial lipid incorporation was also reduced by 25%, total palmitate utilisation was 29% lower in the infarcted rat heart. The protein levels of the cardiac fatty acid transporters were reduced in the infarcted rat heart; FAT/CD36 by 36%, FABPpm by 12%, FATP6 by 21% and FATP1 by 26%, and the cytosolic fatty acid binding protein (cFABP) was 47% lower than in sham-operated rat hearts. Fatty acid transporter levels correlated with both palmitate oxidation rates and cardiac ejection fractions. CONCLUSIONS: Reductions in fatty acid oxidation and lipid incorporation rates were accompanied by downregulation of the cardiac fatty acid transporters. The metabolic shift away from fatty acid utilisation was proportional to the degree of functional impairment in the chronically infarcted rat heart.

Animals↗

PubMed2006

Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart.

OBJECTIVE: Many patients with heart failure have whole-body insulin resistance and reduced cardiac fluorodeoxyglucose uptake, but whether these metabolic changes have detrimental effects on the heart is unknown. Here, we tested whether there is a link between insulin resistance and ischemic damage in the chronically infarcted Wistar rat heart, postulating that the heart would have decreased insulin sensitivity, with lower GLUT4 glucose transporter protein levels due to high circulating free fatty acid (FFA) concentrations. A decreased capacity for glucose uptake would lower glycolytic adenosine triphosphate (ATP) production and thereby increase ischemic injury in the infarcted heart. METHODS AND RESULTS: In vivo left ventricular ejection fractions, measured using echocardiography, were 40% lower in rats 10 weeks after coronary artery ligation than in sham-operated control rats. Insulin-stimulated D[2-3H]glucose uptake was 42% lower in isolated, perfused, infarcted hearts. Myocardial GLUT4 glucose transporter protein levels were 28% lower in the infarcted hearts and correlated negatively with ejection fractions and with fasting plasma FFA concentrations. Compared with controls, chronically infarcted hearts had 46% lower total glucose uptake and three-fold faster ATP hydrolysis rates, measured using phosphorus-31 nuclear magnetic resonance spectroscopy, during 32-min ischemia at 0.4 ml/min/gww. During reperfusion, recovery of left ventricular developed pressure in infarcted hearts was 42% lower than in control hearts. CONCLUSIONS: Glucose uptake, in response to insulin or ischemia, was lower in the chronically infarcted rat heart and associated with increased circulating FFA concentrations and decreased GLUT4 levels. Thus, infarcted hearts had greater ATP depletion, and consequently incurred greater damage, during ischemia.

Adenosine Triphosphate↗

PubMed2005

Plasma free fatty acids and peroxisome proliferator-activated receptor alpha in the control of myocardial uncoupling protein levels.

Diabetic patients have abnormal cardiac energy metabolism associated with high plasma free fatty acid (FFA) concentrations. We investigated whether high plasma FFAs increase mitochondrial uncoupling protein (UCP) levels in the mouse heart by activating the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR)alpha. We used Western blotting to measure UCP protein levels in isolated cardiac mitochondria from PPARalpha-/- and diabetic mice. Cardiac UCP2 and UCP3 were significantly lower in the PPARalpha-/- mouse than in the wild type. Treatment with the PPARalpha-specific agonist, WY-14,643, increased cardiac UCP2 and UCP3 levels in wild-type mice but did not alter UCP levels in PPARalpha-/- mice. Inhibition of beta-oxidation with etomoxir increased cardiac UCP2 and UCP3 levels in wild-type mice and UCP2 levels in PPARalpha-/- mice but did not alter UCP3 levels in PPARalpha-/- mice. Streptozotocin treatment, which increased circulating FFAs by 91%, did not alter cardiac UCP2 levels in wild-type or PPARalpha-/- mice but increased UCP3 levels in wild-type, and not in PPARalpha-/-, mice. The diabetic db/db mouse had 50% higher plasma FFA concentrations and elevated cardiac UCP2 and UCP3 protein levels. We conclude that high plasma FFAs activated PPARalpha to increase cardiac UCP3 levels, but cardiac UCP2 levels changed via PPARalpha-dependent and -independent mechanisms.

Animals↗

PubMedDate not supplied

Uncoupling proteins in human heart.

Abnormal energetic activity in heart failure correlates inversely with plasma free-fatty-acid concentrations. However, the link between energetic and metabolic abnormalities is unknown. To investigate this association, we obtained blood samples from 39 patients undergoing coronary artery bypass graft surgery. Patients fasted overnight before samples were taken. When plasma free-fatty-acid concentrations were raised, cardiac mitochondrial uncoupling proteins (UCP) increased (isoform UCP2, p<0.0001; isoform UCP3, p=0.0036) and those of glucose transporter (GLUT4) protein decreased (cardiac, p=0.0001; skeletal muscle, p=0.0006). Consequently, energy deficiency in heart failure might result from increased mitochondrial UCPs (ie, less efficient ATP synthesis) and depleted GLUT4 (ie, reduced glucose uptake). New treatment to correct these energy defects would be to simultaneously lower plasma free fatty acids and provide an alternative energy source.

Adenosine Triphosphate↗