Incomplete fatty acid oxidation by ischemic heart: beta-hydroxy fatty acid production

Abstract

A quantitative gas chromatography-mass spectrometry (GC/MS) method was developed to measure nanomolar quantities of long-chain saturated beta-hydroxy fatty acids (12, 14, 16, and 18 carbons long) produced by isolated ischemic heart. Only beta-hydroxymyristate (25-40 nmol/g dry) was found in fresh heart. Isolated rabbit heart perfused with fatty acid by the nonrecirculating Langendorff technique produced negligible beta-hydroxy fatty acids. Ischemic perfusion with 0.25-0.75 mM palmitate prompted heart beta-hydroxy fatty acid accumulation, beta-hydroxypalmitate greater than beta-hydroxystearate, up to 100 nmol x g dry-1 x 10 min-1. beta-Hydroxy fatty acid production was proportional to coronary effluent lactate-to pyruvate ratio, did not continue beyond 10 min of ischemia, was dependent on exogenous fatty acid, and was inhibited by coperfusion with 10 mM acetate. Reperfusion for 5-10 min dissipated accumulated beta-hydroxypalmitate. Hypoxic perfusion prompted beta-hydroxy fatty acid production comparable to that with severe ischemia. These data show that during oxygen deficiency heart fatty acid beta-oxidation is not only depressed but is also incomplete; beta-hydroxy fatty acyl intermediates accumulate and contribute to the increased intracellular fatty acid content characteristic of the ischemic myocardium.

beta-Hydroxy fatty acid production by ischemic rabbit heart.

“…Disproportionate suppression of the latter step is supported by several studies showing #-hydroxypalmitate production by rotenone-inhibited mitochondria oxidizing palmitoylcarnitine (3,4). Our recent report of the accumulation of ,B-hydroxy fatty acids in isolated, perfused rabbit hearts during ischemia or hypoxia shows significant depression of ,B-hydroxy fatty acyl-CoA oxidation in the intact tissue (5).…”

“…Reference methyl esters of nondeuterated and doubly a-deuterated ,8-hydroxystearate, -palmitate, and -myristate were synthesized and purified in the laboratory as previously described (5).…”

Myocardial ischemia-reperfusion and cardioprotection: a study with microdialysis in a porcine model

“…This includes nucleoside intermediates, glucose-6-phosphate, glucose-1-phosphate, glycerol-3-phosphate (G-3-P), and glycerol, in addition to lactate, H + , and NADH as mentioned ( 1 Jennings 1991, Ye 1996. Also intermediates of fatty acid metabolism accumulate (Moore 1980, Neely 1981. In myocardial tissue, metabolic markers of ischemia are initially decreasing levels of creatine phosphate and ATP, followed by increasing lactate, whereas accumulating glycerol may reflect prolonged ischemia (Ye 1996).…”

“…Triacylglycerols may be degraded by lipolysis, glycolytically produced glycerol-3-phosphate may be hydrolyzed enhanced by acidosis, and membrane phospholipids may be degraded. Beta-oxidation of fatty acids is inhibited during ischemia, and incomplete lipid metabolism may lead to the accumulation of fatty acid intermediates (Ford 2002, Moore 1980. In myocardial ischemia, accumulation of glycerol precedes the rise in fatty acid intermediates, suggesting cycling of triacylglycerols (van Bilsen 1989).…”

“…Alternatively, the reesterification may be interpreted as a protective mechanism reducing the accumulation of fatty acids and lipolytic intermediates (Trach 1986). Accumulation of fatty acid intermediates may be associated with cell injury (Moore 1980, van Bilsen 1989. At reperfusion, phospholipids are probably the main source of the accumulated fatty acid intermediates (van Bilsen 1989).…”