Cytosolic lysophospholipase in cardiac myocytes and its inhibition by L-palmitoyl carnitine

Abstract

Since lysophosphatides have been implicated as arrhythmogenic metabolites, modulation of their catabolism in cardiac myocytes has been characterized. Rat cardiac myocytes and mesenchymal cells grown in culture were found to contain cytosolic lysophospholipase with specific activities of 1.3 +/- 0.1 and 0.9 +/- 0.1 nmol X mg-1 X min-1, respectively. Rat myocytic lysophospholipase had a molecular mass of approximately 20,000 daltons, estimated by gel filtration chromatography. Kinetic analysis of cytosolic myocytic lysophospholipase demonstrated a Michaelis constant of 11 microM, a pH optimum of 8.0, and competitive inhibition by L-palmitoyl carnitine (inhibitory constant of 12 microM). Although lysophospholipase-transacylase activity could not be detected in rat myocyte or mesenchymal cell cultures, rabbit myocytes isolated by perfusion of isolated hearts with collagenase contained lysophospholipase-transacylase in cytosolic extracts with a specific activity of 0.2 nmol X mg-1 X min-1. These results demonstrate the presence of lysophospholipase in cardiac myocytes and suggest that the increase in long-chain acyl carnitine, which occurs during myocardial ischemia, may contribute to accumulation of lysophosphatides within cardiac myocytes.

Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation

“…Antiarrhythmic effects of inhibition of carnitine acyltransferase I appear to reflect decreased accumulation of long-chain acylcarnitines and LPC. Because long-chain acylcarnitines inhibit two of the enzymes responsible for catabolism of LPC in heart, lysophospholipase, and lysophospholipase-transacylase (19,20), attenuation of the increase of long-chain acylcarnitines in response to ischemia is likely to attenuate the inhibition of catabolism of LPC preventing its accumulation. Although a reduction of pH inhibits membrane-bound lysophospholipase activity in myocardium (38), the results of the present study suggest that a concomitant increase in the concentration of long-chain acylcarnitines is necessary for inhibition of accumulation of LPC.…”

“…Because the activity of catabolic enzymes responsible for the degradation of LPC exceeds the activity of synthetic enzymes under physiologic conditions, accumulation of LPC in the ischemic heart appears to reflect inhibition of catabolism (1). At concentrations that prevail in ischemic myocardium, long-chain acylcarnitines competitively inhibit two key catabolic enzymes, lysophospholipase-transacylase and lysophospholipase (19,20). Accordingly, inhibition of the accumulation of long-chain acylcarnitines by inhibition of carnitine acyltransferase I may attenuate accumulation of LPC in ischemic myocardium thereby reducing arrhythmogenicity.…”

Interaction of palmitoyl carnitine with calcium antagonists in myocytes

“…Such an approach would indicate whether palmitoyl carnitine had a site of action in the myocardial Ca2 + channel and could be considered as an endogenous activator. As palmitoyl carnitine has detergent effects in high concentrations, we have also compared its effects with those of the lysophospholipids which also accumulate during ischaemia; much of this accumulation will be consequent to inhibition of lysophospholipase and lysophospholipase transacylase by acylcarnitines Gross & Sobel, 1983). Some of this work has been presented to the British Pharmacological Society (Duncan et al, 1986;.…”

Lysoplasmenylethanolamine accumulation in ischemic/reperfused isolated fatty acid-perfused hearts.

“…'4'25 Despite the abundance and potential importance of myocardial plasmalogens, however, little is known about their fate during ischemia/reperfusion. The effect of high concentrations of exogenous fatty acids on plasmalogen catabolism is also unknown, despite the fact that fatty acid intermediates are thought to be an important factor in the accumulation of lysophospholipids during ischemia.1"12, 13 We therefore measured lysoplasmenylcholine and lysoplasmenylethanolamine content of isolated perfused working rat hearts under aerobic conditions, after transient global ischemia, and after reperfusion, in the presence and absence of high concentrations of exogenous fatty acid. To perform these studies, we used a sensitive two-stage high-performance liquid chromatographic (HPLC) technique that reduces problems previously encountered in plasmalogen analysis.…”