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Query: UNIPROT:P06889 (Mol)
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Recent studies have implicated accelerated sarcolemmal phospholipid catabolism as a mediator of the lethal sequelae of atherosclerotic heart disease. We have demonstrated that plasmalogens are the predominant phospholipid constituents of canine myocardium and that plasmalogens are hydrolyzed by a novel calcium independent plasmalogen selective phospholipase A2. Since the activities of phospholipases are modulated by the molecular dynamics and interfacial characteristics of their phospholipid substrates, we compared the molecular dynamics of plasmenylcholine and phosphatidylcholine vesicles by electron spin resonance spectroscopy and deuterium magnetic resonance spectroscopy. Plasmenylcholine vesicles have separate and distinct molecular dynamics in comparisons to their phosphatidylcholine counterparts as ascertained by substantial decreases in the angular fluctuations and motional velocities of probes attached to their sn-2 aliphatic constituents. Furthermore, since free radical oxidation of myocardial lipid constituents occurs during myocardial ischemia and reperfusion, we demonstrated that 1O2 mediated oxidation of plasmenylcholine resulted in the generation of several products which have chromatographic characteristics and molecular masses corresponding to 2-acyl lysophosphatide derivatives. Taken together, these studies underscore the biologic significance of the predominance of sarcolemmal plasmalogens present in mammalian myocardium and suggest that their catabolism by plasmalogen selective phospholipases and/or oxidative processes may contribute to the lethal sequelae of myocardial ischemia.
Mol Cell Biochem
PMID:Subcellular distribution, molecular dynamics and catabolism of plasmalogens in myocardium. 267 69

Fatty acids and their metabolites have been implicated as a cause of myocardial damage during ischemia. Fatty acid binding protein (FABP), an abundant low molecular weight protein present in the cytosol of myocytes, has been postulated to be a key fatty acid carrier protein in the myocardium. Postulating that loss of FABP during ischemia could cause an increase in unbound intracellular fatty acids contributing to myocardial damage, we measured plasma FABP levels during 60 min of myocardial ischemia followed by 60 min of reperfusion in the rat. Peak levels were seen 15 min after reperfusion. Plasma levels were higher with larger areas of myocardial ischemia (1720 +/- 528 ng/ml vs. 216 +/- 76 ng/ml with smaller areas, P less than 0.02). Tissue levels after 60 min of ischemia and 60 min of reperfusion were decreased by over 50%, (1.0 +/- 0.3 mg FABP/g wet wt compared with 2.9 +/- 0.4 mg FABP/g wet wt in normal myocardium, P less than 0.005). The data is consistent with the proposal that loss of FABP contributes to the myocardial damage associated with ischemia and reperfusion. Additional studies are needed to determine the exact role of FABP in the regulation of fatty acid metabolism in the heart.
J Mol Cell Cardiol 1989 Jun
PMID:Leakage of heart fatty acid binding protein with ischemia and reperfusion in the rat. 277 9

Cardiac extraction, oxidation and release of plasma free fatty acids (FFA) was measured by coronary sinus catheterization, utilizing infusions of 3H palmitate and 14C oleate, in patients with ischaemic heart disease (IHD) at rest and during pacing induced angina pectoris and, for comparison, in healthy men of similar and younger age and men with hypertriglyceridaemia (HTG). At rest IHD patients differed from healthy men only by greater cardiac fatty acid release, which correlated with a significant glycerol release. In IHD patients, unlike in healthy men, myocardial extraction of both palmitate and oleate decreased while fractional oxidation of oleate increased during pacing. Fatty acid release was unaltered. Men with HTG had at rest higher myocardial FFA extraction than IHD patients, which did not decrease during pacing, but like in the patients oleate fractional oxidation increased on pacing. It is concluded that, in the moderately ischaemic human heart, the restricted blood flow may contribute to limit the fatty acid flux into the myocardium. The augmented cardiac fatty acid release in IHD patients is not related to ischaemia per se but may derive from an increased amount of cardiac interstitial fat.
Mol Cell Biochem
PMID:Fatty acid turnover in the ischaemic compared to the non-ischaemic human heart. 277 38

Cis-unsaturated fatty acids, but not saturated fatty acids, inhibited phospholipase A2 activity (PLA2) in vitro, and may function as endogenous suppressors of lipolysis. To probe the possible role of lipid peroxidation in the regulation of myocardial lipid catabolism, a neutral-active and Ca2+-dependent PLA2 was extracted from rat heart and was partially purified by sulfopropyl cation exchange chromatography. Myocardial PLA2 activity was inhibited in a dose-dependent manner by oleic, linoleic, linolenic, and arachidonic acids; the IC50 for arachidonic acid was approx 65 microM. Palmitic acid was not inhibitory. When arachidonic acid was incubated at 37 degrees C, exposed to air, there was a time- and pH-dependent peroxidation of the arachidonic acid as monitored by turbidity, thiobarbituric acid reactivity, and thin layer chromatography. Peroxidation was increased as the pH was lowered from 7.5 to 4.5, and was accompanied by a decrease in PLA2 inhibitory potency. Thus, arachidonate incubated for 24 hours at pH's 4.5, 6.0 and 7.5 lost 84%, 32%, and 20% respectively, of its inhibitory potency. Therefore, in vitro acidosis promotes the oxidation of cis-unsaturated fatty acids and relieves their inhibitory or suppressive activity toward PLA2s. Increased lipid peroxidation of unesterified unsaturated fatty acids during acidosis may therefore promote lipolysis observed during myocardial ischemia and reperfusion injury.
Mol Cell Biochem
PMID:Fatty acid oxidation and myocardial phospholipase A2 activity. 277 34

Xanthine oxidoreductase has been demonstrated in the heart of various species. However, its presence in human heart is still debated. In the literature, high to undetectable levels have been reported. We studied the arterial-venous urate difference across the heart of patients undergoing both routine cardiac catheterization and percutaneous transluminal coronary angioplasty. Urate is the end product of the reaction catalysed by xanthine oxidoreductase. In 10 patients, studied before angioplasty, the plasma urate level in the great cardiac vein exceeded the arterial one by 26 +/- 10 nmol/ml (P = 0.028). In a further 13 patients, urate production was maximal immediately after the last of four consecutive occlusions (23 +/- 8 nmol/ml, P = 0.018) and concomitant with increased coronary sinus hypoxanthine levels. We conclude that xanthine oxidoreductase is probably present in the heart of patients, suffering from ischemic heart disease, and responsible for the increase in urate production during transient myocardial ischemia.
J Mol Cell Cardiol 1989 Jul
PMID:Urate production by human heart. 279 62

The protective effect of angiotensin-converting enzyme inhibitors (ACEI) on myocardial ischemia and reperfusion damage was estimated in rat hearts, both in vivo and in vitro. Enalapril 2.5 mg/kg ip pretreatment at 24 and 5 h before coronary occlusion, significantly blunted the rise of CPK (445 +/- 151 vs 649 +/- 244 mu/ml, P less than 0.05) and improved electrocardiogram (ECG) 8 h after coronary occlusion. In global ischemia and reperfusion ex vivo, enalapril improved contractility (0.9 +/- 0.2 vs 0.3 +/- 0.3 g, P less than 0.05) and coronary flow (15.6 +/- 3.3 vs 11.9 +/- 3.1 ml/min/g, P less than 0.05), shortened significantly the duration of reperfusion arrhythmia (3.1 +/- 2.7 vs 9.7 +/- 8.1 min, P less than 0.05). In Langendorffs heart, captopril remarkably preserved force of contraction (2.1 +/- 0.4 vs 1.4 +/- 0.4 g, P less than 0.01) and coronary flow (2.7 +/- 0.5 vs 3.6 +/- 0.9 ml/min/g, P less than 0.05) in segmental infarction deteriorated by angiotensin I. Captopril 10(-5) M infusion reduced the release of CPK (435 +/- 112 vs 640 +/- 123 mu/min coronary flow, P less than 0.05). This action was almost completely abolished by pretreating and infusing with indomethacin. As a positive control, prostacyclin 5 X 10(-7) M infusion further reduced the release of CPK to 330 +/- 77 mu/min. It is concluded that angiotensin-converting enzyme inhibitor can protect both myocardial ischemia and reperfusion damage in rat hearts. The mechanism of protection was ascribed to reduced production of angiotensin II by ACE inhibition and increased prostacyclin release in the myocardium.
J Mol Cell Cardiol 1987 Sep
PMID:Protective effects of captopril and enalapril on myocardial ischemia and reperfusion damage of rat. 282 45

An increased myocardial beta-adrenergic receptor density has been reported following myocardial ischemia. However, it is not clear whether these receptors are effectively coupled to adenylate cyclase which would be necessary for enhanced physiological responsiveness. We, therefore, examined the effects of myocardial ischemia in six conscious dogs (4 intact and 2 with posterior wall denervation) in which the left circumflex coronary artery was occluded. Ischemia was verified by measurement of regional blood flow by radioactive microspheres. After 1 h of coronary artery occlusion, the dogs were anesthetized with pentobarbital and the left ventricle was divided into normal, intermediate and ischemic regions. A crude membrane fraction was prepared from each region. beta-Adrenergic receptors were quantitated with 125I-cyanopindolol binding and adenylate cyclase activity was measured. In all six animals studied, beta-adrenergic receptor density increased progressively and adenylate cyclase activity decreased progressively, when the ischemic myocardium was compared to the intermediate and the non-ischemic myocardium. Since adenylate cyclase activity declined, these results do not support the concept that the increased beta-receptor density induced by myocardial ischemia is causally related to enhanced beta-adrenergic sensitivity.
J Mol Cell Cardiol 1988 Jan
PMID:One hour of myocardial ischemia in conscious dogs increases beta-adrenergic receptors, but decreases adenylate cyclase activity. 283 89

To examine the effects of acute myocardial ischemia and reperfusion on regional coronary vasodilator (or flow) reserve, peak reactive hyperemic blood flow following a 10 s occlusion was obtained in dogs subjected to circumflex (Cx) coronary artery occlusion for 1 h followed by reperfusion for 1 h. Acute myocardial ischemia resulting from Cx artery occlusion-reperfusion caused an attenuation in peak reactive hyperemic Cx flow (mean +/- S.E., from 215 +/- 29% to 87 +/- 17%, P less than or equal to 0.001). Acetylcholine-induced increase in Cx flow was also significantly (P less than or equal to 0.01) attenuated following Cx occlusion-reperfusion. These alterations were not observed in the left anterior descending (LAD) coronary artery, which was not subjected to occlusion. Pre-treatment of four dogs with indomethacin inhibited prostaglandin release (P less than or equal to 0.01), but did not affect peak reactive hyperemic coronary flow or acetylcholine-induced increase in coronary flow before or after occlusion-reperfusion. Histopathology revealed extensive myocardial neutrophil infiltration in the Cx-supplied region compared to the LAD-supplied region. Myocardial myeloperoxidase activity, an index of neutrophil infiltration, was also increased in the Cx compared to the LAD region (P less than or equal to 0.02). Myocardial neutrophil accumulation and myeloperoxidase activity were similar in the control and indomethacin-treated animals. These observations suggest that acute myocardial ischemia resulting from coronary artery occlusion-reperfusion impairs coronary vasodilator reserve in anesthetized dogs. This impairment, which was not modified by prostaglandin inhibition, may be related to the loss of endothelium-derived relaxing factor and/or decreased microvascular cross-sectional area resulting from capillary plugging by neutrophils.
J Mol Cell Cardiol 1988 Oct
PMID:Reduction in coronary vasodilator reserve following coronary occlusion and reperfusion in anesthetized dog: role of endothelium-derived relaxing factor, myocardial neutrophil infiltration and prostaglandins. 285 Oct 52

The effects of the inhibition of phospholipid degradation and superoxide radical generation on prostaglandin synthesis associated with myocardial ischemia and reperfusion were studied in the isolated, in-situ pig heart model subjected to 60 mins of regional ischemia and a further 60 mins of hypothermic potassium cardioplegic arrest, followed by 60 mins of reperfusion. Myocardial biopsies were taken from the ischemic and non-ischemic regions of the myocardium for measurement of phospholipids, and samples of the perfusate were drawn for estimation of the end-products of arachidonic acid metabolism, 6-keto-prostaglandin-F1 alpha and thromboxane B2. A significant amount of 6-keto-prostaglandin F1 alpha and thromboxane B2 appeared during reperfusion, corresponding with the loss of membrane phospholipids in control animals. Mepacrine, a phospholipase inhibitor, protected the depletion of membrane phospholipids and inhibited the products of arachidonate metabolism. Superoxide dismutase (SOD) and catalase, on the other hand, enhanced the formation of 6-keto-prostaglandin F1 alpha and thromboxane B2. The effects of both mepacrine and the free radical scavengers were pronounced during the reperfusion phase when the most significant depletion in membrane phospholipids occurred. These results suggest that the arachidonate cascade is activated during reperfusion of ischemic myocardium as a consequence of phospholipid breakdown, and this activation can be attenuated by inhibiting phospholipases or enhanced by scavenging oxygen-free radicals generated during reperfusion.
J Mol Cell Cardiol 1986 Sep
PMID:Enhanced prostaglandin synthesis due to phospholipid breakdown in ischemic-reperfused myocardium. Control of its production by a phospholipase inhibitor or free radical scavengers. 309 30

Circulatory blood corpuscles have enzymes catalyzing arachidonic acid. Platelets have cyclo-oxygenase system which produce highly vasoconstrictive and thrombogenic thromboxane A2 (TXA2). Neutrophils have another type of arachidonate metabolism system, lipoxygenase enzymes, which produce hydroxyeicosatetraenoic acids (HETE) and leukotrienes (LT), mediating inflammatory reactions. These arachidonate metabolites were found to play important roles in the evolution of myocardial ischemia. Thromboxane B2 (TXB2) a stable metabolite of TXA2, was elevated in peripheral blood of patients with angina pectoris. This elevation of TXB2 was supposed to be derived from platelet activation in coronary circulation due to altered production of TXA2 and prostacyclin (PGI2). Augmentation of TXA2 was also observed in patients with acute myocardial infarction. TXA2 synthetase inhibitors decreased plasma levels of TXB2 in these patients accompanied by attenuation of infarct size. Neutrophils were found to accumulate in ischemic myocardium and were augmented at reperfusion phase especially at interface between infarcted and risk zone. These infiltrated neutrophils may also provide deleterious effects on myocardial cells by producing lipoxygenase metabolites. In fact, a chemotactic and vasoconstrictive lipoxygenase product, 12-HETE, was produced selectively in ischemic myocardial tissue of an occlusion-reperfusion model. During evolution of myocardial cell damage, platelets and neutrophils, accumulated in ischemic tissue, may contribute to the exacerbation of microcirculatory disorders by producing vasoactive prostanoids, leading to expansion of myocardial necrosis. We should gain insights into these cellular interactions through arachidonate metabolism under normal and catastrophic conditions of coronary circulation.
J Mol Cell Cardiol 1988 Mar
PMID:Arachidonate metabolism in myocardial ischemia and reperfusion. 313 47


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