ABSTRACT
Internalization of modified low-density lipoprotein (LDL) via macrophage scavenger receptors (e.g. scavenger receptor A and CD36) is thought to play a crucial role in the development of atherosclerotic lesions. Cilostazol, an antiplatelet agent with selective phosphodiesterase 3 inhibitory action, has been reported to ameliorate atherosclerosis in mouse models. However, the effect of cilostazol on modified LDL uptake in macrophages is not known. Thus, we investigated the effect of cilostazol on LDL uptake in mouse peritoneal macrophages (MPM). Cilostazol significantly inhibited oxidized and acetylated LDL uptake in MPM, while cyclic AMP (cAMP)-elevating agents, db-cAMP and other phosphodiesterase 3 or 4 inhibitors, did not inhibit the uptake. Cilostazol did not change cytosolic cAMP levels in MPM, and a protein kinase A (PKA) inhibitor did not influence the inhibitory effects of cilostazol. Cilostazol decreased scavenger receptor A but not CD36 expression. Moreover, cilostazol significantly inhibited foam cell formation, which was represented by an increase in esterified cholesterol content. In conclusion, cilostazol significantly inhibits the uptake of modified LDL and foam cell formation in mouse peritoneal macrophages, and the inhibitory effect of cilostazol can be induced in a cAMP- and PKA-independent manner.
Subject(s)
Cardiovascular Agents/pharmacology , Endocytosis/drug effects , Foam Cells/drug effects , Lipoproteins, LDL/metabolism , Macrophages, Peritoneal/drug effects , Tetrazoles/pharmacology , Animals , CD36 Antigens/drug effects , CD36 Antigens/metabolism , Cells, Cultured , Cholesterol Esters/metabolism , Cilostazol , Cyclic AMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Dose-Response Relationship, Drug , Foam Cells/metabolism , Macrophages, Peritoneal/metabolism , Mice , Phosphodiesterase 3 Inhibitors , Phosphodiesterase 4 Inhibitors , Phosphodiesterase Inhibitors/pharmacology , Protein Kinase C/antagonists & inhibitors , Protein Kinase C/metabolism , Protein Kinase Inhibitors/pharmacology , Scavenger Receptors, Class A/drug effects , Scavenger Receptors, Class A/metabolismABSTRACT
An asthmatic patient with corticosteroid treatment for 45 years presented with slowly progressive limb muscle atrophy. His muscle symptoms were involved in four limbs and tongue, and deep tendon reflexes were exaggerated. Biopsied muscle pathology indicated the presence of neurogenic muscular atrophy in combination with corticosteroid myopathy. Furthermore, 8-hydroxy-deoxyguanosine (8-OH-dG) was prominently increased in mitochondrial and nuclear DNA. An aerobic exercise test demonstrated remarkable serum lactate elevation, which was attenuated by the administration of coenzyme Q10. These findings are consistent with the assumption that long-term corticosteroid administration potentially induces not only myopathy but also motor neuron involvement as in mitochondrial diseases.
Subject(s)
Betamethasone/adverse effects , Glucocorticoids/adverse effects , Motor Neuron Disease/chemically induced , Muscle, Skeletal/pathology , Aged , Asthma/drug therapy , Biopsy , Electromyography , Humans , Male , Mitochondria, Muscle/drug effects , Mitochondrial Myopathies/chemically induced , Mitochondrial Myopathies/diagnosis , Mitochondrial Myopathies/metabolism , Motor Neuron Disease/diagnosis , Motor Neuron Disease/metabolism , Muscle, Skeletal/innervation , Muscular Atrophy/chemically induced , Muscular Atrophy/pathology , Muscular Atrophy/physiopathology , Oxidative Stress/physiologyABSTRACT
Corticosteroid myopathy is a major clinical problem in patients undergoing chronic corticosteroid treatment and shows insidious and progressive muscle atrophy in proximal limbs. Although several mechanisms underlying the pathophysiology of muscle injury have been postulated, precise pathogenesis is still not clear. We evaluated the mitochondrial functions in patients receiving corticosteroids compared with those in healthy controls or patients not receiving corticosteroids. The serum levels and total production of lactate were investigated by an aerobic exercise test using a bicycle ergometer. Mitochondrial respiratory activities and oxidative damage in biopsied skeletal muscles were also studied. The results of aerobic exercise tests revealed a significant overproduction of lactate in patients treated with corticosteroids ( p < 0.005), which was positively correlated with total corticosteroid doses administered ( p < 0.0001). In these patients, mitochondrial enzyme activity in complex I was significantly decreased ( p < 0.05) and oxidative damage of biopsied skeletal muscle was remarkable both in mitochondrial and nuclear DNAs ( p < 0.001). The results suggest that chronic corticosteroid administration induces mitochondrial dysfunction and oxidative damage in skeletal muscles, which may be the pathogenesis, at least in part, of corticosteroid-induced myopathy.
Subject(s)
Adrenal Cortex Hormones/adverse effects , Deoxyguanosine/analogs & derivatives , Mitochondria/drug effects , Muscle, Skeletal/drug effects , 8-Hydroxy-2'-Deoxyguanosine , Adrenal Cortex Hormones/therapeutic use , Case-Control Studies , DNA Damage , Deoxyguanosine/analysis , Dose-Response Relationship, Drug , Electron Transport Complex I , Electron Transport Complex II , Electron Transport Complex III/analysis , Exercise Test , Female , Humans , Lactic Acid/blood , Male , Middle Aged , Mitochondria/chemistry , Multienzyme Complexes/analysis , NADH, NADPH Oxidoreductases/analysis , Oxidative Stress , Oxidoreductases/analysis , Pyruvic Acid/blood , Succinate Dehydrogenase/analysis , Time FactorsABSTRACT
Two patients with long-term corticosteroid administration sporadically developed limb muscle wasting followed by ophthalmoplegia, and the skeletal muscle pathology revealed ragged-red fibers (RRFs) with abnormal mitochondria, in addition to the findings of corticosteroid myopathy. The oculoskeletal symptoms of the present cases resemble those of chronic progressive external ophthalmoplegia, a type of mitochondrial disease. The ocular muscles have more RRFs than limb muscles, and large multiple deletions of mitochondrial DNA was detected in ocular and limb muscles of the two patients by PCR but not by Southern blotting. Immunohistochemistry demonstrated that 8-hydroxy-deoxyguanosine (8-OH-dG) and 4-hydroxy-2-nonenal were intensely stained in skeletal muscles of these patients particularly in RRFs. High-performance liquid chromatography with electrochemical detection analysis revealed an increase in 8-OH-dG from mitochondrial DNA. These findings may suggest that long-term corticosteroid administration potentially induces oxidative stress-mediated mitochondrial damage, resulting in the development of the oculoskeletal symptoms in some patients.
