Abstract
Bioassay-guided evaluation shows that a deep sea-derived fungus, Spiromastix sp. MCCC 3A00308, possesses lipid-lowering activity. Chromatographic separation of a culture broth resulted in the isolation of 15 known depsidone-based analogues, labeled spiromastixones A–O (1–15). Each of these compounds was tested for its ability to inhibit oxidized low-density lipoprotein (oxLDL)-induced foam cell formation in RAW264.7 macrophages. Spiromastixones 6–8 and 12–14 significantly decreased oxLDL-induced lipid over-accumulation, reduced cell surface area, and reduced intracellular cholesterol concentration. Of these compounds, spiromastixones 6 and 14 exerted the strongest inhibitory effects. Spiromastixones 6 and 14 dramatically inhibited cholesterol uptake and stimulated cholesterol efflux to apolipoprotein A1 (ApoA1) and high-density lipoprotein (HDL) in RAW264.7 macrophages. Mechanistic investigation indicated that spiromastixones 6, 7, 12 and 14 significantly up-regulated the mRNA levels of ATP-binding cassette sub-family A1 (ABCA1) and down-regulated those of scavenger receptor CD36, while the transcription of ATP-binding cassette sub-family A1 (ABCG1) and proliferator-activated receptor gamma (PPARγ) were selectively up-regulated by 6 and 14. A transactivation reporter assay revealed that spiromastixones 6 and 14 remarkably enhanced the transcriptional activity of PPARγ. These results suggest that spiromastixones inhibit foam cell formation through upregulation of PPARγ and ABCA1/G1 and downregulation of CD36, indicating that spiromastixones 6 and 14 are promising lead compounds for further development as anti-atherogenic agents.
Highlights
Atherosclerosis (AS) is the primary risk factor associated with coronary artery disease, is the leading cause of morbidity and mortality in developed countries, and is becoming increasingly prevalent in developing countries [1]
ATP-binding cassette sub-family A1 (ABCA1) promotes the efflux of cholesterol to lipid-poor apolipoproteins, such as apolipoprotein A1, while ABCG1 plays a critical role in mediating cholesterol efflux to high-density lipoprotein (HDL) [10,11,12]
We report the inhibitory effects of spiromastixones A–O on oxidized low-density lipoprotein (oxLDL)-induced foam cell formation and detail the potential mechanisms of this inhibition in RAW264.7 macrophages
Summary
Atherosclerosis (AS) is the primary risk factor associated with coronary artery disease, is the leading cause of morbidity and mortality in developed countries, and is becoming increasingly prevalent in developing countries [1]. According to the current understanding of the cellular and molecular mechanisms underlying atherogenesis, the most important event in the development of atherosclerosis is the accumulation of extracellular and intracellular lipids in the arterial intima caused by low-density lipoprotein (LDL) [4,5]. Foam cell formation is associated with increased macrophage cholesterol levels and results from imbalanced lipid efflux and influx [4]. Macrophages express scavenger receptors on their plasma membranes; uptake oxidized LDL, which is deposited into blood vessel walls; and develop into foam cells [6]. Scavenger receptors CD36, SR-A1 and SR-A2 bind to and uptake excess oxidized low-density lipoprotein (oxLDL) into macrophages [7], leading to the accumulation of excess cholesterol, which is toxic to cells. We report the inhibitory effects of spiromastixones A–O on oxLDL-induced foam cell formation and detail the potential mechanisms of this inhibition in RAW264.7 macrophages
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