alpha-cyclodextrin and Atherosclerosis

Atherosclerosis is an inflammatory disease resulting from subendothelial accumulation of lipoprotein-derived cholesterol in susceptible arterial segments, ultimately leading to the formation of clinically significant atherosclerotic plaques. Despite significant advances in the treatment of atherosclerosis, atherosclerotic cardiovascular diseases remain the leading cause of death and disabilities worldwide. Accordingly, there is an urgent need for novel therapies. Cyclodextrins are cyclic oligosaccharides produced from many sources of starch by enzymatic degradation. The frequently used cyclodextrins are α-, β-, and γ-cyclodextrins, which are composed of six, seven, and eight glucose moieties, respectively. Especially β-cyclodextrin can entrap hydrophobic compounds, such as cholesterol, into its hydrophobic cavity and form stable inclusion complexes with cholesterol. This inherent affinity of cyclodextrins has been exploited to extract excess cholesterol from cultured cells, as well as intra- and extracellular cholesterol stores present in atherosclerotic lesions of experimental animals. Accordingly, cyclodextrins could be considered as potentially effective therapeutic agents for the treatment of atherosclerosis. In this review, we address recent advances and the current status of the development of cyclodextrins and provide an update of the latest in vitro and in vivo experiments that pave the way to clinical studies. The emerging therapeutic opportunities by using cyclodextrins could aid us in our efforts to ultimately eradicate the residual risk after other cholesterol-lowering pharmacotherapies, and also reduce the associated burden of premature deaths due to atherosclerotic cardiovascular diseases.

Topics: alpha-Cyclodextrins; Animals; Arteries; Atherosclerosis; beta-Cyclodextrins; Biomarkers; Humans; Lipids; Plaque, Atherosclerotic

Cholesterol crystal (CC)-induced inflammation is a critical step in the development of atherosclerosis. CCs activate the complement system and induce an inflammatory response resulting in phagocytosis of the CCs, production of reactive oxygen species (ROS) and release of cytokines. The cyclodextrin 2-hydroxypropyl-β-cyclodextrin has been found to reduce CC-induced complement activation and induce regression of established atherosclerotic plaques in a mouse model of atherosclerosis, thus inhibition of complement with cyclodextrins is a potential new strategy for treatment of inflammation during atherosclerosis. We hypothesized that other cyclodextrins, like α-cyclodextrin, may have related functions.. The effect of cyclodextrins on CC-induced complement activation, phagocytosis, and production of ROS from granulocytes and monocytes was investigated by flow cytometry and ELISA.. We showed that α-cyclodextrin strongly inhibited CC-induced complement activation by inhibiting binding of the pattern recognition molecules C1q (via IgM) and ficolin-2. The reduced CC-induced complement activation mediated by α-cyclodextrin resulted in reduced phagocytosis and reduced ROS production in monocytes and granulocytes. Alpha-cyclodextrin was the most effective inhibitor of CC-induced complement activation, with the reduction in deposition of complement activation products being significantly different from the reduction induced by 2-hydroxypropyl-β-cyclodextrin. We also found that α-cyclodextrin was able to dissolve CCs.. This study identified α-cyclodextrin as a potential candidate in the search for therapeutics to prevent CC-induced inflammation in atherosclerosis.

Topics: alpha-Cyclodextrins; Atherosclerosis; Cholesterol; Complement Activation; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Inflammation; Male; Monocytes; Phagocytosis; Reactive Oxygen Species

α-Cyclodextrin (α-CD), a cyclic polymer of glucose, has been shown to lower plasma cholesterol in animals and humans; however, its effect on atherosclerosis has not been previously described.. apoE-knockout mice were fed either low-fat diet (LFD; 5.2% fat, w/w), or Western high fat diet (21.2% fat) containing either no additions (WD), 1.5% α-CD (WDA); 1.5% β-CD (WDB); or 1.5% oligofructose-enriched inulin (WDI). Although plasma lipids were similar after 11 weeks on the WD vs. WDA diets, aortic atherosclerotic lesions were 65% less in mice on WDA compared to WD (P < 0.05), and similar to mice fed the LFD. No effect on atherosclerosis was observed for the other WD supplemented diets. By RNA-seq analysis of 16S rRNA, addition of α-CD to the WD resulted in significantly decreased cecal bacterial counts in genera Clostridium and Turicibacterium, and significantly increased Dehalobacteriaceae. At family level, Comamonadaceae significantly increased and Peptostreptococcaceae showed a negative trend. Several of these bacterial count changes correlated negatively with % atherosclerotic lesion and were associated with increased cecum weight and decreased plasma cholesterol levels.. Addition of α-CD to the diet of apoE-knockout mice decreases atherosclerosis and is associated with changes in the gut flora.

Topics: alpha-Cyclodextrins; Animals; Aorta; Atherosclerosis; beta-Cyclodextrins; Body Weight; Cecum; Diet, Fat-Restricted; Diet, High-Fat; Dietary Supplements; Female; Gastrointestinal Microbiome; Intestinal Absorption; Lipids; Mice, Knockout, ApoE

High dietary intake of saturated fat and cholesterol, and elevated low-density lipoprotein cholesterol levels are some of the modifiable risk factors for cardiovascular disease. Alpha-cyclodextrin (a-CD) when given orally has been shown in rats to increase fecal saturated fat excretion and to reduce blood total cholesterol levels in obese hypertriglyceridemic subjects with type 2 diabetes mellitus. In this study, the effects of dietary a-CD on lipid metabolism in low-density lipoprotein receptor knockout mice were investigated. Low-density lipoprotein receptor knockout mice were fed a "Western diet" (21% milk fat) with or without 2.1% of a-CD (10% of dietary fat content) for 14 weeks. At sacrifice, there was no difference in body weight; but significant decreases were observed in plasma cholesterol (15.3%), free cholesterol (20%), cholesterol esters (14%), and phospholipid (17.5%) levels in mice treated with alpha-CD compared with control mice. The decrease in total cholesterol was primarily in the proatherogenic apolipoprotein B-containing lipoprotein fractions, with no significant change in the high-density lipoprotein fraction. Furthermore, alpha-CD improved the blood fatty acid profile, reducing the saturated fatty acids (4.5%) and trans-isomers (11%) while increasing (2.5%) unsaturated fatty acids. In summary, the addition of alpha-CD improved the lipid profile by lowering proatherogenic lipoproteins and trans-fatty acids and by decreasing the ratio of saturated and trans-fatty acids to polyunsaturated fatty acids (-5.8%), thus suggesting that it may be useful as a dietary supplement for reducing cardiovascular disease.

Topics: alpha-Cyclodextrins; Animals; Atherosclerosis; Body Weight; Cholesterol Esters; Cholesterol, LDL; Dietary Fats; Eating; Fatty Acids, Nonesterified; Female; Lipid Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Random Allocation; Receptors, LDL; Triglycerides