The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice.

Hyperlipidemia is a well-recognized risk factor for atherosclerosis and can be regulated by adipokines. Expression of the adipokine resistin-like molecule alpha (Retnla) is regulated by food intake; whether Retnla has a role in the pathogenesis of hyperlipidemia and atherosclerosis is unknown. Here we report that Retnla has a cholesterol-lowering effect and protects against atherosclerosis in low-density lipoprotein receptor-deficient mice. On a high-fat diet, Retnla deficiency promotes hypercholesterolaemia and atherosclerosis, whereas Retnla overexpression reverses these effects and improves the serum lipoprotein profile, with decreased cholesterol in the very low-density lipoprotein fraction concomitant with reduced serum apolipoprotein B levels. We show that Retnla upregulates cholesterol-7-α-hydroxylase, a key hepatic enzyme in the cholesterol catabolic pathway, through induction of its transcriptional activator liver receptor homologue-1, leading to increased excretion of cholesterol in the form of bile acids. These findings define Retnla as a novel therapeutic target for treating hypercholesterolaemia and atherosclerosis.

Evaluation of VCAM-1 antibodies as therapeutic agent for atherosclerosis in apolipoprotein E-deficient mice.

OBJECTIVE: Blocking agents targeting cell adhesion molecules have been developed to prevent cardiovascular diseases such as atherosclerosis, whereas relatively little attention has been paid to the therapeutic potential of vascular cell adhesion molecule (VCAM)-1 as an inflammatory disease target. Two novel, fully human antibodies, H6 and 7H, against human VCAM-1 (hVCAM-1) were developed and tested to validate the hypothesis that blocking VCAM-1 ameliorates atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice. METHODS AND RESULTS: Treatment with H6 or 7H effectively inhibited VCAM-1 adhesion to inflammatory cells, and reduced RhoA activation and the production of reactive oxygen species in human umbilical cord vascular endothelial cells. As 7H showed binding affinity to both murine VCAM-1 (mVCAM-1) and hVCAM-1, the therapeutic effects of 7H in ApoE(-/-) mice were tested. After confirming specific in vivo binding activity of 7H to mVCAM-1, we showed that administering 7H resulted in significantly ameliorated plaque formation compared to administering a control antibody in ApoE(-/-) mice fed a Western diet for 12 weeks. Also, 7H treatment significantly reduced infiltration of CD45(+) cells into plaques and reduced inflammation and improved plaque stability. CONCLUSION: These results indicate that the anti-VCAM-1 antibody attenuates atherosclerosis in ApoE(-/-) mice, improves plaque inflammation and stability as well as inhibiting the adhesion of inflammatory cell, and suggest that blocking VCAM-1 with a monoclonal antibody may be an effective means of anti-atherosclerotic therapy.

Ginkgo biloba extract (GbE) enhances the anti-atherogenic effect of cilostazol by inhibiting ROS generation.

In this study, the synergistic effect of 6-[4-(1-cyclohexyl- 1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2(1H )-quinolinone (cilostazol) and Ginkgo biloba extract (GbE) was examined in apolipoprotein E (ApoE) null mice. Co-treatment with GbE and cilostazol synergistically decreased reactive oxygen species (ROS) production in ApoE null mice fed a high-fat diet. Co-treatment resulted in a significantly decreased atherosclerotic lesion area compared to untreated ApoE mice. The inflammatory cytokines and adhesion molecules such as monocyte chemoattractant-1 (MCP-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and VCAM-1 which can initiate atherosclerosis were significantly reduced by the co-treatment of cilostazol with GbE. Further, the infiltration of macrophages into the intima was decreased by co-treatment. These results suggest that co-treatment of GbE with cilostazol has a more potent anti-atherosclerotic effect than treatment with cilostazol alone in hyperlipidemic ApoE null mice and could be a valuable therapeutic strategy for the treatment of atherosclerosis.