Cardiovascular Protection Mediated by the Chemokine CXCL5

Abstract

One out of every four deaths in the United States can be attributed to heart disease. Atherosclerosis is a prevalent form of cardiovascular disease that describes the narrowing of arteries, leading to the restriction of blood flow. Atherosclerosis is caused in part by the accumulation of lipid‐laden macrophages (foam cells) in the walls of arteries. Determining mechanisms that influence lipid metabolism in macrophages may uncover new approaches to modify the disease process and decrease the disease burden. Recently, our lab identified a genetic link between the expression of the chemokine CXCL5 and atherosclerosis in patients that is consistent with a cardioprotective role for CXCL5. One effect of CXCL5 appears to be in the regulation of reverse cholesterol transporters. We found that exposure to CXCL5 decreases foam cell forming macrophages, suggesting CXCL5 may directly impact lipid metabolism. What is not known is how CXCL5 modifies the pathophysiological response to conditions that contribute to atherosclerosis, such as a high fat diet (HFD). We hypothesized that CXCL5 mediates cardioprotection by altering the physiological response to a HFD, such that, lower levels of CXCL5 will lead to altered lipid handling and predisposition to more severe atherosclerosis. We challenged wild‐type (WT) and CXCL5−/− mice with either a HFD (0.2% cholesterol, 42% calories from fat, N = 17 per genotype), or normal chow (NC, 0% cholesterol, 16% calories from fat, N = 15 per genotype) for 16 w. To determine the effect of the diet on circulating lipid levels, we performed blood lipid analysis after the feeding regimen. Interestingly, HFD did not increase cholesterol levels to the same extent in CXCL5−/− mice as compared to WT mice. Specifically, we found that WT mice had a robust, diet‐dependent increase in both high‐density lipoprotein and low‐density lipoprotein levels (LDL: 59.6 mg/dl vs 11.3 mg/dl and HDL: 118.7 mg/dl vs 68.1 mg/dl in HFD vs NC, respectively), whereas in CXCL5−/− mice, this response was diminished (LDL: 20.6 mg/dl vs 8.8 mg/dl and HDL: 82.6 mg/dl vs 56.8 mg/dl in HFD vs NC, respectively). These results suggest that the genetic depletion of CXCL5 alters lipid handling in vivo. Additionally, white blood cell analysis identified that WT mice responded to the HFD with an increase in the number of lymphocytes (10.3e3 cells/μl vs 5.2e3 cells/μl in HFD WT vs NC WT, p = 0.0224) and basophils (20 cells/μl vs 4.0 cells/μl, p = 0.0038), an effect that was attenuated in KO mice in response to the HFD (p > 0.05). These findings suggest that CXCL5 may modify a specific component in the chronic inflammatory response to the HFD. Unexpectedly, HFD led to a modest decrease in cardiac function in KO mice after 16 w of the HFD compared to WT mice (74% vs 82% ejection fraction in CXCL5−/− vs WT mice, respectively, p = 0.0058). These preliminary findings suggest that CXCL5 plays a multifaceted role in the cardiovascular system’s response to an atherogenic diet. Currently, studies are underway using athero‐prone mice to study the effect of CXCL5 on plaque formation, using the ApoE−/− model. Future directions include treating mice with CXCL5 to study the effects on both the progression and regression of atherosclerosis. If successful, our studies would bring light to a new therapeutic target that could be used to combat cardiovascular disease.