Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8337902 | The Journal of Steroid Biochemistry and Molecular Biology | 2018 | 20 Pages |
Abstract
The c-Jun N-terminal kinase 2 (JNK2) signaling pathway contributes to inflammation and plays a key role in the development of obesity-induced insulin resistance and cardiovascular disease. Macrophages are key cells implicated in these metabolic abnormalities. Active vitamin D downregulates macrophage JNK activation, suppressing oxidized LDL cholesterol uptake and foam cell formation and promoting an anti-inflammatory phenotype. To determine whether deletion of JNK2 prevents high blood pressure and atherosclerosis known to be induced by vitamin D deficiency in mice, we generated mice with knockout of JNK2 in a background susceptible to diet-induced atherosclerosis (LDLRâ/â). JNK2â/â LDLRâ/â and LDLRâ/â control mice were fed vitamin D-deficient chow for 8 weeks followed by vitamin D-deficient high fat diet (HFD) for 10 weeks and assessed before and after HFD. There was no difference in fasting glucose, cholesterol, triglycerides, or free fatty acid levels. However, JNK2â/â mice, despite vitamin D-deficient diet, had 20-30Â mmHg lower systolic (SBP) and diastolic (DBP) blood pressure before HFD compared to control mice fed vitamin D-deficient diets, with persistent SBP differences after HFD. Moreover, deletion of JNK2 reduced HFD-induced atherosclerosis by 30% in the proximal aorta when compared to control mice fed vitamin D-deficient diets. We have previously shown that peritoneal macrophages obtained from LDLRâ/â mice fed vitamin D-deficient HFD diets have higher foam cell formation compared to those from mice on vitamin D-sufficient HFD. The increased total cellular cholesterol and modified cholesterol uptake in macrophages from mice on vitamin D-deficient HFD were blunted by deletion of JNK2. These data suggest that JNK2 signaling activation is necessary for the atherosclerosis and hypertension induced by vitamin D deficiency.
Keywords
CD36VCAM-1VDRT2DMICAM1HTNJnk2eNOSLDLRRASscavenger receptor class A1,25-dihydroxy vitamin DSR-A1Jnkp-PERK1,25(OH)2D25(OH)D25-hydroxy vitamin DAtherosclerosiscardiovascular diseaseCHOPcluster of differentiation 36CVDendothelial nitric oxide synthaserenin-angiotensin systemendoplasmic reticulumHypertensionMacrophagesIntercellular adhesion molecule 1Vascular cell adhesion molecule 1Vitamin Dlow density lipoprotein receptorVitamin D receptor
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Authors
Jisu Oh, Amy E. Riek, Rong M. Zhang, Samantha A.S. Williams, Isra Darwech, Carlos Bernal-Mizrachi,