Deletion of JNK2 prevents vitamin-D-deficiency-induced hypertension and atherosclerosis in mice.

Autor: Oh J; Division of Endocrinology, Metabolism, and Lipid Research, Washington University, 660 South Euclid Ave., Campus Box 8127, St. Louis, MO 63110, USA., Riek AE; Division of Endocrinology, Metabolism, and Lipid Research, Washington University, 660 South Euclid Ave., Campus Box 8127, St. Louis, MO 63110, USA., Zhang RM; Division of Endocrinology, Metabolism, and Lipid Research, Washington University, 660 South Euclid Ave., Campus Box 8127, St. Louis, MO 63110, USA., Williams SAS; Division of Endocrinology, Metabolism, and Lipid Research, Washington University, 660 South Euclid Ave., Campus Box 8127, St. Louis, MO 63110, USA., Darwech I; Division of Endocrinology, Metabolism, and Lipid Research, Washington University, 660 South Euclid Ave., Campus Box 8127, St. Louis, MO 63110, USA., Bernal-Mizrachi C; Division of Endocrinology, Metabolism, and Lipid Research, Washington University, 660 South Euclid Ave., Campus Box 8127, St. Louis, MO 63110, USA; Division of Endocrinology, Metabolism, and Lipid Research, Department of Cell Biology and Physiology, Washington University, 660 South Euclid Ave., Campus Box 8127, St. Louis, MO 63110, USA; Division of Endocrinology, Saint Louis VA Medical Center, 915 N Grant Blvd, Saint Louis, MO 63106, USA. Electronic address: cbernal@wustl.edu.
Jazyk: angličtina
Zdroj: The Journal of steroid biochemistry and molecular biology [J Steroid Biochem Mol Biol] 2018 Mar; Vol. 177, pp. 179-186. Date of Electronic Publication: 2017 Sep 23.
DOI: 10.1016/j.jsbmb.2017.09.014
Abstrakt: 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 (LDLR -/- ). JNK2 -/- LDLR -/- and LDLR -/- 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, JNK2 -/- mice, despite vitamin D-deficient diet, had 20-30mmHg 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 LDLR -/- 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.
(Published by Elsevier Ltd.)
Databáze: MEDLINE
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