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

J Steroid Biochem Mol Biol. 2018 Mar;177:179-186. doi: 10.1016/j.jsbmb.2017.09.014. Epub 2017 Sep 23.

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 (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.

Keywords: Atherosclerosis; Hypertension; JNK; Macrophages; Vitamin D.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / etiology*
  • Atherosclerosis / metabolism
  • Cholesterol / metabolism
  • Diet, High-Fat
  • Female
  • Hypertension / etiology*
  • Hypertension / metabolism
  • Macrophages, Peritoneal / metabolism
  • Male
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 9 / genetics*
  • Receptors, LDL / genetics
  • Vitamin D Deficiency / complications*
  • Vitamin D Deficiency / metabolism

Substances

  • Receptors, LDL
  • Cholesterol
  • Mitogen-Activated Protein Kinase 9