Carlos Bernal-Mizrachi, M.D.

Associate Professor
Internal Medicine
Endocrinology/Metabolism and Lipid Research

Molecular Cell Biology Program

  • 314-362-0947

  • 314-747-4477

  • cbernal@wustl.edu

  • Novel mechanisms of cardiovascular disease in human and mouse models with insulin resistance and type 2 DM

Research Abstract:

Characterization of the effects of vitamin D deficiency on the development of metabolic syndrome and vascular complications

The long-term goal of our laboratory is to determine the mechanisms responsible for metabolic syndrome and its vascular complications. We are particularly interested in understanding the mechanisms of the interactions between vitamin D signal transduction, intracellular calcium, and endoplasmic reticulum stress in critical tissues responsible for the development of metabolic syndrome and its complications. We and others have shown that vitamin D treatment improves factors linked to vascular inflammation in patients with metabolic syndrome: it improves peripheral insulin action, suppresses the renin angiotensin system, decreases systemic inflammatory mediators, decreases macrophage cytokine release, and prevents macrophage cholesterol deposition by downregulation of endoplasmic reticulum stress. In our laboratory, we have generated mouse models of diet-induced vitamin D deficiency and engineered mice with altered vitamin D receptor and endoplasmic reticulum stress signaling in order to identify the role of this vitamin in different tissues involved in the development of metabolic syndrome and vascular inflammation

Identification of signaling pathways controlling macrophage phenotype and function

Macrophages play a critical role in the development of metabolic syndrome and atherosclerosis. Monocytes recruited to the subendothelial space at sites of endothelial cell activation respond to environmental signals and differentiate into macrophages with diverse functional programs. We are identifying the effects of different environmental conditions on signaling pathways that regulate monocyte/macrophage differentiation and function in patients with type 2 diabetes. We also use genetically-modified mouse models to dissect the signaling pathways implicated in cellular differentiation, cholesterol deposition, and inflammatory responses.

Translation of Basic Science Results into Human Trials
We are actively enrolling patients into two clinical trials of patients with type 2 diabetes to assess the effects of vitamin D supplementation on blood pressure and subclinical markers of cardiovascular disease. For more details or if you are interested in participating, please see lab web page.

Selected Publications:

1. Oh J, Matkovich, et al. Renal macrophage secretion of miR-106b-5p causes renal renin production and hypertension. Nat. Comm. 2020; 11:4798.
2. Riek AE, et al. Vitamin D3 supplementation decreases a unique circulating monocyte cholesterol pool in patients with type 2 diabetes. J Steroid Biochem Mol Biol. 2018;177:187-192.
3. Oh J, et al. Deletion of JNK2 prevents Vitamin-D-deficiency-induced hypertension and atherosclerosis in mice. J Steroid Biochem Mol Biol. 2018;177:179-186.
4. Oh J et al. Deletion of Macrophage Vitamin D Receptor Promotes Insulin Resistance and Monocyte Cholesterol Transport to Accelerate Atherosclerosis in Mice. Cell Reports (15): 2211-1247, 2015 
5. Riek AE,et al. 25(OH) vitamin D suppresses macrophage adhesion and migration by downregulation of ER stress and scavenger receptor A1 in type 2 diabetes. The Journal of Steroid Biochemistry and Molecular Biology, 144:172-79, 2014 PMC 4026336. 
6. Riek AE, et al.1,25(OH)(2) vitamin D suppresses macrophage migration and reverses atherogenic cholesterol metabolism in type 2 diabetic patients. The Journal of Steroid Biochemistry and Molecular Biology. 136:309-12. 2013. 
7. Weng S, Sprague JE, et al. Vitamin D deficiency induces high blood pressure and accelerates atherosclerosis in mice. PLoS One, 8(1):e54625, 2013. 
8. Riek AE et al. Vitamin D suppression of ER stress promotes and anti-atherogenic monocyte/macrophage phenotype in type 2 diabetic patients. J Biol Chem, 287(46):38482-94, 2012. PMC3493893. 
9. Oh J et al. Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem, 287(15):11629-41, 2012. 
10. Riek AE,et al. Vitamin D regulates macrophage cholesterol metabolism in diabetes. The Journal of Steroid Biochemistry and Molecular Biology, 121(1-2):430-433, 2010.
11. Oh J, et al. 1,25(OH)2 vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes. Circulation, 120(8):687-698, 2009. 
12. Mulligan ML, et al. Implications of vitamin D deficiency in pregnancy and lactation. Am J Obstet Gynecol. 2010;202(5):429 e421-429. 
13. Bernal-Mizrachi C, et al. An afferent vagal nerve pathway links hepatic PPARalpha activation to glucocorticoid-induced insulin resistance and hypertension. Cell Metab. 2007;5(2):91-102
14. Bernal-Mizrachi C, et al. Vascular respiratory uncoupling increases blood pressure and atherosclerosis. Nature. 2005;435(7041):502-506
15. Bernal-Mizrachi C, et al. Dexamethasone induction of hypertension and diabetes is PPAR-alpha dependent in LDL receptor-null mice. Nat Med. 2003;9(8):1069-1075

Last Updated: 3/23/2021 4:29:04 PM

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