Atherosclerosis and Coronary Heart Disease

Buildup of plaque, as a result of the accumulation of cholesterol, oxidized lipids, leukocytes, cellular waste products, and calcium, inside the artery wall results in atherosclerosis and the narrowing of large and medium-sized arteries that can lead to coronary heart diseases and myocardial infarction. Artery wall metabolism, lipoproteins, immune system and coagulation factors play major roles in atherogenesis, narrowing of the arteries and eventual occlusion. Genetic and environmental factors affect the rate of atherogenesis in different individuals.
 

Current Research Projects

In addition, gut microbiota have now been associated with a variety of atherosclerosis risk factors, including plasma lipids, bile acids, insulin resistance, and inflammation. Recently, trimethylamine-N-oxide, a metabolite derived through the action of microbiota, was shown to be strongly associated with atherosclerosis. The participating laboratories (Jake Lusis, Mohamad Navab, Alan Fogelman) are primarily interested in mechanistic studies of host-microbiota interactions in mouse models. We are also carrying a large epidemiologic study on gut microbiota in a cross-sectional population from Finland.

We have observed that a number of peptides that suppress inflammation do so by acting at the level of the intestine, and we are exploring the possibility that their actions are mediated in part by effects on the gut microbiota. We have observed that upon feeding a diet containing a pro inflammatory lipid in LDL receptor null mice, the proportion of the P. Bacteriodeted and P. Verruccomicrobia was altered and our anti-inflammatory peptide reversed the changes.

Representative Publications:

  • Navab M, Hough G, Buga GM, Su F, Wagner AC, Meriwether D, Chattopadhyay A, Gao F, Grijalva V, Danciger JS, Van Lenten BJ, Org E, Lusis AJ, Pan C, Anantharamaiah GM, Farias-Eisner R, Smyth SS, Reddy ST, Fogelman AM. Transgenic 6F tomatoes act on the small intestine to prevent systemic inflammation and dyslipidemia caused by Western diet and intestinally derived lysophosphatidic acid. J Lipid Res. 2013 Dec;54(12):3403-18. PMCID: PMC3826687.
  • Navab M, Chattopadhyay A, Hough G, Meriwether D, Fogelman SI, Wagner AC, Grijalva V, Su F, Anantharamaiah GM, Hwang LH, Faull KF, Reddy ST, Fogelman AM. Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis. J Lipid Res. 2015 Apr;56(4):871-87. PMCID: PMC4373744.

 

Key People

Photo of Laurent Bentolila, PhD
Laurent Bentolila, PhD
Scientific Director, Advanced Light Microscopy/Spectroscopy Lab; Scientific Director, Macro-Scale Imaging Lab; Researcher, California NanoSystems Institute, UCLA
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Address Advanced Light Microscopy/Spectroscopy Laboratory California NanoSystems Institute 570 Westwood Plaza Bldg 114 Los Angeles CA 90095 Phone: (310) 983-1076Website: Laboratory

Dr. Bentolila is a senior researcher at the California NanoSystems Institute (CNSI) at the University of California, Los Angeles (UCLA). He is also the Scientific Director of the Advanced Light Microscopy/Spectroscopy Laboratory (ALMS) and the Macro-Scale Imaging Laboratory (MSI) at CNSI. Dr. Bentolila earned his B.S. in Biochemistry and M.S. in Genetics from Paris-XI University, Orsay and Ph.D. in Molecular Genetics and Immunology from the Pasteur Institute, Paris, France. He was a European Molecular Biology Organization Postdoctoral fellow at the University of California, Berkeley before joining the Department of Chemistry and Biochemistry at UCLA in 2002.

Dr. Bentolila’s long-standing research interest focuses on the application of novel fluorescent probes and advanced microscopy techniques to biology and medicine. Towards this goal, Dr. Bentolila has developed and assembled a unique collection of custom-made and commercial light microscopes for the application of novel spectroscopic methods and advanced microscopy techniques used for the study of macromolecules, cellular dynamics and nano-scale characterization of biomaterials. His most recent research projects include developing new experimental tools for visualizing and tracking cells, bacteria and parasites within a host.

Dr. Bentolila is the recipient of several awards from the Burroughs Wellcome Fund, the European Molecular Biology Organization and the Roux Foundation.

Relevant Recent Publications

  1. Bentolila LA, Prakash R, Mihic-Probst D, Wadehra M, Kleinman HK, Carmichael TS, Péault B, Barnhill RL and Lugassy C. Imaging of Angiotropism/Vascular Co-Option in a Murine Model of Brain Melanoma. Implications for Melanoma Progression along Extravascular Pathways. 2016. Scientific Reports. In press.
  2. Chen AL, Kim EW, Toh JY, Vashisht AA, Rashoff AQ, Van C, Huang AS, Moon AS, Bell HN, Bentolila LA, Wohlschlegel JA and Bradley PJ. Novel components of the Toxoplasma inner membrane complex revealed by BioID. 2015. mBio 6(1) e02357-14.
  3. Kisalu NK, Langousis GD, Bentolila LA, Ralston KS, Hill KL. Mouse infection and pathogenesis by Trypanosoma brucei motility mutants. Cellular Microbiology. 2014. 16(6):912-924.
  4. Mitchell-Jordan S, Chen H, Franklin S, Stefani E, Bentolila LA and Vondriska TM. Features of endogenous cardiomyocyte chromatin revealed by super resolution STED microscopy. J Mol Cell Cardiol. 2012. 53(4):552-8.

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Photo of Dino Di Carlo, PhD
Dino Di Carlo, PhD
Professor, Department of Bioengineering; Member, California NanoSystems Institute, Jonsson Comprehensive Cancer Center
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Address 5121E Engineering V Los Angeles CA 90095 Phone: (310) 983-3235Website: Di Carlo Laboratory

Dino Di Carlo is a Professor in the Department of Bioengineering at UCLA. Over the last 8 years he pioneered using inertial fluid dynamic effects for the control, separation, and analysis of cells in microfluidic devices. His work now extends into numerous fields of biomedicine and biotechnology including directed cellular evolution of microbes, cell and microbial analysis for rapid diagnostics, new amplified molecular assays, next generation biomaterials, and phenotypic drug screening. He also serves as Director of the Cancer Nanotechnology Program of the Jonsson Comprehensive Cancer Center at UCLA and holds a visiting Professorship at the University of Tokyo. He co-founded and currently advises four companies that are commercializing intellectual property developed in his lab over the last six years (CytoVale, Vortex Biosciences, Tempo Therapeutics, and Ferrologix). He has received numerous honors and awards including the Pioneers of Miniaturization Prize in 2015, Analytical Chemistry Young Innovator Award in 2014, the National Science Foundation (NSF) CAREER award, the U.S. Office of Naval Research (ONR) Young Investigator Award, the Packard Fellowship, the Defense Advanced Research Projects Agency (DARPA) Young Faculty Award, the National Institutes of Health (NIH) Director’s New Innovator Award and the Coulter Translational Research Award.

Publications:
Weaver WM, Milisavljevic V, Miller JF, Di Carlo D., “Fluid flow induces biofilm formation in Staphylococcus epidermidis polysaccharide intracellular adhesin-positive clinical isolates,” Appl Environ Microbiol. 2012 Aug;78(16):5890-6. doi: 10.1128/AEM.01139-12. Epub 2012 Jun 15.

Weaver WM, Dharmaraja S, Milisavljevic V, Di Carlo D., “The effects of shear stress on isolated receptor-ligand interactions of Staphylococcus epidermidis and human plasma fibrinogen using molecularly patterned microfluidics,” Lab Chip. 2011 Mar 7;11(5):883-9. doi: 10.1039/c0lc00414f. Epub 2011 Jan 20.

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Photo of Jake Lusis, PhD
Jake Lusis, PhD
Professor, Departments of Medicine, Cardiology, Human Genetics, Microbiology, Immunology & Molecular Genetics, UCLA
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Home UCLA Med-Cardio/Microbio 3730 MRL BOX 951679 Los Angeles CA 90095-1679 Phone: (310) 825-1359Website: Lusis Laboratory

My PhD is in biophysics but somehow I ended up doing mouse genetics for my postdoc. I’m still doing mouse genetics, now with a focus on complex genetic traits, particularly those related to cardiovascular and metabolic disorders. With the development of high throughput technologies, such as expression arrays and sequencing, we have found it useful to marry such data with genetic analysis (‘systems genetics’). I also enjoy teaching.

Relevant Recent Publications

  1. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 472:57-63. PMCID:PMC3086762
  2. Bennett BJ, Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen S, Lusis AJ. (2013) Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 17:49-60. PMCID:PMC3771112
  3. Elin Org, Brian W. Parks, Jong Wha J Joo, Benjamin Emert, William Schwartzman, Eun Yong Kang, Margarete Mehrabian, Calvin Pan, Rob Knight, Robert Gunsalus, Thomas A. Drake, Eleazar Eskin, and Aldons J. Lusis. (2015) Genetic and environmental control of host-gut microbiota interactions. Genome Res., in press.

Active Funding in Microbiome-Related Research

Funding Agency/Grant Number:NIH PO1 HL28481
Title:“Molecular genetic approaches in atherosclerosis research.”
Goals:This program project is concerned with the identification and characterization of genetic factors contributing to energy homeostasis and metabolic disease. The emphasis is on combined human-mouse approaches.

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Photo of Mohamad Navab, PhD
Mohamad Navab, PhD
Adjunct Professor of Medicine, Department of Cardiology, David Geffen School of Medicine at UCLA
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Address 52-266 CHS Los Angeles CA 90095 Phone: (310) 206-2678

Dr. Mohamad Navab is a Professor in the Departments of Medicine, Cardiology at the David Geffen School of Medicine at UCLA, with 32 years of research experience in the study of atherosclerosis, lipids and artery wall metabolism. His work has been continuously supported by the National Institutes of Health (NIH). He is CoProject Leader on an NIH PPG/grant that is going into its 31st year. He has published 195 peer-reviewed articles (average H index 90), including 100 chapters and reviews, co-edited two books, and organized three interdisciplinary symposia in the area of lipids and artery wall metabolism. His current research focus is on the role of the role of small intestine, systemic inflammation and cardiovascular function. He has been involved in studies of gut microbiota in dyslipidemia and the effect of HDL mimetic peptides on it.

Relevant Recent Publications

Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis. Navab M et al. J Lipid Res. 2015;56:871-87

Transgenic 6F tomatoes act on the small intestine to prevent systemic inflammation and dyslipidemia caused by Western diet and intestinally derived lysophosphatidic acid. Navab M, et al. J Lipid Res. 2013;54:3403-18

Intestine may be a major site of action for the ApoA-I mimetic peptide 4F whether administered subcutaneously or orally. Navab M, et al. J Lipid Res. 2011; 52:1200-10.

HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Navab M, Nat Rev Cardiol. 2011;8:222-32

Mechanisms of disease: proatherogenic HDL–an evolving field. Navab M, Nat Clin Pract Endocrinol Metab. 2006 ;2:504-11.

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