Mass spectrometry for the evaluation of cardiovascular diseases based on proteomics and lipidomics

Summary

The identification and quantification of proteins and lipids is of major importance for the diagnosis, prognosis and understanding of the molecular mechanisms involved in disease development. Owing to its selectivity and sensitivity, mass spectrometry has become a key technique in analytical platforms for proteomic and lipidomic investigations. Using this technique, many strategies have been developed based on unbiased or targeted approaches to highlight or monitor molecules of interest from biomatrices. Although these approaches have largely been employed in cancer research, this type of investigation has been met by a growing interest in the field of cardiovascular disorders, potentially leading to the discovery of novel biomarkers and the development of new therapies. In this paper, we will review the different mass spectrometry- based proteomic and lipidomic strategies applied in cardiovascular diseases, especially atherosclerosis. Particular attention will be given to recent developments and the role of bioinformatics in data treatment. This review will be of broad interest to the medical community by providing a tutorial of how mass spectrometric strategies can support clinical trials.

Keywords

Mass spectrometry - proteomics - lipidomics - cardiovascular diseases - imaging mass spectrometry

• References

• 1 Ford ES, Ajani UA, Croft JB. et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med 2007; 356: 2388-2398.
• 2 American Heart Association. Heart Disease and Stroke Statistics-2008 Update.. Dallas, Texas: AHA; 2008
• 3 Blankenhorn DH, Hodis HN. Atherosclerosis–reversal with therapy. West J Med 1993; 159: 172-179.
• 4 Elkind MS. Inflammatory mechanisms of stroke. Stroke 2010; 41 (Suppl. 10) S3-8.
• 5 Glass CK, Witztum JL. Atherosclerosis. the road ahead. Cell 2001; 104: 503-516.
• 6 Bucova M, Bernadic M, Buckingham T. C-reactive protein, cytokines and inflammation in cardiovascular diseases. Bratisl Lek Listy 2008; 109: 333-340.
• 7 Ito T, Ikeda U. Inflammatory cytokines and cardiovascular disease. Curr Drug Targets Inflamm Allergy 2003; 2: 257-265.
• 8 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-1695.
• 9 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874.
• 10 Hansson GK. Atherosclerosis–an immune disease: The Anitschkov Lecture 2007. Atherosclerosis 2009; 202: 2-10.
• 11 Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 1876-1890.
• 12 Dettmer K, Aronov PA, Hammock BD. Mass spectrometry-based metabolomics. Mass Spectrom Rev 2007; 26: 51-78.
• 13 Fiehn O. Metabolomics–the link between genotypes and phenotypes. Plant Mol Biol 2002; 48: 155-171.
• 14 Boccard J, Veuthey JL, Rudaz S. Knowledge discovery in metabolomics: an overview of MS data handling. J Sep Sci 2010; 33: 290-304.
• 15 Wolfender JL, Glauser G, Boccard J. et al. MS-based plant metabolomic approaches for biomarker discovery. Nat Prod Commun 2009; 4: 1417-1430.
• 16 Zhou M, Veenstra T. Mass spectrometry: m/z 1983-2008. Biotechniques 2008; 44: 667-668 670.
• 17 Griffiths WJ, Wang Y. Mass spectrometry: from proteomics to metabolomics and lipidomics. Chem Soc Rev 2009; 38: 1882-1896.
• 18 Shevchenko A, Simons K. Lipidomics: coming to grips with lipid diversity. Nat Rev Mol Cell Biol 2010; 11: 593-598.
• 19 Domon B, Aebersold R. Mass spectrometry and protein analysis. Science 2006; 312: 212-217.
• 20 Tunon J, Martin-Ventura JL, Blanco-Colio LM. et al. Proteomic strategies in the search of new biomarkers in atherothrombosis. J Am Coll Cardiol 2010; 55: 2009-2016.
• 21 Anderson NL, Anderson NG. The human plasma proteome: history, character, and diagnostic prospects. Mol Cell Proteomics 2002; 1: 845-867.
• 22 Martinez-Pinna R, Martin-Ventura JL, Mas S. et al. Proteomics in atherosclerosis. Curr Atheroscler Rep 2008; 10: 209-215.
• 23 Moxon JV, Padula MP, Herbert BR. et al. Challenges, current status and future perspectives of proteomics in improving understanding, diagnosis and treatment of vascular disease. Eur J Vasc Endovasc Surg 2009; 38: 346-355.
• 24 Barrett J, Brophy PM, Hamilton JV. Analysing proteomic data. Int J Parasitol 2005; 35: 543-553.
• 25 Mayr M, Zhang J, Greene AS. et al. Proteomics-based development of biomarkers in cardiovascular disease: mechanistic, clinical, and therapeutic insights. Mol Cell Proteomics 2006; 5: 1853-1864.
• 26 Beranova-Giorgianni S. Proteome analysis by two-dimensional gel electrophoresis and mass spectrometry: strengths and limitations. Trends Analyt Chem 2003; 22: 273-281.
• 27 Schoenhoff FS, Fu Q, Van Eyk JE. Cardiovascular proteomics: implications for clinical applications. Clin Lab Med 2009; 29: 87-99.
• 28 Hopfgartner G, Varesio E, Tschappat V. et al. Triple quadrupole linear ion trap mass spectrometer for the analysis of small molecules and macromolecules. J Mass Spectrom 2004; 39: 845-855.
• 29 Chernushevich IV, Loboda AV, Thomson BA. An introduction to quadrupole- time-of-flight mass spectrometry. J Mass Spectrom 2001; 36: 849-865.
• 30 Perry RH, Cooks RG, Noll RJ. Orbitrap mass spectrometry: instrumentation, ion motion and applications. Mass Spectrom Rev 2008; 27: 661-699.
• 31 Page JS, Masselon CD, Smith RD. FTICR mass spectrometry for qualitative and quantitative bioanalyses. Curr Opin Biotechnol 2004; 15: 3-11.
• 32 Gygi SP, Corthals GL, Zhang Y. et al. Evaluation of two-dimensional gel electrophoresis-based proteome analysis technology. Proc Natl Acad Sci USA 2000; 97: 9390-9395.
• 33 Wilkins MR, Gasteiger E, Sanchez JC. et al. Two-dimensional gel electrophoresis for proteome projects: the effects of protein hydrophobicity and copy number. Electrophoresis 1998; 19: 1501-1505.
• 34 Lepedda AJ, Cigliano A, Cherchi GM. et al. A proteomic approach to differentiate histologically classified stable and unstable plaques from human carotid arteries. Atherosclerosis 2009; 203: 112-118.
• 35 Urbonavicius S, Lindholt JS, Vorum H. et al. Proteomic identification of differentially expressed proteins in aortic wall of patients with ruptured and nonruptured abdominal aortic aneurysms. J Vasc Surg 2009; 49: 455-463.
• 36 Dupont A, Corseaux D, Dekeyzer O. et al. The proteome and secretome of human arterial smooth muscle cells. Proteomics 2005; 5: 585-596.
• 37 Barderas MG, Tunon J, Darde VM. et al. Circulating human monocytes in the acute coronary syndrome express a characteristic proteomic profile. J Proteome Res 2007; 6: 876-886.
• 38 Sung HJ, Ryang YS, Jang SW. et al. Proteomic analysis of differential protein expression in atherosclerosis. Biomarkers 2006; 11: 279-290.
• 39 Lilley KS, Friedman DB. All about DIGE: quantification technology for differential-display 2D-gel proteomics. Expert Rev Proteomics 2004; 1: 401-409.
• 40 Gustin C, Delaive E, Dieu M. et al. Upregulation of pentraxin-3 in human endothelial cells after lysophosphatidic acid exposure. Arterioscler Thromb Vasc Biol 2008; 28: 491-497.
• 41 Chen EI, Yates JR. 3rd. Cancer proteomics by quantitative shotgun proteomics. Mol Oncol 2007; 1: 144-159.
• 42 Lu B, McClatchy DB, Kim JY. et al. Strategies for shotgun identification of integral membrane proteins by tandem mass spectrometry. Proteomics 2008; 8: 3947-3955.
• 43 Wilm M, Mann M. Analytical properties of the nanoelectrospray ion source. Anal Chem 1996; 68: 1-8.
• 44 Peng J, Gygi SP. Proteomics: the move to mixtures. J Mass Spectrom 2001; 36: 1083-1091.
• 45 Scigelova M, Makarov A. Orbitrap mass analyzer–overview and applications in proteomics. Proteomics 2006; 6 (Suppl. 02) 16-21.
• 46 Bergquist J. FTICR mass spectrometry in proteomics. Curr Opin Mol Ther 2003; 5: 310-314.
• 47 Blackburn K, Goshe MB. Challenges and strategies for targeted phosphorylation site identification and quantification using mass spectrometry analysis. Brief Funct Genomic Proteomic 2009; 8: 90-103.
• 48 Blackburn K, Mbeunkui F, Mitra SK. et al. Improving protein and proteome coverage through data-independent multiplexed peptide fragmentation. J Pro- teome Res 2010; 9: 3621-3637.
• 49 Bagnato C, Thumar J, Mayya V. et al. Proteomics analysis of human coronary atherosclerotic plaque: a feasibility study of direct tissue proteomics by liquid chromatography and tandem mass spectrometry. Mol Cell Proteomics 2007; 6: 1088-1102.
• 50 Zieske LR. A perspective on the use of iTRAQ reagent technology for protein complex and profiling studies. J Exp Bot 2006; 57: 1501-1508.
• 51 Gygi SP, Rist B, Gerber SA. et al. Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat Biotechnol 1999; 17: 994-999.
• 52 Emadali A, Gallagher-Gambarelli M. Quantitative proteomics by SILAC: practicalities and perspectives for an evolving approach. Med Sci (Paris) 2009; 25: 835-842.
• 53 Ong SE, Foster LJ, Mann M. Mass spectrometric-based approaches in quantitative proteomics. Methods 2003; 29: 124-130.
• 54 Lutfalla G, Uze G. Performing quantitative reverse-transcribed polymerase chain reaction experiments. Methods Enzymol 2006; 410: 386-400.
• 55 Schwarz M, Spath L, Lux CA. et al. Potential protective role of apoprotein J (clusterin) in atherogenesis: binding to enzymatically modified low-density lipoprotein reduces fatty acid-mediated cytotoxicity. Thromb Haemost 2008; 100: 110-118.
• 56 Guo Y, Singleton PA, Rowshan A. et al. Quantitative proteomics analysis of human endothelial cell membrane rafts: evidence of MARCKS and MRP regulation in the sphingosine 1-phosphate-induced barrier enhancement. Mol Cell Proteomics 2007; 6: 689-696.
• 57 Gasparri C, Curcio A, Torella D. et al. Proteomics reveals high levels of vitamin D binding protein in myocardial infarction. Front Biosci (Elite Ed) 2010; 2: 796-804.
• 58 Huttenhain R, Malmstrom J, Picotti P. et al. Perspectives of targeted mass spectrometry for protein biomarker verification. Curr Opin Chem Biol 2009; 13: 518-525.
• 59 Anderson L, Hunter CL. Quantitative mass spectrometric multiple reaction monitoring assays for major plasma proteins. Mol Cell Proteomics 2006; 5: 573-588.
• 60 Pan S, Aebersold R, Chen R. et al. Mass spectrometry based targeted protein quantification: methods and applications. J Proteome Res 2009; 8: 787-797.
• 61 Kay RG, Gregory B, Grace PB. et al. The application of ultra-performance liquid chromatography/tandem mass spectrometry to the detection and quantitation of apolipoproteins in human serum. Rapid Commun Mass Spectrom 2007; 21: 2585-2593.
• 62 Anderson L. Candidate-based proteomics in the search for biomarkers of cardiovascular disease. J Physiol 2005; 563: 23-60.
• 63 Chaurand P, Schwartz SA, Reyzer ML. et al. Imaging mass spectrometry: principles and potentials. Toxicol Pathol 2005; 33: 92-101.
• 64 Chaurand P, Stoeckli M, Caprioli RM. Direct profiling of proteins in biological tissue sections by MALDI mass spectrometry. Anal Chem 1999; 71: 5263-5270.
• 65 Reyzer ML, Caprioli RM. MALDI-MS-based imaging of small molecules and proteins in tissues. Curr Opin Chem Biol 2007; 11: 29-35.
• 66 Franck J, Arafah K, Elayed M. et al. MALDI imaging mass spectrometry: state of the art technology in clinical proteomics. Mol Cell Proteomics 2009; 8: 2023-2033.
• 67 Chaurand P, Schwartz SA, Billheimer D. et al. Integrating histology and imaging mass spectrometry. Anal Chem 2004; 76: 1145-1155.
• 68 Chaurand P, Caprioli RM. Direct profiling and imaging of peptides and proteins from mammalian cells and tissue sections by mass spectrometry. Electrophoresis 2002; 23: 3125-3135.
• 69 Dreisewerd K. The desorption process in MALDI. Chem Rev 2003; 103: 395-426.
• 70 Seeley EH, Oppenheimer SR, Mi D. et al. Enhancement of protein sensitivity for MALDI imaging mass spectrometry after chemical treatment of tissue sections. J Am Soc Mass Spectrom 2008; 19: 1069-1077.
• 71 Lemaire R, Wisztorski M, Desmons A. et al. MALDI-MS direct tissue analysis of proteins: Improving signal sensitivity using organic treatments. Anal Chem 2006; 78: 7145-7153.
• 72 Schwamborn K, Caprioli RM. Molecular imaging by mass spectrometry–looking beyond classical histology. Nat Rev Cancer 2010; 10: 639-646.
• 73 Chaurand P, Schriver KE, Caprioli RM. Instrument design and characterization for high resolution MALDI-MS imaging of tissue sections. J Mass Spectrom 2007; 42: 476-489.
• 74 Setou M, Sugiura Y. Guide to Planning the Sample Preparation Step. Imaging Mass Spectrometry.. Springer; Japan: 2010: 11-30.
• 75 MacAleese L, Stauber J, Heeren RM. Perspectives for imaging mass spectrometry in the proteomics landscape. Proteomics 2009; 9: 819-834.
• 76 Groseclose MR, Andersson M, Hardesty WM. et al. Identification of proteins directly from tissue: in situ tryptic digestions coupled with imaging mass spectrometry. J Mass Spectrom 2007; 42: 254-262.
• 77 Grey AC, Gelasco AK, Section J. et al. Molecular morphology of the chick heart visualized by MALDI imaging mass spectrometry. Anat Rec (Hoboken) 2010; 293: 821-828.
• 78 Chaurand P, Norris JL, Cornett DS. et al. New developments in profiling and imaging of proteins from tissue sections by MALDI mass spectrometry. J Proteome Res 2006; 5: 2889-2900.
• 79 Jurchen JC, Rubakhin SS, Sweedler JV. MALDI-MS imaging of features smaller than the size of the laser beam. J Am Soc Mass Spectrom 2005; 16: 1654-1659.
• 80 Stauber J, Lemaire R, Franck J. et al. MALDI imaging of formalin-fixed paraffin- embedded tissues: application to model animals of Parkinson disease for biomarker hunting. J Proteome Res 2008; 7: 969-978.
• 81 Groseclose MR, Massion PP, Chaurand P. et al. High-throughput proteomic analysis of formalin-fixed paraffin-embedded tissue microarrays using MALDI imaging mass spectrometry. Proteomics 2008; 8: 3715-3724.
• 82 Lemaire R, Desmons A, Tabet JC. et al. Direct analysis and MALDI imaging of formalin-fixed, paraffin-embedded tissue sections. J Proteome Res 2007; 6: 1295-1305.
• 83 Aoki Y, Toyama A, Shimada T. et al. A novel method for analyzing formalin-fixed paraffin embedded (FFPE) tissue sections by mass spectrometry imaging. Proceedings of the Japan Academy, Series B 2007; 83: 205-214.
• 84 Stauber J, MacAleese L, Franck J. et al. On-tissue protein identification and imaging by MALDI-ion mobility mass spectrometry. J Am Soc Mass Spectrom 2010; 21: 338-347.
• 85 Goodacre R, Vaidyanathan S, Dunn WB. et al. Metabolomics by numbers: acquiring and understanding global metabolite data. Trends Biotechnol 2004; 22: 245-252.
• 86 Dunn WB, Bailey NJ, Johnson HE. Measuring the metabolome: current analytical technologies. Analyst 2005; 130: 606-625.
• 87 Dunn WB, Ellis DI. Metabolomics: Current analytical platforms and methodologies. Trends Analyt Chem 2005; 24: 285-294.
• 88 Ekroos K, Janis M, Tarasov K. et al. Lipidomics: a tool for studies of atherosclerosis. Curr Atheroscler Rep 2010; 12: 273-281.
• 89 Goonewardena SN, Prevette LE, Desai AA. Metabolomics and atherosclerosis. Curr Atheroscler Rep 2010; 12: 267-272.
• 90 Guillarme D, Ruta J, Rudaz S. et al. New trends in fast and high-resolution liquid chromatography: a critical comparison of existing approaches. Anal Bioanal Chem 2010; 397: 1069-1082.
• 91 Mesaros C, Lee SH, Blair IA. Targeted quantitative analysis of eicosanoid lipids in biological samples using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877: 2736-2745.
• 92 Food and Drug Administration of the United States.. Guidance for Industry—Bioanalytical Method Validation. US Department of Health and Human Services, Center for Drug Evaluation and Research, Center for Veterinary Medicine,. 2001 Available at: http://www/fda.gov/cder/guidance/index.htm
• 93 Tsikas D. A proposal for comparing methods of quantitative analysis of endogenous compounds in biological systems by using the relative lower limit of quantification (rLLOQ). J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877: 2244-2251.
• 94 van De Merbel NC. Quantitative determination of endogenous compounds in biological samples using chromatographic techniques. Trends Analyt Chem 2008; 27: 924-933.
• 95 Thomas A, Hopfgartner G, Giroud C. et al. Quantitative and qualitative profiling of endocannabinoids in human plasma using a triple quadrupole linear ion trap mass spectrometer with liquid chromatography. Rapid Commun Mass Spectrom 2009; 23: 629-638.
• 96 Williams J, Wood J, Pandarinathan L. et al. Quantitative method for the profiling of the endocannabinoid metabolome by LC-atmospheric pressure chemical ionization-MS. Anal Chem 2007; 79: 5582-5593.
• 97 Richardson D, Ortori CA, Chapman V. et al. Quantitative profiling of endoc- annabinoids and related compounds in rat brain using liquid chromatography- tandem electrospray ionization mass spectrometry. Anal Biochem 2007; 360: 216-226.
• 98 Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 2005; 5: 400-411.
• 99 Klein TW, Newton C, Larsen K. et al. The cannabinoid system and immune modulation. J Leukoc Biol 2003; 74: 486-496.
• 100 Pacher P, Steffens S. The emerging role of the endocannabinoid system in cardiovascular disease. Semin Immunopathol 2009; 31: 63-77.
• 101 Hiley CR. Endocannabinoids and the heart. J Cardiovasc Pharmacol 2009; 53: 267-276.
• 102 Mach F, Steffens S. The role of the endocannabinoid system in atherosclerosis. J Neuroendocrinol 2008; 20 (Suppl. 01) 53-57.
• 103 Montecucco F, Matias I, Lenglet S. et al. Regulation and possible role of endocan- nabinoids and related mediators in hypercholesterolemic mice with atherosclerosis. Atherosclerosis 2009; 205: 433-441.
• 104 Sugamura K, Sugiyama S, Nozaki T. et al. Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages. Circulation 2009; 119: 28-36.
• 105 Gross RW, Han X. Shotgun lipidomics of neutral lipids as an enabling technology for elucidation of lipid-related diseases. Am J Physiol Endocrinol Metab 2009; 297: E297-303.
• 106 Han X, Gross RW. Shotgun lipidomics: electrospray ionization mass spectrometric analysis and quantitation of cellular lipidomes directly from crude extracts of biological samples. Mass Spectrom Rev 2005; 24: 367-412.
• 107 Stahlman M, Ejsing CS, Tarasov K. et al. High-throughput shotgun lipidomics by quadrupole time-of-flight mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877: 2664-2672.
• 108 Ejsing CS, Duchoslav E, Sampaio J. et al. Automated identification and quantification of glycerophospholipid molecular species by multiple precursor ion scanning. Anal Chem 2006; 78: 6202-6214.
• 109 Schwudke D, Oegema J, Burton L. et al. Lipid profiling by multiple precursor and neutral loss scanning driven by the data-dependent acquisition. Anal Chem 2006; 78: 585-595.
• 110 Han X, Jiang X. A review of lipidomic technologies applicable to sphingolipidomics and their relevant applications. Eur J Lipid Sci Technol 2009; 111: 39-52.
• 111 McAnoy AM, Wu CC, Murphy RC. Direct qualitative analysis of triacylglycerols by electrospray mass spectrometry using a linear ion trap. J Am Soc Mass Spec- trom 2005; 16: 1498-1509.
• 112 Liebisch G, Binder M, Schifferer R. et al. High throughput quantification of cholesterol and cholesteryl ester by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Biochim Biophys Acta 2006; 1761: 121-128.
• 113 Herzog R, Schwudke D, Schuhmann K. et al. A novel informatics concept for high-throughput shotgun lipidomics based on the molecular fragmentation query language. Genome Biol 2011; 12: R8.
• 114 Han X, Yang J, Cheng H. et al. Shotgun lipidomics identifies cardiolipin depletion in diabetic myocardium linking altered substrate utilization with mitochondrial dysfunction. Biochemistry 2005; 44: 16684-16694.
• 115 Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol 1959; 37: 911-917.
• 116 Madsen R, Lundstedt T, Trygg J. Chemometrics in metabolomics–a review in human disease diagnosis. Anal Chim Acta 2010; 659: 23-33.
• 117 Vallejo M, Garcia A, Tunon J. et al. Plasma fingerprinting with GC-MS in acute coronary syndrome. Anal Bioanal Chem 2009; 394: 1517-1524.
• 118 Zhang F, Jia Z, Gao P. et al. Metabonomics study of atherosclerosis rats by ultra fast liquid chromatography coupled with ion trap-time of flight mass spectrometry. Talanta 2009; 79: 836-844.
• 119 Bergheanu SC, Reijmers T, Zwinderman AH. et al. Lipidomic approach to evaluate rosuvastatin and atorvastatin at various dosages: investigating differential effects among statins. Curr Med Res Opin 2008; 24: 2477-2487.
• 120 Laaksonen R, Katajamaa M, Paiva H. et al. A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin- induced changes in muscle. PLoS One 2006; 1: e97
• 121 Schwudke D, Hannich JT, Surendranath V. et al. Top-down lipidomic screens by multivariate analysis of high-resolution survey mass spectra. Anal Chem 2007; 79: 4083-4093.
• 122 Thomas A, Deglon J, Lenglet S. et al. High-Throughput Phospholipidic Fingerprinting by Online Desorption of Dried Spots and Quadrupole-Linear Ion Trap Mass Spectrometry: Evaluation of Atherosclerosis Biomarkers in Mouse Plasma. Anal Chem 2010; 82: 6687-6694.
• 123 Graessler J, Schwudke D, Schwarz PE. et al. Top-down lipidomics reveals ether lipid deficiency in blood plasma of hypertensive patients. PLoS One 2009; 4: e6261.
• 124 Chaurand P, Cornett DS, Angel PM. et al. From Whole-body Sections down to Cellular Level, Multiscale Imaging of Phospholipids by MALDI Mass Spectrometry. Mol Cell Proteomics. 2011 10. 0110.004259.
• 125 Meriaux C, Franck J, Wisztorski M. et al. Liquid ionic matrixes for MALDI mass spectrometry imaging of lipids. J Proteomics 2010; 73: 1204-1218.
• 126 Sugiura Y, Setou M. Selective imaging of positively charged polar and nonpolar lipids by optimizing matrix solution composition. Rapid Commun Mass Spec- trom 2009; 23: 3269-3278.
• 127 Taira S, Sugiura Y, Moritake S. et al. Nanoparticle-assisted laser desorption/ion- ization based mass imaging with cellular resolution. Anal Chem 2008; 80: 4761-4766.
• 128 Puolitaival SM, Burnum KE, Cornett DS. et al. Solvent-free matrix dry-coating for MALDI imaging of phospholipids. J Am Soc Mass Spectrom 2008; 19: 882-886.
• 129 Hankin JA, Barkley RM, Murphy RC. Sublimation as a method of matrix application for mass spectrometric imaging. J Am Soc Mass Spectrom 2007; 18: 1646-1652.
• 130 Sugiura Y, Konishi Y, Zaima N. et al. Visualization of the cell-selective distribution of PUFA-containing phosphatidylcholines in mouse brain by imaging mass spectrometry. J Lipid Res 2009; 50: 1776-1788.
• 131 Garrett TJ, Yost RA. Tandem mass spectrometric methods for phospholipid analysis from brain tissue. Methods Mol Biol 2010; 656: 209-230.
• 132 Shimma S, Sugiura Y, Hayasaka T. et al. Mass imaging and identification of biomolecules with MALDI-QIT-TOF-based system. Anal Chem 2008; 80: 878-885.
• 133 Woods AS, Jackson SN. The application and potential of ion mobility mass spectrometry in imaging MS with a focus on lipids. Methods Mol Biol 2010; 656: 99-111.
• 134 McLean JA, Ridenour WB, Caprioli RM. Profiling and imaging of tissues by imaging ion mobility-mass spectrometry. J Mass Spectrom 2007; 42: 1099-1105.
• 135 Landgraf RR, Prieto Conaway MC, Garrett TJ. et al. Imaging of lipids in spinal cord using intermediate pressure matrix-assisted laser desorption-linear ion trap/Orbitrap MS. Anal Chem 2009; 81: 8488-8495.
• 136 Cornett DS, Frappier SL, Caprioli RM. MALDI-FTICR imaging mass spectrometry of drugs and metabolites in tissue. Anal Chem 2008; 80: 5648-5653.
• 137 Walker AV. Why is SIMS underused in chemical and biological analysis? Challenges and opportunities. Anal Chem 2008; 80: 8865-8870.
• 138 Colliver TL, Brummel CL, Pacholski ML. et al. Atomic and molecular imaging at the single-cell level with TOF-SIMS. Anal Chem 1997; 69: 2225-2231.
• 139 Heien ML, Piehowski PD, Winograd N. et al. Lipid detection, identification, and imaging single cells with SIMS. Methods Mol Biol 2010; 656: 85-97.
• 140 Todd PJ, Schaaff TG, Chaurand P. et al. Organic ion imaging of biological tissue with secondary ion mass spectrometry and matrix-assisted laser desorption/ionization. J Mass Spectrom 2001; 36: 355-369.
• 141 Ostrowski SG, Kurczy ME, Roddy TP. et al. Secondary ion MS imaging to relatively quantify cholesterol in the membranes of individual cells from differentially treated populations. Anal Chem 2007; 79: 3554-3560.
• 142 Altelaar AF, van Minnen J, Jimenez CR. et al. Direct molecular imaging of Lym- naea stagnalis nervous tissue at subcellular spatial resolution by mass spectrometry. Anal Chem 2005; 77: 735-741.
• 143 Mas S, Touboul D, Brunelle A. et al. Lipid cartography of atherosclerotic plaque by cluster-TOF-SIMS imaging. Analyst 2007; 132: 24-26.
• 144 Manicke NE, Nefliu M, Wu C. et al. Imaging of lipids in atheroma by desorption electrospray ionization mass spectrometry. Anal Chem 2009; 81: 8702-8707.
• 145 Dill AL, Ifa DR, Manicke NE. et al. Mass spectrometric imaging of lipids using desorption electrospray ionization. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877: 2883-2889.
• 146 Manisali I, Chen DDY, Schneider BB. Electrospray ionization source geometry for mass spectrometry: past, present, and future. Trends Analyt Chem 2006; 25: 243-256.
• 147 Kertesz V, Van Berkel GJ. Improved imaging resolution in desorption electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom 2008; 22: 2639-2644.