title: Fluorescence tomography of rapamycin-induced autophagy and cardioprotection in vivo.
abstract: BACKGROUND
  Autophagy is a biological process during which cells digest organelles in their cytoplasm and recycle the constituents. The impact of autophagy in the heart, however, remains unclear in part because of the inability to noninvasively image this process in living animals.
  
  
  RESULTS
  Here, we report the use of fluorescence molecular tomography and a cathepsin-activatable fluorochrome to image autophagy in the heart in vivo after ischemia/reperfusion and rapamycin (RAP) therapy. We show that cathepsin-B activity in the lysosome is upregulated by RAP and that this allows the expanded lysosomal compartment in autophagy to be imaged in vivo with fluorescence molecular tomography. We further demonstrate that the delivery of diagnostic nanoparticles to the lysosome by endocytosis is enhanced during autophagy. The upregulation of autophagy by RAP was associated with a 23% reduction (P<0.05) of apoptosis in the area at risk and a 45% reduction in final infarct size (19.6±5.6% of area at risk with RAP versus 35.9±9.1% of area at risk without RAP; P<0.05).
  
  
  CONCLUSIONS
  The ability to perform noninvasive tomographic imaging of autophagy in the heart has the potential to provide valuable insights into the pathophysiology of autophagy, particularly its role in cardiomyocyte salvage. Although additional data are needed, our study supports the investigation of RAP therapy in patients with acute coronary syndromes.
authors.affiliation: Martinos Center for Biomedical Imaging, Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Chen
authors.forename: Choukri
authors.initials: C
authors.lastname: Mekkaoui
authors.forename: Hoonsung
authors.initials: H
authors.lastname: Cho
authors.forename: Soeun
authors.initials: S
authors.lastname: Ngoy
authors.forename: Brett
authors.initials: B
authors.lastname: Marinelli
authors.forename: Peter
authors.initials: P
authors.lastname: Waterman
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Lee
authors.initials: L
authors.lastname: Josephson
authors.forename: David E
authors.initials: DE
authors.lastname: Sosnovik
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002401:Cathepsin B / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D005456:Fluorescent Dyes; D057775:Ischemic Postconditioning; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008863:Microspheres; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology*; D061848:Optical Imaging / Q000379:methods*; D011877:Radionuclide Imaging; D020123:Sirolimus / Q000494:pharmacology*; D013997:Time Factors; D014054:Tomography / Q000379:methods*; D055114:X-Ray Microtomography
chemical_list: D002317:Cardiovascular Agents; D005456:Fluorescent Dyes; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D020123:Sirolimus
keywords: apoptosis; autophagy; molecular imaging; myocardium; rapamycin
references.citation: Circulation. 1986 Nov;74(5):1124-36
references.pmid: 3769170
references.citation: Hum Mol Genet. 2006 Apr 1;15(7):1209-16
references.pmid: 16497721
references.citation: Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H579-88
references.pmid: 12860564
references.citation: J Mol Cell Cardiol. 2006 Aug;41(2):256-64
references.pmid: 16769083
references.citation: Lancet. 2000 Jul 15;356(9225):209-12
references.pmid: 10963199
references.citation: Nat Med. 2001 Dec;7(12):1347-52
references.pmid: 11726976
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13807-12
references.pmid: 16174725
references.citation: Circulation. 2007 Mar 20;115(11):1384-91
references.pmid: 17339546
references.citation: Nat Rev Mol Cell Biol. 2005 Jun;6(6):505-10
references.pmid: 15928714
references.citation: J Trauma. 1998 Mar;44(3):475-84
references.pmid: 9529174
references.citation: Circ Cardiovasc Imaging. 2009 Nov;2(6):460-7
references.pmid: 19920044
references.citation: Circulation. 2005 Oct 4;112(14):2143-8
references.pmid: 16186417
references.citation: J Exp Med. 2007 Nov 26;204(12):3037-47
references.pmid: 18025128
references.citation: Am J Nephrol. 2005 Jul-Aug;25(4):400-10
references.pmid: 16088081
references.citation: Circ Res. 2008 Aug 15;103(4):343-51
references.pmid: 18703786
references.citation: Nanomedicine. 2012 Apr;8(3):291-8
references.pmid: 21704591
references.citation: Nat Med. 2002 Jul;8(7):757-60
references.pmid: 12091907
references.citation: J Clin Invest. 1994 Oct;94(4):1621-8
references.pmid: 7929838
references.citation: Circ Res. 2007 Apr 27;100(8):1218-25
references.pmid: 17379832
references.citation: Nature. 2008 Feb 28;451(7182):1069-75
references.pmid: 18305538
references.citation: Histochem Cell Biol. 2008 Apr;129(4):407-20
references.pmid: 18320203
references.citation: Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1580-6
references.pmid: 18689499
references.citation: Am J Pathol. 1980 Feb;98(2):445-56
references.pmid: 6986784
references.citation: Mol Biol Cell. 2004 Mar;15(3):1101-11
references.pmid: 14699058
references.citation: J Am Coll Cardiol. 2009 Dec 15;54(25):2435-46
references.pmid: 20082935
references.citation: FEBS Lett. 2003 Aug 28;550(1-3):94-100
references.pmid: 12935893
references.citation: Nature. 2000 Aug 24;406(6798):902-6
references.pmid: 10972293
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6252-6
references.pmid: 11972044
references.citation: Circ Cardiovasc Imaging. 2011 Nov;4(6):729-37
references.pmid: 21836081
references.citation: J Nucl Med. 2010 Feb;51(2):259-67
references.pmid: 20124049
references.citation: J Biol Chem. 2006 Oct 6;281(40):29776-87
references.pmid: 16882669