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.

METHODS AND 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: Howard H Chen, Choukri Mekkaoui, Hoonsung Cho, Soeun Ngoy, Brett Marinelli, Peter Waterman, Matthias Nahrendorf, Ronglih Liao, Lee Josephson, David E Sosnovik
• Journal: Circulation. Cardiovascular imaging (Circ Cardiovasc Imaging) Vol. 6 Issue 3 Pg. 441-7 (May 01 2013) ISSN: 1942-0080 [Electronic] United States
• PMID: 23537953 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cardiovascular Agents
• Fluorescent Dyes
• Cathepsin B
• Ctsb protein, mouse
• Sirolimus

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cardiovascular Agents (pharmacology)
• Cathepsin B (metabolism)
• Disease Models, Animal
• Enzyme Activation
• Female
• Fluorescent Dyes
• Ischemic Postconditioning
• Lysosomes (drug effects, enzymology)
• Mice
• Mice, Inbred C57BL
• Microscopy, Confocal
• Microspheres
• Myocardial Infarction (diagnostic imaging, enzymology, pathology, prevention & control)
• Myocardial Reperfusion Injury (diagnostic imaging, enzymology, pathology, prevention & control)
• Myocardium (pathology)
• Optical Imaging (methods)
• Radionuclide Imaging
• Sirolimus (pharmacology)
• Time Factors
• Tomography (methods)
• X-Ray Microtomography