Mast cell-derived cathepsin g: a possible role in the adverse remodeling of the failing human heart.
BACKGROUND
The role of cardiac mast cells (MCs) in the progression to heart failure has recently become increasingly evident. Cathepsin g is a neutrophil- and mast cell-derived protease, which can convert angiotensin I to angiotensin II and thereby activate the TGF-beta pathway, resulting in myocyte necrosis, hypertrophy, and increased fibrosis. This study focuses on mast cell-derived cathepsin g in the human heart during heart failure and following mechanical unloading by means of heart-assist devices (LVADs).


METHODS
Myocardial tissue was obtained from 10 patients with end-stage cardiomyopathy at the time of LVAD implantation (pre-LVAD) and following orthotopic heart transplantation (post-LAVD). In addition, biopsies of four normal hearts served as a control group. Paraffin-embedded sections were dual stained for cathepsin g and tryptase, a known marker for mast cells, using standard immunohistochemistry protocols. Total cathepsin g positive mast cells were counted.


RESULTS
No cathepsin g positive MCs were found in normal hearts. However, we found evidence for cathepsin g in cardiac MCs in heart failure tissues (pre-LVAD). During heart failure, 46% of total MCs were cathepsin g positive as compared to after mechanical unloading, where only 11% of total MCs were cathepsin g positive (P<0.001).


CONCLUSIONS
Heart failure causes an increase of myocardial MCs. We have provided evidence that cathepsin g positive MCs accumulate during heart failure and their total percentage decreases after ventricular unloading. This coincides with the decrease in myocyte necrosis, hypertrophy, and fibrosis. Thus, cathepsin g may play a role in the progression to heart failure by activating angiotensin II, leading to detrimental effects on the heart.
Jahanyar
Jama
J
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. jahanyar@bcm.tmc.edu
Youker
Keith A
KA
Loebe
Matthias
M
Assad-Kottner
Christian
C
Koerner
Michael M
MM
Torre-Amione
Guillermo
G
Noon
George P
GP
D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000378:metabolism; D002303:Cardiac Output, Low / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D016022:Case-Control Studies; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000502:physiology*; D053818:Chymases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000473:pathology / Q000502:physiology*; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D009336:Necrosis / Q000517:prevention & control; D012697:Serine Endopeptidases / Q000502:physiology*; D053802:Tryptases / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
D000804:Angiotensin II; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D053818:Chymases; D053802:Tryptases