Type IV collagen degradation in the myocardial basement membrane after unloading of the failing heart by a left ventricular assist device.
After left ventricular assist device (LVAD) support in patients with end-stage cardiomyopathy, cardiomyocytes decrease in size. We hypothesized that during this process, known as reverse remodeling, the basement membrane (BM), which is closely connected to, and forms the interface between the cardiomyocytes and the extracellular matrix, will be severely affected. Therefore, the changes in the myocardial BM in patients with end-stage heart failure before and after LVAD support were studied. The role of MMP-2 in this process was also investigated. Transmission electron microscopy showed that the BM thickness decreased post-LVAD compared to pre-LVAD. Immunohistochemistry indicated a reduced immunoreactivity for type IV collagen in the BM after LVAD support. Quantitative PCR showed a similar mRNA expression for type IV collagen pre- and post-LVAD. MMP-2 mRNA almost doubled post-LVAD (P<0.01). In addition, active MMP-2 protein as identified by gelatin zymography and confirmed by Western blot analysis was detected after LVAD support and in controls, but not before LVAD support. Active MMP was localized in the BM of the cardiomyocyte, as detected by type IV collagen in situ zymography. Furthermore, in situ hybridization/immunohistochemical double staining showed that MMP-2 mRNA was expressed in cardiomyocytes, macrophages, T-cells and endothelial cells. Taken together, these findings show reduced type IV collagen content in the BM of cardiomyocytes after LVAD support. This reduction is at least in part the result of increased MMP-2 activity and not due to reduced synthesis of type IV collagen.
Bruggink
Annette H
AH
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. a.h.bruggink@umcutrecht.nll
van Oosterhout
Matthijs F M
MF
de Jonge
Nicolaas
N
Cleutjens
Jack P M
JP
van Wichen
Dick F
DF
van Kuik
Joyce
J
Tilanus
Marcel G J
MG
Gmelig-Meyling
Frits H J
FH
van den Tweel
Jan G
JG
de Weger
Roel A
RA
D000293:Adolescent; D000328:Adult; D001485:Basement Membrane / Q000378:metabolism* / Q000473:pathology; D024141:Collagen Type IV / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006353:Heart-Assist Devices / Q000009:adverse effects*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000473:pathology / Q000628:therapy
D024141:Collagen Type IV; D012333:RNA, Messenger; D020778:Matrix Metalloproteinase 2