Experimental heart transplantation: effect of cyclosporine on expression and activity of metzincins

Berthier, C C; Pally, C; Weckbecker, G; Raulf, F; Rehrauer, H; Wagner, U; Le Hir, M; Marti, H P (2009). Experimental heart transplantation: effect of cyclosporine on expression and activity of metzincins. Swiss medical weekly, 139(15-16), pp. 233-40. Muttenz: EMH Schweizerischer Ärzteverlag

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Metzincins, such as matrix metalloproteases (MMP), and extracellular matrix (ECM) proteins are differentially regulated in inflammation. We hypothesised that metzincins are also dysregulated in experimental acute cardiac allograft rejection. We investigated the Dark Agouti-to-Lewis (DA-to-Lew) rat model of acute cardiac allograft rejection. Cyclosporine (CsA) (7.5 mg/kg/d) was given from transplantation to sacrifice (day +5). At that time, mRNA levels were analysed by Affymetrix genechip and quantitative reverse transcription polymerase chain reaction (qRTPCR). MMP protein and activities were analysed by immunohistology, fluorometry, zymography and Western blots. In untreated rejected DA allografts, mRNA levels of MMP-2/-7/-9/-/12-/14, a disintegrin and metalloprotease (ADAM)-17, tissue inhibitor of metalloprotease (TIMP)-1/-3 were increased, whereas MMP-11/-16/-24 and TIMP-2/-4 were lowered compared to native DA hearts. With respect to these untreated allografts, CsA lowered mRNA levels of MMP-7, TIMP-1/-3 (TIMP-2/-4 remained relatively low) and ADAM17, but augmented mRNA levels of MMP-11/-16/-23 and of many ECM genes. Immunohistology showed increased staining of MMP-2 in acute rejection (AR). Overall MMP activity was augmented in both transplanted groups, but CsA reduced MMP-9 activity and MMP-14 production. Taken together, MMP and TIMP were upregulated during acute AR. CsA ameliorated histology of rejection but showed potential pro-fibrotic effects. Thus, MMP and TIMP may play a role in acute cardiac allograft rejection, and beneficial modification of the MMP-ECM balance requires interventions beyond CsA.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension

UniBE Contributor:

Marti, Hans-Peter

ISSN:

1424-7860

Publisher:

EMH Schweizerischer Ärzteverlag

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:14

Last Modified:

04 May 2014 23:23

PubMed ID:

19418307

Web of Science ID:

000265459600004

URI:

https://boris.unibe.ch/id/eprint/32425 (FactScience: 197604)

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