The role of cell death and myofibrillar damage in contractile dysfunction of long-term cultured adult cardiomyocytes exposed to doxorubicin

Timolati, Francesco; Anliker, Tobias; Groppalli, Vittoria; Perriard, Jean-Claude; Eppenberger, Hans M; Suter, Thomas M; Zuppinger, Christian (2009). The role of cell death and myofibrillar damage in contractile dysfunction of long-term cultured adult cardiomyocytes exposed to doxorubicin. Cytotechnology, 61(1-2), pp. 25-36. Dordrecht: Springer Netherlands 10.1007/s10616-009-9238-4

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In failing hearts cardiomyocytes undergo alterations in cytoskeleton structure, contractility and viability. It is not known presently, how stress-induced changes of myofibrils correlate with markers for cell death and contractile function in cardiomyocytes. Therefore, we have studied the progression of contractile dysfunction, myofibrillar damage and cell death in cultured adult cardiomyocytes exposed to the cancer therapy doxorubicin. We demonstrate, that long-term cultured adult cardiomyocytes, a well-established model for the study of myofibrillar structure and effects of growth factors, can also be used to assess contractility and calcium handling. Adult rat ventricular myocytes (ARVM) were isolated and cultured for a total of 14 days in serum containing medium. The organization of calcium-handling proteins and myofibrillar structure in freshly isolated and in long-term cultured adult cardiomyocytes was studied by immunofluorescence and electron microscopy. Excitation contraction-coupling was analyzed by fura 2 and video edge detection in electrically paced cardiomyocytes forming a monolayer, and cell death and viability was measured by TUNEL assay, LDH release, MTT assay, and Western blot for LC3. Adult cardiomyocytes treated with Doxo showed apoptosis and necrosis only at supraclinical concentrations. Treated cells displayed merely alterations in cytoskeleton organization and integrity concomitant with contractile dysfunction and up-regulation of autophagosome formation, but no change in total sarcomeric protein content. We propose, that myofibrillar damage contributes to contractile dysfunction prior to cell death in adult cardiomyocytes exposed to clinically relevant concentrations of anthracyclines.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology

UniBE Contributor:

Suter, Thomas and Zuppinger, Christian

ISSN:

0920-9069

ISBN:

19890731

Publisher:

Springer Netherlands

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:09

Last Modified:

23 Oct 2019 00:16

Publisher DOI:

10.1007/s10616-009-9238-4

PubMed ID:

19890731

Web of Science ID:

000272868400004

BORIS DOI:

10.7892/boris.30271

URI:

https://boris.unibe.ch/id/eprint/30271 (FactScience: 191649)

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