Dynamic patterns of ventricular remodeling and apoptosis in hearts unloaded by heterotopic transplantation

Brinks, Henriette; Giraud, Marie-Noelle; Segiser, Adrian; Ferrié, Celine; Longnus, Sarah; Ullrich, Nina; Koch, Walter J.; Most, Patrick; Carrel, Thierry; Tevaearai, Hendrik (2014). Dynamic patterns of ventricular remodeling and apoptosis in hearts unloaded by heterotopic transplantation. Journal of heart and lung transplantation, 33(2), pp. 203-210. Elsevier 10.1016/j.healun.2013.10.006

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BACKGROUND Mechanical unloading of failing hearts can trigger functional recovery but results in progressive atrophy and possibly detrimental adaptation. In an unbiased approach, we examined the dynamic effects of unloading duration on molecular markers indicative of myocardial damage, hypothesizing that potential recovery may be improved by optimized unloading time. METHODS Heterotopically transplanted normal rat hearts were harvested at 3, 8, 15, 30, and 60 days. Forty-seven genes were analyzed using TaqMan-based microarray, Western blot, and immunohistochemistry. RESULTS In parallel with marked atrophy (22% to 64% volume loss at 3 respectively 60 days), expression of myosin heavy-chain isoforms (MHC-α/-β) was characteristically switched in a time-dependent manner. Genes involved in tissue remodeling (FGF-2, CTGF, TGFb, IGF-1) were increasingly upregulated with duration of unloading. A distinct pattern was observed for genes involved in generation of contractile force; an indiscriminate early downregulation was followed by a new steady-state below normal. For pro-apoptotic transcripts bax, bnip-3, and cCasp-6 and -9 mRNA levels demonstrated a slight increase up to 30 days unloading with pronunciation at 60 days. Findings regarding cell death were confirmed on the protein level. Proteasome activity indicated early increase of protein degradation but decreased below baseline in unloaded hearts at 60 days. CONCLUSIONS We identified incrementally increased apoptosis after myocardial unloading of the normal rat heart, which is exacerbated at late time points (60 days) and inversely related to loss of myocardial mass. Our findings suggest an irreversible detrimental effect of long-term unloading on myocardium that may be precluded by partial reloading and amenable to molecular therapeutic intervention.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiovascular Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Physiology

UniBE Contributor:

Most, Henriette; Giraud, Marie-Noelle; Segiser, Adrian; Longnus, Sarah; Ullrich, Nina; Carrel, Thierry and Tevaearai, Hendrik

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1053-2498

Publisher:

Elsevier

Language:

English

Submitter:

Laura Seidel

Date Deposited:

18 Jun 2014 17:00

Last Modified:

25 Nov 2015 09:20

Publisher DOI:

10.1016/j.healun.2013.10.006

PubMed ID:

24315785

Uncontrolled Keywords:

myocardial unloading, cardiac recovery, apoptosis, atrophy, heterotopic heart transplantation

BORIS DOI:

10.7892/boris.40970

URI:

https://boris.unibe.ch/id/eprint/40970

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