Myocardial cell death and regeneration during progression of cardiac hypertrophy to heart failure
Authors: Joe G Hollyfield
David Young
Mary E Rayborn
Sagartirtha Sarkar
Mamta Chawla-Sarkar
Subha Sen
Kazutoshi Nishiyama
Journal: Journal of Biological Chemistry (2004)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Cardiac hypertrophy; heart failure; myotrophin; transgenic mouse model; apoptosis
Affiliations: Department of Molecular Cardiology, Lerner Research Institute, Taussig Cancer Center, and Cole Eye Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

Abstract:  Cardiac hypertrophy and ensuing heart failure are among the most common causes of mortality worldwide, yet the triggering mechanisms for progression of hypertrophy to failure are not fully understood. Tissue homeostasis depends on proper relationships between cell proliferation, differentiation, and death and any imbalance between them results in compromised cardiac function. Recently, we developed a transgenic (Tg) mouse model that overexpress myotrophin (a 12-kDa protein that stimulates myocyte growth) in heart resulting in hypertrophy that progresses to heart failure. This provided us an appropriate model to study the disease process at any point from initiation of hypertrophy end-stage heart failure. We studied detailed apoptotic signaling and regenerative pathways and found that the Tg mouse heart undergoes myocyte loss and regeneration, but only at a late stage (during transition to heart failure). Several apoptotic genes were up-regulated in 9-month-old Tg hearts compared with age-matched wild type or 4-week-old Tg hearts. Cardiac cell death during heart failure involved activation of Fas, tumor necrosis factor-alpha, and caspases 9, 8, and 3 and poly(ADP-ribose) polymerase cleavage. Tg mice with hypertrophy associated with compromised function showed significant up-regulation of cyclins,cyclin-dependent kinases (Cdks), and cell regeneration markers in myocytes. Furthermore, in human failing and nonfailing hearts, similar observations were documented including induction of active caspase 3 and Ki-67 proteins in dilated cardiomyopathic myocytes. Taken together, our data suggest that the stress of extensive myocardial damage from longstanding hypertrophy may cause myocytes to reenter the cell cycle. We demonstrate, for the first time in an animal model, that cell death and regeneration occur simultaneously in myocytes during end-stage heart failure, a phenomenon not observed at the onset of the disease process. 

Retracted: No

PubPeer comments:
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 #3 All the marked pairs look different to me. You can make a case that the 4WT1 and 4WT2 lanes in the Cdk1 lane are problematical, though the low resolution does not help... ![file] ... but the other two pairs do differ. Your posts #1 and #2 need no comment from me! , 
 There is a lot of clumsy splicing of blots throughout this paper, but I agree that posts 1 2 raise matters the authors should address, while post 3 is pushing matters too far. Are the authors willing to comment here? , 
 #4 What about lanes 1 and 2 of the FAS panel in figure 3B? There seems to be an array of dark spots in these lanes which look very similar in size and relative location. What about lanes 1 to 3 and lanes 4 to 6 GAPDH panel figure 3B? In the GAPDH panel there is a paatern of dark spots and streaks abouve the main black streak, which seems very similar in lanes 1 to 3 and lanes 4 to 6. , 
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 2020 expression of concern. https: www.jbc.org content 295 10 3386 The publisher of the Journal of Biological Chemistry is issuing an Expression of Concern to inform readers that credible concerns have been raised regarding some of the data and conclusions in the article listed above. The Journal of Biological Chemistry will provide additional information as it becomes available. , 
 https: retractionwatch.com 2020 03 17 cleveland-clinic-heart-researchers-earn-two-expressions-of-concern , 
 Withdrawal: Myocardial cell death and regeneration during progression of cardiac hypertrophy to heart failure. VOLUME 279 (2004) PAGES 52630u201352642 This article has been withdrawn by Sagartirtha Sarkar, Mamta Chawla-Sarkar, Kazutoshi Nishiyama, Joe G. Hollyfield, and Subha Sen. David Young and Mary E. Rayborn could not be reached. The images from 9-month-old mice in Fig. 1A were reused from Sarkar, S., et al. (2004) J. Biol. Chem. 279, 20422u201320434 as 1-year-old and 18-week-old mice. The withdrawing authors state that they showed the images of the heart at the recommendation of a reviewer to introduce the model. The first four lanes of the GAPDH immunoblot in Fig. 3B were reused in the last four lanes as well as in Figs. 3D, 6 (B and C), and 8B and Sarkar, S., et al. (2004) J. Biol. Chem. 279, 20422u201320434. Additionally, the GAPDH immunoblots in Figs. 3D and 6 (B and C) are the same. In Fig. 3B, the first two lanes of the Fas immunoblot are the same. In Fig. 6B, the first two lanes of the cyclin D3 immunoblot are the same. In Fig. 6C, the first two lanes of the Cdk1 immunoblot are the same. The withdrawing authors do not agree that the first four lanes of the GAPDH immunoblot in Fig 3B were reused in the last four lanes as well as in Figs. 3D, 6 (B and C), and 8B and in Sarkar, S., et al. (2004) J. Biol. Chem. 279, 20422u201320434. The withdrawing authors state that they provided evidence that these images are different based on different densitometric scan values for each lane under question, as well as few background differences among the GAPDH lanes. Similar evidence was also presented for the GAPDH immunoblots in Figs. 3D and 6 (B and C). However, the Journal did not agree with the withdrawing authors evidence. The withdrawing authors strongly disagree on any duplication between the first two lanes of the Fas immunoblot in Fig. 3B, the first two lanes of the cyclin D3 immunoblot in Fig. 6B, and the first two lanes of the Cdk1 immunoblot in Fig. 6C. The withdrawing authors could not produce any original autoradiograms or scans to support their claims for the publication, which is 17 years old due to closure of the laboratory for more than a decade. Therefore, due to the unavailability of the original data after so many years, the withdrawing authors decided to withdraw the manuscript. The withdrawing authors state that none of the results presented in this article were compromised and the conclusions of each experiment remain unaltered. , 
 https: retractionwatch.com 2021 02 23 former-cleveland-clinic-researchers-papers-more-likely-than-not-included-falsified-images-says-investigation ,