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SMALL DEDIFFERENTIATED CARDIOMYOCYTES BORDERING ON MICRODOMAINS OF FIBROSIS: EVIDENCE FOR REVERSE REMODELING WITH ASSISTED RECOVERY.
MedLine Citation:
PMID:  24785345     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
With the perspective of functional myocardial regeneration, we investigated small cardiomyocytes bordering on microdomains of fibrosis, where they are dedifferentiated re-expressing fetal genes, and determined: i) whether they are atrophied segments of the myofiber syncytium; ii) their redox state; iii) their anatomic relationship to activated myofibroblasts (myoFb), given their putative regulatory role in myocyte dedifferentiation and re-differentiation; iv) the relevance of proteolytic ligases of the ubiquitin-proteasome system (UPS) as a mechanistic link to their size; and v) whether they could be rescued from their dedifferentiated phenotype. Chronic aldosterone/salt treatment (ALDOST) was invoked, where hypertensive heart disease with attendant myocardial fibrosis creates the fibrillar collagen substrate for myocyte sequestration with propensity for disuse atrophy, activated myoFb and oxidative stress. To address phenotype rescue, 4 wks ALDOST was terminated followed by 4 wks neurohormonal withdrawal combined with a regimen of exogenous antioxidants, ZnSO4 and nebivolol (assisted recovery). Compared to controls, at 4 wks ALDOST we found small myocytes to be: 1) sequestered by collagen fibrils emanating from microdomains of fibrosis and representing atrophic segments of the myofiber syncytia; 2) dedifferentiated re-expressing fetal genes (β-myosin heavy chain and atrial natriuretic peptide); 3) proximal to activated myoFb expressing α-smooth muscle actin microfilaments and angiotensin-converting enzyme; 4) expressing reactive oxygen species and nitric oxide (NO) with increased tissue 8-isoprostane, coupled to ventricular diastolic and systolic dysfunction; and 5) associated with upregulated redox-sensitive, proteolytic ligases MuRF1 and atrogin-1. In a separate study, we did not find evidence of myocyte replication (BrdU labeling) or expression of stem cell antigen (c-Kit) at wks 1-4 ALDOST. Assisted recovery caused: complete disappearance of myoFb from sites of fibrosis with re-differentiation of these myocytes; loss of oxidative stress and UPS activation, with restoration of NO and improved ventricular function. Thus, small dedifferentiated myocytes bordering on microdomains of fibrosis can re-differentiate and represent a potential source of autologous cells for functional myocardial regeneration.
Authors:
Fahed Al Darazi; Wenyuan Zhao; Tieqiang Zhao; Yao Sun; Tony N Marion; Robert A Ahokas; Syamal K Bhattacharya; Ivan C Gerling; Karl T Weber
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-5-1
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  -     ISSN:  1533-4023     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  2014 May 
Date Detail:
Created Date:  2014-5-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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