Small dedifferentiated cardiomyocytes bordering on microdomains of fibrosis: Evidence for reverse remodeling assisted recovery with

Fahed Al Darazi, Wenyuan Zhao, Tieqiang Zhao, Yao Sun, Tony Marion, Robert A. Ahokas, Syamal Bhattacharya, Ivan Gerling, Karl Weber

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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: (1) whether they are atrophied segments of the myofiber syncytium, (2) their redox state, (3) their anatomic relationship to activated myofibroblasts (myoFb), given their putative regulatory role in myocyte dedifferentiation and redifferentiation, (4) the relevance of proteolytic ligases of the ubiquitin- proteasome system as a mechanistic link to their size, and (5) 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 weeks of ALDOST was terminated followed by 4 weeks of neurohormonal withdrawal combined with a regimen of exogenous antioxidants, ZnSO4, and nebivolol (assisted recovery). Compared with controls, at 4 weeks of 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 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 weeks 1-4 ALDOST. Assisted recovery caused complete disappearance of myoFb from sites of fibrosis with redifferentiation of these myocytes, loss of oxidative stress, and ubiquitin-proteasome system activation, with restoration of nitric oxide and improved ventricular function. Thus, small dedifferentiated myocytes bordering on microdomains of fibrosis can redifferentiate and represent a potential source of autologous cells for functional myocardial regeneration.

Original languageEnglish (US)
Pages (from-to)237-246
Number of pages10
JournalJournal of Cardiovascular Pharmacology
Volume64
Issue number3
StatePublished - Sep 1 2014

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Cardiac Myocytes
Muscle Cells
Fibrosis
Myofibroblasts
Aldosterone
Salts
8-epi-prostaglandin F2alpha
Nebivolol
Proteasome Endopeptidase Complex
Giant Cells
Ligases
Ubiquitin
Oxidation-Reduction
Regeneration
Nitric Oxide
Oxidative Stress
Atrophic Muscular Disorders
Fibrillar Collagens
Phenotype
Ventricular Function

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Small dedifferentiated cardiomyocytes bordering on microdomains of fibrosis : Evidence for reverse remodeling assisted recovery with. / Darazi, Fahed Al; Zhao, Wenyuan; Zhao, Tieqiang; Sun, Yao; Marion, Tony; Ahokas, Robert A.; Bhattacharya, Syamal; Gerling, Ivan; Weber, Karl.

In: Journal of Cardiovascular Pharmacology, Vol. 64, No. 3, 01.09.2014, p. 237-246.

Research output: Contribution to journalArticle

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N2 - 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: (1) whether they are atrophied segments of the myofiber syncytium, (2) their redox state, (3) their anatomic relationship to activated myofibroblasts (myoFb), given their putative regulatory role in myocyte dedifferentiation and redifferentiation, (4) the relevance of proteolytic ligases of the ubiquitin- proteasome system as a mechanistic link to their size, and (5) 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 weeks of ALDOST was terminated followed by 4 weeks of neurohormonal withdrawal combined with a regimen of exogenous antioxidants, ZnSO4, and nebivolol (assisted recovery). Compared with controls, at 4 weeks of 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 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 weeks 1-4 ALDOST. Assisted recovery caused complete disappearance of myoFb from sites of fibrosis with redifferentiation of these myocytes, loss of oxidative stress, and ubiquitin-proteasome system activation, with restoration of nitric oxide and improved ventricular function. Thus, small dedifferentiated myocytes bordering on microdomains of fibrosis can redifferentiate and represent a potential source of autologous cells for functional myocardial regeneration.

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