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Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure.

Lee HG, Chen Q, Wolfram JA, Richardson SL, Liner A, Siedlak SL, Zhu X, Ziats NP, Fujioka H, Felsher DW, Castellani RJ, Valencik ML, McDonald JA, Hoit BD, Lesnefsky EJ, Smith MA - PLoS ONE (2009)

Bottom Line: Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction.Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III.These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America. hyoung-gon.lee@case.edu

ABSTRACT
While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.

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Related in: MedlinePlus

The change of molecular markers for cardiac hypertrophy by over expression of Myc.Total ventricular RNA from mice with indicated Myc induction duration was analyzed by RT-PCR with specific primers. Each gene expression level was quantified and normalized with GAPDH expression level and expressed as a relative intensity.
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pone-0007172-g004: The change of molecular markers for cardiac hypertrophy by over expression of Myc.Total ventricular RNA from mice with indicated Myc induction duration was analyzed by RT-PCR with specific primers. Each gene expression level was quantified and normalized with GAPDH expression level and expressed as a relative intensity.

Mentions: Consistent with the echocardiographic data, a two week induction of Myc resulted in an approximately 2-fold increase in gravimetric cardiac mass normalized to body weight compared with Myc-OFF mice (Figure 2A,B). Histological analysis revealed typical hypertrophic changes including myocardial disarray, nuclear atypia and marked increase in fiber width (Figure 3A–C) as well as interstitial deposition of collagen (Figure 3D). One of the most conserved features of cardiac hypertrophy is the re-activation of genes that are normally limited in their expression to the embryonic stage of heart development and these are often used as molecular markers for cardiac hypertrophy. Therefore, we examined hypertrophic changes at the molecular level by measuring two well known marker genes, atrial natriuretic peptide and brain natriuretic peptide. As shown in Figure 4, the expression of both atrial and brain natriuretic peptides was significantly increased after 1 week induction and then decreased after 2 weeks induction. This suggests that hypertrophic changes at the molecular level begin early in the time course of Myc expression and that these changes are temporarily regulated.


Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure.

Lee HG, Chen Q, Wolfram JA, Richardson SL, Liner A, Siedlak SL, Zhu X, Ziats NP, Fujioka H, Felsher DW, Castellani RJ, Valencik ML, McDonald JA, Hoit BD, Lesnefsky EJ, Smith MA - PLoS ONE (2009)

The change of molecular markers for cardiac hypertrophy by over expression of Myc.Total ventricular RNA from mice with indicated Myc induction duration was analyzed by RT-PCR with specific primers. Each gene expression level was quantified and normalized with GAPDH expression level and expressed as a relative intensity.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747003&req=5

pone-0007172-g004: The change of molecular markers for cardiac hypertrophy by over expression of Myc.Total ventricular RNA from mice with indicated Myc induction duration was analyzed by RT-PCR with specific primers. Each gene expression level was quantified and normalized with GAPDH expression level and expressed as a relative intensity.
Mentions: Consistent with the echocardiographic data, a two week induction of Myc resulted in an approximately 2-fold increase in gravimetric cardiac mass normalized to body weight compared with Myc-OFF mice (Figure 2A,B). Histological analysis revealed typical hypertrophic changes including myocardial disarray, nuclear atypia and marked increase in fiber width (Figure 3A–C) as well as interstitial deposition of collagen (Figure 3D). One of the most conserved features of cardiac hypertrophy is the re-activation of genes that are normally limited in their expression to the embryonic stage of heart development and these are often used as molecular markers for cardiac hypertrophy. Therefore, we examined hypertrophic changes at the molecular level by measuring two well known marker genes, atrial natriuretic peptide and brain natriuretic peptide. As shown in Figure 4, the expression of both atrial and brain natriuretic peptides was significantly increased after 1 week induction and then decreased after 2 weeks induction. This suggests that hypertrophic changes at the molecular level begin early in the time course of Myc expression and that these changes are temporarily regulated.

Bottom Line: Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction.Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III.These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America. hyoung-gon.lee@case.edu

ABSTRACT
While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.

Show MeSH
Related in: MedlinePlus