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Transcriptome alteration in the diabetic heart by rosiglitazone: implications for cardiovascular mortality.

Wilson KD, Li Z, Wagner R, Yue P, Tsao P, Nestorova G, Huang M, Hirschberg DL, Yock PG, Quertermous T, Wu JC - PLoS ONE (2008)

Bottom Line: Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety.Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT

Background: Recently, the type 2 diabetes medication, rosiglitazone, has come under scrutiny for possibly increasing the risk of cardiac disease and death. To investigate the effects of rosiglitazone on the diabetic heart, we performed cardiac transcriptional profiling and imaging studies of a murine model of type 2 diabetes, the C57BL/KLS-lepr(db)/lepr(db) (db/db) mouse.

Methods and findings: We compared cardiac gene expression profiles from three groups: untreated db/db mice, db/db mice after rosiglitazone treatment, and non-diabetic db/+ mice. Prior to sacrifice, we also performed cardiac magnetic resonance (CMR) and echocardiography. As expected, overall the db/db gene expression signature was markedly different from control, but to our surprise was not significantly reversed with rosiglitazone. In particular, we have uncovered a number of rosiglitazone modulated genes and pathways that may play a role in the pathophysiology of the increase in cardiac mortality as seen in several recent meta-analyses. Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety. Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.

Conclusions: This study maps the genomic expression patterns in the hearts of the db/db murine model of diabetes and illustrates the impact of rosiglitazone on these patterns. The db/db gene expression signature was markedly different from control, and was not reversed with rosiglitazone. A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment. Further study of these genes and molecular pathways will provide important insights into the cardiac decompensation associated with both diabetes and rosiglitazone treatment.

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Cardiac magnetic resonance imaging.CMR imaging at 8 weeks after treatment initiation of rosiglitazone-treated db/db mice (n = 4), untreated db/db mice (n = 4) and db/+ groups (n = 4). Left ventricular mass (LVM), interventricular septal thickness (IVST) and posterior wall thickness (PWT) were significantly increased in both treated and untreated db/db mice relative to db/+ controls, while LVEF was decreased (though not significantly in the rosiglitazone-treated group). No significant differences in LVM, IVST, PWT, or LVEF between rosiglitazone-treated and untreated db/db mice were detected (P = 0.82, 0.66, 0.14, and 0.88, respectively). Values are mean±SEM. *P<0.05 vs. age-matched db/+.
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pone-0002609-g004: Cardiac magnetic resonance imaging.CMR imaging at 8 weeks after treatment initiation of rosiglitazone-treated db/db mice (n = 4), untreated db/db mice (n = 4) and db/+ groups (n = 4). Left ventricular mass (LVM), interventricular septal thickness (IVST) and posterior wall thickness (PWT) were significantly increased in both treated and untreated db/db mice relative to db/+ controls, while LVEF was decreased (though not significantly in the rosiglitazone-treated group). No significant differences in LVM, IVST, PWT, or LVEF between rosiglitazone-treated and untreated db/db mice were detected (P = 0.82, 0.66, 0.14, and 0.88, respectively). Values are mean±SEM. *P<0.05 vs. age-matched db/+.

Mentions: Using cardiac magnetic resonance (CMR) scanning, our group has previously shown progressive cardiomyopathic changes in db/db mice when compared to db/+ controls [17]. Left ventricular mass (LVM), interventricular septal thickness (IVST) and posterior wall thickness (PWT) were significantly increased in db/db mice, while LVEF was only marginally decreased. For the CMR imaging in this new study (Figure 4), we included rosiglitazone-treated db/db mice in addition to the untreated db/db and db/+ groups, and scanned them at 8 weeks after treatment initiation to look for cardiomyopathic changes. CMR scans revealed significant, albeit subtle, cardiomyopathic changes in untreated db/db mice compared to db/+ controls (Figure 4). However, rosiglitazone treatment resulted in no significant improvements in cardiac contractility, which confirmed our echocardiographic studies.


Transcriptome alteration in the diabetic heart by rosiglitazone: implications for cardiovascular mortality.

Wilson KD, Li Z, Wagner R, Yue P, Tsao P, Nestorova G, Huang M, Hirschberg DL, Yock PG, Quertermous T, Wu JC - PLoS ONE (2008)

Cardiac magnetic resonance imaging.CMR imaging at 8 weeks after treatment initiation of rosiglitazone-treated db/db mice (n = 4), untreated db/db mice (n = 4) and db/+ groups (n = 4). Left ventricular mass (LVM), interventricular septal thickness (IVST) and posterior wall thickness (PWT) were significantly increased in both treated and untreated db/db mice relative to db/+ controls, while LVEF was decreased (though not significantly in the rosiglitazone-treated group). No significant differences in LVM, IVST, PWT, or LVEF between rosiglitazone-treated and untreated db/db mice were detected (P = 0.82, 0.66, 0.14, and 0.88, respectively). Values are mean±SEM. *P<0.05 vs. age-matched db/+.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2481284&req=5

pone-0002609-g004: Cardiac magnetic resonance imaging.CMR imaging at 8 weeks after treatment initiation of rosiglitazone-treated db/db mice (n = 4), untreated db/db mice (n = 4) and db/+ groups (n = 4). Left ventricular mass (LVM), interventricular septal thickness (IVST) and posterior wall thickness (PWT) were significantly increased in both treated and untreated db/db mice relative to db/+ controls, while LVEF was decreased (though not significantly in the rosiglitazone-treated group). No significant differences in LVM, IVST, PWT, or LVEF between rosiglitazone-treated and untreated db/db mice were detected (P = 0.82, 0.66, 0.14, and 0.88, respectively). Values are mean±SEM. *P<0.05 vs. age-matched db/+.
Mentions: Using cardiac magnetic resonance (CMR) scanning, our group has previously shown progressive cardiomyopathic changes in db/db mice when compared to db/+ controls [17]. Left ventricular mass (LVM), interventricular septal thickness (IVST) and posterior wall thickness (PWT) were significantly increased in db/db mice, while LVEF was only marginally decreased. For the CMR imaging in this new study (Figure 4), we included rosiglitazone-treated db/db mice in addition to the untreated db/db and db/+ groups, and scanned them at 8 weeks after treatment initiation to look for cardiomyopathic changes. CMR scans revealed significant, albeit subtle, cardiomyopathic changes in untreated db/db mice compared to db/+ controls (Figure 4). However, rosiglitazone treatment resulted in no significant improvements in cardiac contractility, which confirmed our echocardiographic studies.

Bottom Line: Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety.Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT

Background: Recently, the type 2 diabetes medication, rosiglitazone, has come under scrutiny for possibly increasing the risk of cardiac disease and death. To investigate the effects of rosiglitazone on the diabetic heart, we performed cardiac transcriptional profiling and imaging studies of a murine model of type 2 diabetes, the C57BL/KLS-lepr(db)/lepr(db) (db/db) mouse.

Methods and findings: We compared cardiac gene expression profiles from three groups: untreated db/db mice, db/db mice after rosiglitazone treatment, and non-diabetic db/+ mice. Prior to sacrifice, we also performed cardiac magnetic resonance (CMR) and echocardiography. As expected, overall the db/db gene expression signature was markedly different from control, but to our surprise was not significantly reversed with rosiglitazone. In particular, we have uncovered a number of rosiglitazone modulated genes and pathways that may play a role in the pathophysiology of the increase in cardiac mortality as seen in several recent meta-analyses. Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety. Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.

Conclusions: This study maps the genomic expression patterns in the hearts of the db/db murine model of diabetes and illustrates the impact of rosiglitazone on these patterns. The db/db gene expression signature was markedly different from control, and was not reversed with rosiglitazone. A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment. Further study of these genes and molecular pathways will provide important insights into the cardiac decompensation associated with both diabetes and rosiglitazone treatment.

Show MeSH
Related in: MedlinePlus