Loss of Sox9 in cardiomyocytes delays the onset of cardiac hypertrophy and fibrosis.

Abstract

BACKGROUND:

The transcription factor Sox9 has been associated with cardiac injury and remodeling. Studies of mammalian hearts confirm Sox9 upregulation in fibroblasts following ischemic insults associated with enhanced fibrosis. The role of cardiomyocyte-specific Sox9 remains unclear. This study aimed to evaluate the role of cardiomyocyte-specific Sox9 in development and progression of left ventricular (LV) hypertrophy and fibrosis.

METHODS:

In male conditional Sox9 knockout mice (Sox9-KO) or floxed littermates (control group) transverse aortic constriction (TAC) was performed to induce LV hypertrophy. LV function and wall thickness were assessed weekly using echocardiography. LV mRNA- and protein expression levels of hypertrophy-, fibrosis-, and remodeling-associated genes were analyzed for each time point. Histological sections were stained for fibrosis and Sox9 expression.

RESULTS:

Only one week after TAC, the control group showed significantly enhanced heart weights and thickened LV posterior walls accompanied by elevated Anp- and Lox-mRNA levels. Simultaneously, Col1a1- and Col3a1-levels as well as Sox9 expression were strongly upregulated, Contrary, Sox9-KO mice did not develop cardiac hypertrophy until 4 weeks after TAC. Collagen and Sox9 expression also peaked at that later time point. Ejection fraction declined similarly in both groups after TAC. However, the control group showed a slightly better cardiac performance at 2 weeks after TAC.

CONCLUSIONS:

Cardiomyocyte-specific Sox9 mediates hypertrophy and early fibrosis, following cardiac pressure-overload. Loss of Sox9 delays cardiac growth and remodeling processes, however, does not preserve the cardiac function. We suggest that cardiomyocyte-driven Sox9 initiates a pro-hypertrophic cascade, possibly involving a cross-talk between myocytes and fibroblasts.

• Authors: Antje Schauer, Volker Adams, David M Poitz, Peggy Barthel, Dirk Joachim, Janet Friedrich, Axel Linke, Antje Augstein
• Journal: International journal of cardiology (Int J Cardiol) Vol. 282 Pg. 68-75 (05 01 2019) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 30765281 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• SOX9 Transcription Factor
• Sox9 protein, mouse

Topics

• Animals
• Cardiomegaly (diagnostic imaging, metabolism)
• Fibrosis
• Male
• Mice
• Mice, 129 Strain
• Mice, Knockout
• Myocytes, Cardiac (metabolism)
• SOX9 Transcription Factor (genetics, metabolism)