Disruption of mindin exacerbates cardiac hypertrophy and fibrosis.

Abstract

Cardiac hypertrophy is a response of the myocardium to increased workload and is characterised by an increase of myocardial mass and an accumulation of extracellular matrix (ECM). As an ECM protein, an integrin ligand, and an angiogenesis inhibitor, all of which are key players in cardiac hypertrophy, mindin is an attractive target for therapeutic intervention to treat or prevent cardiac hypertrophy and heart failure. In this study, we investigated the role of mindin in cardiac hypertrophy using littermate Mindin knockout (Mindin ( -/- )) and wild-type (WT) mice. Cardiac hypertrophy was induced by aortic banding (AB) or angiotensin II (Ang II) infusion in Mindin ( -/- ) and WT mice. The extent of cardiac hypertrophy was quantitated by echocardiography and by pathological and molecular analyses of heart samples. Mindin ( -/- ) mice were more susceptible to cardiac hypertrophy and fibrosis in response to AB or Ang II stimulation than wild type. Cardiac function was also markedly exacerbated during both systole and diastole in Mindin ( -/- ) mice in response to hypertrophic stimuli. Western blot assays further showed that the activation of AKT/glycogen synthase kinase 3β (GSK3β) signalling in response to hypertrophic stimuli was significantly increased in Mindin ( -/- ) mice. Moreover, blocking AKT/GSK3β signalling with a pharmacological AKT inhibitor reversed cardiac abnormalities in Mindin ( -/- ) mice. Our data show that mindin, as an intrinsic cardioprotective factor, prevents maladaptive remodelling and the transition to heart failure by blocking AKT/GSK3β signalling.

• Authors: Zhou-Yan Bian, Xiang Wei, Shan Deng, Qi-Zhu Tang, Jinghua Feng, Yan Zhang, Chen Liu, Ding-Sheng Jiang, Ling Yan, Lian-Feng Zhang, Manyin Chen, John Fassett, Yingjie Chen, You-Wen He, Qinglin Yang, Peter P Liu, Hongliang Li
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 90 Issue 8 Pg. 895-910 (Aug 2012) ISSN: 1432-1440 [Electronic] Germany
• PMID: 22367478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Extracellular Matrix Proteins
• mindin

Topics

• Animals
• Blotting, Western
• Cardiomegaly (genetics, metabolism)
• Echocardiography
• Extracellular Matrix Proteins (genetics, metabolism)
• Fibrosis (genetics, metabolism)
• Immunohistochemistry
• Male
• Mice
• Mice, Knockout
• Myocardium (pathology)