Regulation of Clusterin in the Heart and Plasma of Mice After Transverse Aortic Constriction

Abstract

Chronic pressure overload induces adverse cardiac remodelling characterised by left ventricular (LV) hypertrophy and fibrosis, leading to heart failure (HF). Identification of new biomarkers for adverse cardiac remodelling enables us to better understand this process and, consequently, to prevent HF. We recently identified clusterin (CLU) as a biomarker of cardiac remodelling and HF after myocardial infarction. The aim of this study was to investigate whether CLU expression is regulated in the heart and could be used as an indicator of adverse cardiac remodelling in response to pressure overload. We quantified CLU in the LV of mice subjected to transverse aortic constriction (TAC) and observed increased CLU mRNA levels and its mature protein form (m-CLU) compared to the sham. Interestingly, CLU mRNA levels were positively correlated with pro-hypertrophic (ANP, BNP, B-MHC), pro- and anti-fibrotic (TGFb, ColI and CILP) genes. In addition, m-CLU was positively correlated with LV hypertrophy, LV end diastolic and systolic diameters, and negatively correlated with LV ejection fraction. Finally, we observed that m-CLU levels only increased in TAC mice with severe cardiac remodelling and dysfunction without any significant difference in plasma CLU levels. This is the first study to demonstrate that cardiac expression of CLU is induced in the LV of TAC mice during adverse cardiac remodelling. However, plasma CLU levels could not be used as biomarkers of TAC-induced cardiac remodelling and dysfunction.

Keywords: TAC mice; cardiac remodelling; clusterin; heart failure; pressure overload.