Up-Regulation of Alpha-Smooth Muscle Actin in Transgenic Mouse Hearts Expressing N-Terminal Truncated Cardiac Troponin I without Hypertrophy or Failure

Abstract

Myocardial remodeling is a structural adaptation in response to injury or stress, and is characterized by changes such as hypertrophy and weakened contractility, potentially resulting in heart failure. A naturally occurring N-terminal truncation of cardiac troponin I (cTnI-ND) has been shown to be an adaptation to heart failure (Yu et al., JBC 276:15753-60, 2001). Over-expression of cTnI-ND in the hearts of transgenic mice has shown functional benefit such as increased relaxation and myocardial compliance (Barbato et al., JBC 280:6602-9, 2005; Feng et al., JBC 283:33384-93, 2008), but the mechanism remains to be investigated. Microarray analysis of cardiac mRNA from 2 months old cTnI-ND mice without cardiac hypertrophy or failure revealed prominently up-regulated (3.3-fold) expression of alpha-smooth muscle actin (SMA), an actin isoform normally expressed in differentiated cardiomyocytes and a marker for myocardial hypertrophy due to pressure overload. Immunohistochemical analysis of heart slices showed significant increases in concentration of blood vessels in the ventricular wall of cTnI-ND hearts, however this increase was comparable to another group of transgenic mouse hearts with no change in SMA. There was no evidence of vessel thickening. Instead, immunohistochemical quantification suggested that SMA was increased within cTnI-ND cardiomyocytes. using quantitative immunoblotting, the expression of SMA in cardiomyocytes was confirmed in isolated myocytes, but not isolated myofibrils, from cTnI-ND mouse hearts. Specific subcellular localization of the SMA remains to be determined. Our results suggest that SMA may play a role in compensatory myocardial remodeling in cTnI-ND hearts, possibly via its function in the cytoskeleton of cardiomyocytes.