Intra-uterine growth restriction and the programming of left ventricular remodelling in female rats

Abstract

Epidemiological studies link intra-uterine growth restriction (IUGR) with increased incidence of hypertension and cardiac disease in adulthood. Our rat model of IUGR supports this contention and provides evidence for the programming of susceptibility for hypertension in all offspring. Moreover, in the female offspring only, gross anatomical changes (cardiac ventricle to body ratios) and increased left cardiac ventricular atrial natriuretic peptide (ANP) mRNA levels provide evidence for programming of cardiac disease in this gender. The aim of the current study was to measure changes in cardiac tissue that support remodelling that could be implicated in the initiation of hypertrophy. Adult female rats from our IUGR model and age- and sex-matched controls were killed at 12 weeks of age. Left cardiac ventricles were removed and used for monitoring changes in several key genes, Na+,K+-ATPase beta1 protein expression, cardiomyocyte morphology and contractility as well as citrate synthase and aconitase activities. When compared to controls, female offspring of our IUGR rat model exhibit higher expression (mRNA) of ANP and the atrial isoform of the myosin light chain, lower levels of Na+,K+-ATPase beta1 protein, increased cardiomyocyte depth and volume, increased sarcomere length, diminished cardiomyocyte contractility and lower aconitase activity. Female offspring of our IUGR rat model exhibit changes as adults that are consistent with the onset of cardiac remodelling. The decrease in aconitase activity suggests that oxidative stress may be implicated in this response.

Figure 1. Comparative gene expression

Comparative gene expression for MRLC-2 (A), β-MHC (B), Na⁺,K⁺-ATPase β1 (C), aMLC-1 (D) and ANP (E) relative to GAPDH by RT-PCR in left ventricles from adult female control and IUGR rats using column statistic analysis. *P≤ 0.05; ***P≤ 0.001 compared to controls.

Figure 2. Western blot analysis of Na⁺,K⁺-ATPase β1 protein from left ventricles of adult female control and IUGR rats

Representative immunoblot (A) and corresponding densitometric analyses (B). Brain microsomes serve as positive control and buffer as negative control. *P≤ 0.05 compared to controls.

Figure 3. Activities for two TCA cycle enzymes in left cardiac ventricles of adult female control and IUGR rats

Activity of citrate synthase (A) and aconitase (B). **P≤ 0.01 compared to controls.