Specific and sustained down-regulation of genes involved in fatty acid metabolism is not a hallmark of progression to cardiac failure in mice.

Preferential and specific down-regulation of genes involved in fatty acid (FA) uptake and metabolism is considered a hallmark of severe hypertrophic remodeling and progression to cardiac failure. Therefore, we investigated the time course of changes in cardiac metabolic gene expression (1) in mice subjected to regional myocardial infarction (MI) for 4 days, 1 month, or 3 months and (2) in mice overexpressing calcineurin (Cn) which initially develop concentric hypertrophy progressing after the age of 4 weeks to dilated cardiomyopathy and failure. In both models, hypertrophy was characterized by increased expression of beta-myosin heavy chain protein and atrial natriuretic factor mRNA, indicative of marked structural remodeling. Fractional shortening progressively decreased from 31% to 15.1% and 3.7% 1 and 3 months after MI, respectively. One month post-MI, the expression of several metabolic genes, i.e., acyl-CoA synthetase (-50%), muscle-type carnitine palmitoyl transferase 1 (-37%) and citrate synthase (-28%), was significantly reduced in the surviving myocardium. Despite overt signs of cardiac failure 3 months post-MI, the expression of these genes had returned to normal levels. In hearts of both 4- and 6-week-old Cn mice, genes involved in both FA and glucose metabolism and mitochondrial citrate synthase were down-regulated, reflecting an overall decline in metabolic gene expression, rather than a specific and preferential down-regulation of genes involved in FA uptake and metabolism. These findings challenge the concept that specific and sustained down-regulation of genes involved in FA uptake and metabolism represents a hallmark of the development of cardiac hypertrophy and progression to failure.

Dissociation of pulmonary vascular remodeling and right ventricular pressure in tissue angiotensin-converting enzyme-deficient mice under conditions of chronic alveolar hypoxia.

The present study was designed to characterize the role of tissue angiotensin-converting enzyme (ACE) on pulmonary vascular remodeling and its functional consequences in chronic hypoxia. On the basis of data obtained by pharmacological inhibition of ACE in rats we hypothesized that, under chronic hypoxic conditions, tissue ACE-deficient mice show less remodeling of pulmonary arterioles as compared with wild-type mice, but have equally increased right ventricular pressures. Wild-type and tissue ACE-deficient mice were exposed to chronic hypoxia for 4 wk. Absence of tissue ACE did not affect the increase in the mean right ventricular pressures (MRVP) and the extent of right ventricular hypertrophy under chronic hypoxic conditions. Chronic hypoxia induced significant remodeling of pulmonary arterioles in tissue ACE-deficient mice. The percentage of completely muscularized arterioles was, however, lower in tissue ACE-deficient mice compared with wild-type animals (29 +/- 12 versus 41 +/- 18%, p < 0.05), whereas the percentage of partially muscularized arterioles had increased (48 +/- 11 versus 39 +/- 11%, p < 0.05). No sex-based effects were found. We conclude that the absence of tissue ACE does not prevent the MRVP and right ventricular weight from increasing during chronic hypoxia in the mouse. Also, pulmonary vascular remodeling occurs in hypoxic tissue ACE-deficient mice, albeit to a lower level than in mice that do have an intact ACE gene.

Heart fatty acid binding protein and cardiac troponin T plasma concentrations as markers for myocardial infarction after coronary artery ligation in mice.

Ligation of the main left coronary artery in mice serves as a model for myocardial infarction (MI). We tested whether plasma concentrations of heart-type fatty acid-binding protein (H-FABP) and/or cardiac troponin T (cTnT) discriminate between infarcted and sham-operated mice and allow estimation of infarct size. Mice were subjected to coronary artery ligation or sham surgery and release curves of H-FABP and cTnT were determined. At 4 h after surgery the mean (+/-SD) H-FABP plasma concentration was 461+/-134 microg/l (n=10) in MI and 185+/-51 microg/l (n=6; P<0.001) in sham-operated mice. By 24 h after surgery H-FABP levels had returned to normal in both groups. cTnT plasma concentrations increased up to 48 h after MI to 13.5+/-6.2 microg/l (n=6; P<0.001) compared with 0.031+/-0.063 microg/l (n=7) in sham-operated mice. Linear regression analysis revealed a significant correlation between plasma H-FABP at 4 h and infarct size assessed 7 days after surgery. Plasma cTnT did not correlate significantly with infarct size. In conclusion, plasma cTnT concentration at 48 h after infarction can be used to distinguish MI from sham mice, whereas H-FABP concentration at 4 h can be used for stratification of animals according to infarct size.