Myoglobin-deficient mice activate a distinct cardiac gene expression program in response to isoproterenol-induced hypertrophy

Abstract

Myoglobin knockout mice (myo−/−) adapt to the loss of myoglobin by the activation of a variety of compensatory mechanisms acting on the structural and functional level. To analyze to what extent myo−/− mice would tolerate cardiac stress we used the model of chronic isoproterenol application to induce cardiac hypertrophy in myo−/− mice and wild-type (WT) controls. After 14 days of isoproterenol infusion cardiac hypertrophy in WT and myo−/− mice reached a similar level. WT mice developed lung edema and left ventricular dilatation suggesting the development of heart failure. In contrast, myo−/− mice displayed conserved cardiac function and no signs of left ventricular dilatation. Analysis of the cardiac gene expression profiles using 40K mouse oligonucleotide arrays showed that isoproterenol affected the expression of 180 genes in WT but only 92 genes of myo−/− hearts. Only 40 of these genes were regulated in WT as well as in myo−/− hearts. In WT hearts a pronounced induction of genes of the extracellular matrix occurred suggesting a higher level of cardiac remodeling. myo−/− hearts showed altered transcription of genes involved in carbon metabolism, inhibition of apoptosis and muscular repair. Interestingly, a subset of genes that was altered in myo−/− mice already under basal conditions was differentially expressed in WT hearts under isoproterenol treatment. In summary, our data show a high capacity of myoglobin-deficient mice to adapt to catecholamine induced cardiac stress which is associated with activation of a distinct cardiac gene expression program.