Abstract
BackgroundMechanical overload leads to cardiac hypertrophy and mechanical unloading to cardiac atrophy. Both conditions produce similar transcriptional changes including a re-expression of fetal genes, despite obvious differences in phenotype. MicroRNAs (miRNAs) are discussed as superordinate regulators of global gene networks acting mainly at the translational level. Here, we hypothesized that defined sets of miRNAs may determine the direction of cardiomyocyte plasticity responses.Methodology/Principal FindingsWe employed ascending aortic stenosis (AS) and heterotopic heart transplantation (HTX) in syngenic Lewis rats to induce mechanical overloading and unloading, respectively. Heart weight was 26±3% higher in AS (n = 7) and 33±2% lower in HTX (n = 7) as compared to sham-operated (n = 6) and healthy controls (n = 7). Small RNAs were enriched from the left ventricles and subjected to quantitative stem-loop specific RT-PCR targeting a panel of 351 miRNAs. In total, 153 miRNAs could be unambiguously detected. Out of 72 miRNAs previously implicated in the cardiovascular system, 40 miRNAs were regulated in AS and/or HTX. Overall, HTX displayed a slightly broader activation pattern for moderately regulated miRNAs. Surprisingly, however, the regulation of individual miRNA expression was strikingly similar in direction and amplitude in AS and HTX with no miRNA being regulated in opposite direction. In contrast, fetal hearts from Lewis rats at embryonic day 18 exhibited an entirely different miRNA expression pattern.ConclusionsTaken together, our findings demonstrate that opposite changes in cardiac workload induce a common miRNA expression pattern which is markedly different from the fetal miRNA expression pattern. The direction of postnatal adaptive cardiac growth does, therefore, not appear to be determined at the level of single miRNAs or a specific set of miRNAs. Moreover, miRNAs themselves are not reprogrammed to a fetal program in response to changes in hemodynamic load.
Highlights
Physiological and pathological changes in cardiac workload can cause prominent alterations in gene expression [1]
Taken together, our findings demonstrate that opposite changes in cardiac workload induce a common miRNA expression pattern which is markedly different from the fetal miRNA expression pattern
To assess the hemodynamic load-induced changes on miRNA pattern, male Lewis rats were subjected to increased cardiac workload by ascending aortic stenosis (AS) or to decreased cardiac workload by heterotopic heart transplantation (HTX)
Summary
Physiological and pathological changes in cardiac workload can cause prominent alterations in gene expression [1]. Opposite changes in cardiac workload (i.e. hemodynamic overloading versus unloading), associated with distinct phenotypes (hypertrophy versus atrophy), produce strikingly similar transcriptional changes [3]. This principle finding was confirmed by several groups demonstrating uni-directional changes in hypertrophy-associated mRNAs - including ANP, bMHC and a-skeletal actin - in hypertrophied and atrophied hearts (for review see [4]). MicroRNAs (miRNAs) have recently been identified as superordinate regulators of global gene networks acting mainly at the translational level. Mechanical overload leads to cardiac hypertrophy and mechanical unloading to cardiac atrophy Both conditions produce similar transcriptional changes including a re-expression of fetal genes, despite obvious differences in phenotype. We hypothesized that defined sets of miRNAs may determine the direction of cardiomyocyte plasticity responses
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