![]() Previous studies have also shown that forced expression of miR-1 or miR-133 prevented hypertrophic cell growth in cultured cardiomyocytes and cardiac hypertrophy in transgenic mice 17, 18. Similarly, cardiac overexpression of miR-208a, which is located in the non-coding region of the α-myosin heavy chain (α-MHC) gene, is sufficient to induce hypertrophy, while analyses of miR-208a-deficient mice exhibited defects in stress-dependent cardiac growth and proper cardiac conduction 15, 16. The cardiac overexpression of miR-195, which is upregulated during cardiac hypertrophy, induces pathological cardiac growth and HF in transgenic mice 14. The cardiac-specific knockout of Dgcr8 or Dicer, which are essential for the biogenesis and processing of miRNA, leads to a rapidly progressive dilated cardiomyopathy, HF and postnatal lethality 11, 12, 13. Several studies have shown that miRNA expressions are altered in mouse and human HFs. Increasing evidences have revealed that miRNAs play important roles in cardiac hypertrophy and dysfunction 11, 12, 13, 14. The miRNA inhibit the expression of specific genes by either degrading the target mRNA or direct translational inhibition 10. MicroRNAs (miRNAs) are small, endogenous non-coding RNAs, which are approximately 22 nucleotides in length. However, the molecular mechanisms that regulate the cellular responses of cardiomyocytes to TGF-β signaling, which antagonizes cardiac hypertrophy, still have still not been elucidated. In addition, cardiac-specific overexpression of bone morphogenetic protein-10 (BMP-10) impairs the postnatal cardiac hypertrophic growth by activation of Smad1/5/8-mediated signaling 9. Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, antagonizes the hypertrophic response possibly through a mechanism involving the Smad proteins 7, 8. Our previous study reveals that Smad4 deletion in cardiomyocytes results in cardiac hypertrophy characterized by enlargement of cardiomyocytes, age-associated fibrosis and re-expression of certain fetal genes 6. Although many in vitro and in vivo studies have shown that TGF-β1 overexpression leads to cardiac hypertrophy and HF 4, 5, recent studies have shown that TGF-β signaling may play a role in the protective mechanism in cardiac hypertrophy 6, 7, 8, 9. The members of the transforming growth factor-β (TGF-β) superfamily signal through receptor serine/threonine kinases and intracellular Smad proteins 2, and play a complex and often contradictory role in the development of cardiac hypertrophy 3. Numerous regulatory pathways are implicated in the transduction of hypertrophic signaling 1. The underlying causes of HF are diverse, but HF is often associated with cardiac hypertrophy. Heart failure (HF) is one of the most frequent causes of death worldwide. The results of our study demonstrate that TGF-β1-regulated miR-27b is involved in the regulation of cardiac hypertrophy, and validate miR-27b as an efficient therapeutic target for cardiac diseases. Furthermore, in vivo silencing of miR-27b using a specific antagomir in a pressure-overload-induced mouse model of HF increased cardiac PPAR-γ expression, attenuated cardiac hypertrophy and dysfunction. Consistently, the miR-27b transgenic mice displayed significantly lower levels of PPAR-γ than the control mice. We validated the peroxisome proliferator-activated receptor-γ (PPAR-γ) as a direct target of miR-27b in cardiomyocyte. ![]() Furthermore, the analysis of transgenic mice with cardiomyocyte-specific overexpression of miR-27b revealed that miR-27b overexpression was sufficient to induce cardiac hypertrophy and dysfunction. In vitro experiments showed that the miR-27b expression could be inhibited by TGF-β1 and that its overexpression promoted hypertrophic cell growth, while the miR-27b suppression led to inhibition of the hypertrophic cell growth caused by phenylephrine (PE) treatment. We observed that miR-27b was upregulated in hearts of cardiomyocyte-specific Smad4 knockout mice, which developed cardiac hypertrophy. In this study, we tested whether a transforming growth factor-β (TGF-β)-regulated miRNA played a pivotal role in the development of cardiac hypertrophy and heart failure (HF). Recent studies have begun to reveal critical roles of microRNAs (miRNAs) in the pathogenesis of cardiac hypertrophy and dysfunction. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |