MicroRNA-22 Downregulation by Atorvastatin in a Mouse Model of Cardiac Hypertrophy: a new Mechanism for Antihypertrophic Intervention

Abstract

Background: Growing evidence shows that microRNAs (miRNAs) are involved in various cardiac processes including cardiac hypertrophy. However, the modulation of miRNA by pharmacological intervention in cardiomyocyte hypertrophy has not been disclosed yet. Methods: We constructed neonatal rat cardiomyocyte hypertrophy induced by angiotensin II stimulation and subjected to cardiomyocyte immunochemistry, qRT-PCR and immunoblotting analysis. In addition, we constructed the mouse cardiac hypertrophy using angomir-22 stimulation and demonstrated the potential antihypertrophic mechnism of atorvastatin. Results: The results showed that a collection of miRNAs were aberrantly expressed in hypertrophic cardiomyocytes induced by angiotensin II stimulation. In addition, overexpression of miR-22 was found in angiotensin II-induced hypertrophic cardiomyocytes, whereas administration of atorvastatin could reverse the upregulation of miRNA-22 nearly back to the control level. Furthermore, up-regulation of miRNA-22 in cardiomyocytes in vitro and in vivo could induce cardiac hypertrophy, which could suppress the protein level of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Concomitantly, the production of ANP, BNP and β-MHC was enhanced and cardiomyocyte size was increased. However, atorvastatin could markedly knockdown miRNA-22 expression and reverse these changes in cardiomyocytes. These results suggest that the contribution of atrovastatin to cardiomyocyte hypertrophy may be involved in downregulation of miRNA-22 expression, which modulates the activity of PTEN in cardiomyocyte hypertrophy. Conclusion: This study demonstrates for the first time the modulation of miRNA-22 can be achieved by pharmacological intervention. The data generated from this study provides a rationale for the development of miRNA-based strategies for antihypertrophic treatment.

How to be young at heart? miR-22 as a potential therapeutic target to boost autophagy and protect the old myocardium

“…It will be important to evaluate whether the pharmacological inhibition of miR-22 ameliorates symptoms and outcomes in these subjects. Of note, atorvastatin was previously seen to reduce the expression of miR-22 in cardiomyocytes (24) and was also shown to ameliorate heart failure in patients (25).…”

Calhex231 Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro

“…However, the role of Calhex 231 in cardiac hypertrophy is still unknown. Cardiac hypertrophy is controlled by a complex signal transduction and gene regulatory network [8,9]. Recently, autophagy has been shown to be involved in the pathogenesis of cardiac hypertrophy [10].…”

Identification of Amino Acid Residues in Angiotensin II Type 1 Receptor Sensing Mechanical Stretch and Function in Cardiomyocyte Hypertrophy

“…In the presence of AngII, AT 1 R undergoes a conformational change from inactive states to active states, as well as other GPCRs [7,8] to induce cardiac hypertrophy [9,10] and fibrosis [11]. Upon activation of the GPCR by agonist, the receptor experiences specific movements in the transmembrane (TM) helices exposing a binding site for a G-protein complex, resulting in the release of GTP and the activation of downstream signaling pathways [7,12].…”