Cardiac-Specific Overexpression of miR-222 Induces Heart Failure and Inhibits Autophagy in Mice

Abstract

Background: MicroRNAs play a crucial role in the regulation of pathological cardiac remodeling and heart failure. Previously, we found that overexpression of miR-221 induces heart failure in mice. The miR-222 and miR-221 share the same gene cluster, however, the role of miR-222 in the regulation of cardiac function remained ill-defined. Methods and Results: Transgenic mice with cardiac-specific expression of miR-222 (Tg-miR-222) mice were generated. The Tg-miR-222 mice developed significantly enlarged hearts at 4 weeks of age. Transthoracic echocardiograph data indicated that the hearts of Tg-miR-222 mice exhibited an increased left ventricular end-diastolic internal diameter and decreased fractional shortening. We observed that the LC3-II in Tg-miR-222 mice was decreased accompanied with the upregulation of p62, indicating the autophagy inhibition in the hearts of Tg-miR-222 mice. The mTOR pathway, a negative regulator of autophagy, was activated in the hearts of Tg-miR-222 mice. The expression of p27 was downregulated by miR-222 overexpression. Conclusion: Our data indicate that miR-222 overexpression induces heart failure in mice. The downregulation of p27 and the activation of mTOR pathway may be involved in miR-222-induced heart failure and autophagy inhibition. Thus, targeting miR-222 expression may be a therapeutic strategy against pathological cardiac remodeling.

MicroRNA-199a-5p Induced Autophagy and Inhibits the Pathogenesis of Ankylosing Spondylitis by Modulating the mTOR Signaling via Directly Targeting Ras Homolog Enriched in Brain (Rheb)

“…According to previous studies, miR-222 helps to regulate of pathological cardiac remodeling and heart failure by mediating cardiomyocyte autophagy [25], miR-124 is involved autophagy in the peripheral blood from AS patients [26], and miRNA let-7i induces autophagy to protect T cells from apoptosis [27]. Our data show that miR-199a-5p was down-regulated in T cells from AS patients, and that the administration of miR-199a-5p mimics markedly enhanced the expression of autophagy-related genes.…”

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

“…cardiac‐specific overexpression of miR‐222 could induce pathological cardiac remodeling and heart failure. miR‐221‐induced cardiac remodeling is associated with the downregulation of p27 kip1 (p27), activation of the mTOR pathway, and the subsequent inhibition of autophagy in cardiomyocytes . Cardiac fibrosis is characterized by the net accumulation of extracellular matrix proteins in the cardiac interstitium and contributes to compromised cardiac function and potentially heart failure.…”

Predictive Effects of Circulating miR-221, miR-130a and miR-155 for Coronary Heart Disease: A Multi-Ethnic Study in China

“…miRNAs are endogenous, small non-coding RNAs which are ∼22 nucleotides in length, and are involved in the post-transcriptional regulation of genes. Functional changes, including up-regulation and down-regulation of miRNAsare known to be involved in the pathogenesis of many diseases such as myocardial infarction [6-9], coronary artery calcification (CAC) [10], arrhythmia [11], cardiomyocyte hypertrophy [12-13], heart failure [14], renal ischemia-reperfusion injury [15], non-alcoholic fatty liver disease [16], tuberculosis [17], pancreatic ductal adenocarcinoma [18], and diabetes mellitus [19]. miRNAs are reported to not only exist within the cell but also reside stably in the extracellular compartments such as the circulation, which enables relatively simple detection of miRNAs as disease biomarkers.…”