دانلود مقاله ترجمه شده خاموش کردن فارماکولوژیک miR-152 از نارسایی قلبی ناشی از فشار بیش از حد جلوگیری می کند

Abstract

Background: MicroRNAs (miRNAs) are small, non-coding RNAs that play a key role in gene expression. Accumulating evidence suggests that aberrant miRNA expression contributes to the heart failure (HF) phenotype, however, the underlying molecular mechanisms are not well understood. A better understanding of the mechanisms of action miRNAs could potentially lead to targeted therapies that could halt the progression or even reverse HF.

Methods and Results: We identified that miR-152 expression was upregulated in the failing human heart and experimental animal models of HF. Transgenic mice with cardiomyocyte-specific miR-152 overexpression developed impaired systolic function (mean difference, −38.74% [95% CI: −45.73% to −31.74%]; P<0.001) and dilated cardiomyopathy. At the cellular level, miR-152 overexpression induced aberrant mitochondrial ultrastructure and dysregulation of key genes involved in cardiomyocyte metabolism and inflammation. Mechanistically, we identified monothiol Glutaredoxin 5 (Glrx5), a critical regulator of mitochondrial iron and iron-sulfur cluster synthesis, as a direct miR-152 target. Finally, a proof-of-concept of the therapeutic efficacy of targeting miR-152 in vivo was obtained by utilizing a locked nucleic acid (LNA)-based inhibitor of miR-152 (LNA-152) in a murine model of heart failure subjected to transverse aortic constriction. We demonstrated that animals treated with LNA-152 (n=10) showed preservation of systolic function when compared to LNA-control treated animals (n=9) (mean difference, -18.25% [95% CI: −25.10% to – 11.39%] P<0.001).

Conclusion: The upregulation of miR-152 expression in the failing myocardium contributes to the HF pathophysiology. Preclinical evidence suggests that miR-152 inhibition preserves cardiac function in a model of pressure overload-induced HF. These findings offer new insights into the pathophysiology of HF and point to miR-152 as a potential novel therapeutic target.