Diem Q. Ngo

Introduction. Cardiac remodeling is any structural changes in size, shape, and structure of the heart in response to increase cardiac stress. Cardiac remodeling can be seen in pathological conditions (e.g. heart failure) and show distinct characteristics such as fetal gene expression and myocyte apoptosis.¹ Pathways involved in cardiac remodeling include the PI3K-Akt pathway and Gαq signaling.² miRNAs, non-coding regulatory RNAs, participate in the regulation of these pathways by degrading specific mRNA through activation of RNA-induced silencing complex (RISC). Therefore, understanding the role of cardiac specific miRNA, such as miRNA-1, 133a, and 22, will improve understanding of molecular changes during cardiac remodeling and potential future therapy options.³ Methods. Pressure overload cardiac conditions were created through abdominal aortic constriction (AAC) and transverse aortic constriction (TAC). Standard PCR and echocardiogram techniques were used to observe changes in miRNA levels, mRNA levels, and cardiac function in IGF-1 deficient mice and miRNA-22 KO mice. Cardiomyocytes were also transfected with miRNA-22 mimic and inhibitors and treated with phenylephrine to induce cardiac hypertrophy. Mice treated with lentiviruses with a combination of miRNA-1, 133, 208, or 499 had cardiac function analyzed using echocardiogram and cardiac myocytes were observed under microscopy. Results. Only WT mice with AAC showed decrease in miRNA-1 and 133a. These changes were not seen in WT mice without AAC or with IGF-1 deficient mice. Furthermore, IGF1 deficient mice with AAC did not show induced hypertrophic response.⁴ In the TAC mice, miRNA-22 levels were found to be initially elevated after one week but returned to baseline level after four weeks. Mice treated miRNA-22 mimics showed increase cardiomyocyte cell size while miRNA-22 inhibitors were able to inhibit the hypertrophic response. miRNA-22 KO mice showed vulnerability to decompensated dilated cardiomyopathy.⁵ miRNA-22 KO showed increased expression of PURB which is an important regulator of cardiac gene expression.⁶ Using lentiviruses to deliver a combination of miRNAs, cardiac fibroblast showed reprogrammed similarities with mature cardiac myocytes in terms of structure and physiological qualities.⁷ Conclusion. Studies miRNA-1, 133a and 22 showed involvement in the response to cardiac stress and cardiac hypertrophy. Loss of miRNA-1 and 133a were associated with hypertrophic response and miRNA-22 showed involvement in decompensated dilated heart. Treatment of miRNA combinations in mice yielded reprogrammed cells that functions similar to normal cardiomyocyte showing a potential for future uses of miRNA combination to modulate cardiac remodeling.

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