MIRNA-1 IN THE HEART: ITS TARGETS AND ROLE IN CARDIAC HYPERTROPHY AND DIABETIC CARDIOMYOPATHY

MicroRNAs (or miRNAs) are small endogenous single-stranded RNA molecules that inhibit the expression of specific mRNA targets through base pairing to their 3' untranslated region (UTR). As the modulatory function of a miRNA is ultimately defined by the genes it targets, identification of these genes is crucial. MicroRNA-1 (miRNA-1) was the first miRNA to be studied in cardiac biology; it is expressed specifically in striated muscle and its sequence is highly conserved across species ranging from fruit flies to humans. MiRNA-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of several regulatory proteins. In an effort to demystify the biological implications of miR-1 downregulation occurring during hypertrophic responses, bioinformatic softwares were explored for potential miR-1-targeted genes associated with this cardiac phenomenon. Insulin growth factor (IGF)-1 and its receptor, IGF-1R, were identified as potential targets; these are pivotal members of the PI3K/Akt signaling pathway known to play a critical role in many aspects of cardiac development and function, as well as skeletal muscle cell differentiation and proliferation. Moreover, the IGF-1 axis has been implicated in pathological conditions, such as cardiac hypertrophy and diabetic cardiomyopathy, a unique form of cardiac disease. Main findings of this study show that in conditions in which miR-1 is decreased, such as cardiac hypertrophy, IGF-1 is increased. This regulation appears reciprocal since IGF-1 stimulation leads to downregulation of miR-1 levels; thus, by translationally repressing its upstream modulator IGF-1, miR-1 intervenes in regulation of its own expression. This observation is clinically relevant since, in cardiac biopsies from patients affected by acromegaly, miR-1 levels inversely correlate with echocardiographic parameters of cardiac mass. Futhermore, miR-1 and the cotranscribed miR-133a were analyzed in different mouse models of type 1 and type 2 diabetes, where cardiac IGF-1 and Akt signaling cascade have been found dysregulated. Despite previuos findings, both muscle-specific miRNAs were not, or only minimally, affected by the establishment of diabetic cardiomyopathy. In conclusion, the findings show miR-1 as modulator of IGF-1 and IGF-1 receptor expression, confirming this miRNA as an essential regulator in development of cardiac hypertrophy, albeit with some controversy related to its role in the establishement of diabetic cardiomyopathy.