98 Moreover, Thum et al used antagomirs to inhibit mir-21 in TAC mice, and as a result the TAC-induced cardiac hypertrophy Nilotinib solubility was attenuated. 84 Interestingly though, Patrick et al claimed that
genetic deletion or inhibition of miR-21 in mice did not altered the hypertrophy they displayed in response to cardiac stressing stimuli (TAC, MI, chronic calcineurin activation, infusion of Ang II), implying that mir-21 is not essential for the development of pathological cardiac hypertrophy. 168 This discrepancy was subject to further discussion, and the different length of the anti- mir-21 oligonucleotides used by the groups of Thum and Patrick (22-mer vs 8-mer) were suggested as the cause of this inconsistence, whilst the difference in the phenotype of the mir-21 deficient mice has yet to be explained. 169,170 MiR-21, being mainly expresses by CFs, has also emerged as a regulator of cardiac fibrosis, and as such Thum and Patrick also investigated the effect of miR-21 inhibition in this subpathhology. According to Thum et al, miR-21 inhibition protected TAC mice against cardiac fibrosis, but
Patrick et al has called into question the role of mir-21 in cardiac fibrosis, as well as hypertrophy. The latter reported that genetic deletion or inhibition of miR-21 in mice did not have an effect on the fibrosis the developed in response to a variety of cardiac stressing stimuli (TAC, MI, chronic calcineurin activation, infusion of Ang II). This inconsistence may be due to a technicality (antagomir length), but leaves open the possibility of a contributing role of miR-21 in the development of cardiac fibrosis. MiRNA mimics have been utilized in the experimental setting in order to normalize the expression of miR-9 which is observed downregulated during cardiac hypertrophy. Wang et al administered a double-stranded RNA miRNA mimic for miR-9 in rats with isoproterenol-induced cardiac hypertrophy, and successfully reduced the levels of miR-9 target myocardin, ultimately leading to attenuation of cardiac hypertrophy and
improvement of cardiac function. 109 Although the efficiency of miRNA mimics is subject to a number of limitations, regarding in vivo delivery methods, cellular uptake and off-target effects, this study provides a paradigm Drug_discovery of a possible therapeutic approach, where exogenous supplementation of miRNA mimics could be used to replenish endogenous miRNAs that are reduced during cardiac disease. Overall, it is important to note that mimics (other than viral delivery) have thus far not proven to be a viable option in vivo. In fact, it is thought that in vivo methods, other than viral delivery of mimics, actually result in an miR inhibitory effect, rather than a mimic effect. According to the aforementioned studies, miRNA modulation appears to be a promising tool for the development of novel therapeutic strategies against cardiac disease and HF.