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Introduction: MicroRNAs (miRNAs) are altered in heart disease and have emerged as promising therapeutic targets. We recently reported that therapeutic inhibition of the miR-34 family (with an 8 mer antimiR) was effective in attenuation of pathological cardiac remodeling. We hypothesized the efficacy of antimiR-34 may be due to its regulation of other miRNAs, producing direct and indirect target effects.Objectives: To identify miRNAs regulated by miR-34 and understand miRNA networks involved in miR-34 inhibition therapy for pathological cardiac hypertrophy.Methods: MiRNA sequencing (Illumina HiSeq 2000) was performed on hearts of mice subjected to transverse aortic constriction (TAC) for 5 weeks, and subcutaneously administered a locked nucleic acid (LNA)-antimiR-34 for 6 weeks (n=3-4).Results: Expression of miR-34 family members (miR-34a, miR-34b, miR-34c) is increased in the hearts of TAC mice compared to Sham controls (1.7, 2.5, 4-fold, P<0.05) and attenuated with antimiR-34 treatment (85% decrease [0.85 of 1], p<0.05). TAC mice developed pathological cardiac hypertrophy (60% increase [4.8 of 8] in heart weight/tibial length ratio compared to Sham controls, P<0.05) and treatment with antimiR-34 significantly attenuated heart size (P<0.05). To uncover the underlying miRNA interactions, we carried out miRNA-Seq to identify other miRNAs that might be dysregulated in response to antimiR-34-based therapy. We identified several miRNAs (e.g., miR-3083 and miR-20b) that were downregulated in hearts from TAC vs Sham but not significantly downregulated in the TAC antimiR-34 group. Conversely, two miRNAs (miR-8103, miR-1933) were increased in response to TAC vs Sham but not significantly upregulated in TAC antimiR-34 treated mice. Our data suggests that miR-34 can regulate other miRNA and that these miRNAs can work together to regulate pathways leading to pathological cardiac hypertrophy.Conclusion: The identification of other miRNAs regulated by miR-34 may improve our understanding of miRNA networks for optimization of better therapeutic targets for treatment of complex diseases such as heart failure.