Abstract 13650: Microrna Signatures in the Transition From Left Ventricular Hypertrophy to Cardiac Dysfunction

Abstract

Purpose: Left ventricular hypertrophy (LVH) is not just a compensatory response to increased biomechanical stress but is often associated with unfavorable outcome in patients. Mechanisms that govern transition from subclinical LVH to LV dysfunction are incompletely understood. Lately, single microRNAs (miRs), a class of small non-coding RNAs, have been implicated in LVH, but the expression dynamics and their role in transition to LV dysfunction remain unknown. Methods: We subjected mice to transverse aortic constriction (TAC) for 2, 4 and 10 weeks(wks) or to Ang-2 infusion for 4wks. Cardiac function was examined using serial echocardiography (TTE) and compared to sham mice (SH). MiR profiles in LV tissue were studied using the Nanostring platform, with significant differences between TAC or Ang2 vs SH set at a >2 up-or down-regulation with p<0.01. Western blotting and luciferase assay were performed for target confirmation. The impact of up-regulated miRs was validated in vivo by administration of specific AntagomiR vs Scrambled miRs (SCR) after TAC. Results-TTE showed a modest increase in LV end-systolic dimensions and a decline in fractional shortening (FS) after 4wks TAC and Ang2 . However, after 10wks TAC, LV dilation was present together with a reduction in FS (table1). Cardiac miR signatures indicated that 3 miRs were selectively up-regulated when transition to LV dysfunction was present at 10wks TAC. A common target gene for 2 of these up-regulated miRs (miR764-3p and miR-130b-3p) was confirmed. Moreover, in vivo antagomiR treatment for both miRs protected against cardiac dysfunction and fibrosis(table 1). Conclusion: miR analyses show important time- and stressor-dependent dynamic expression patterns during pressure overload. The miR signatures associated with transition from LVH to LV dysfunction and subsequent targeted antagomiR administration may hold promise for future therapy.