Session: MON 723-757-Renin-Angiotensin-Aldosterone System/Endocrine Hypertension
Bench to Bedside
Poster Board MON-754
MicroRNAs (miRNAs) are endogenous, small, non-coding RNAs that have important roles in development and cell proliferation and differentiation. miRNAs downregulate the expression levels of specific proteins by translational repression or mRNA degradation. Several miRNAs have been implicated in diverse cardiac pathologies in humans and experimental models. We previously reported that ALDO/SALT treatment increases rat cardiac left ventricle miR-21 expression and miR-21 downregulation exacerbated ALDO/SALT-mediated cardiac injury.
We aimed to identify the cardiac cells in which miR-21 is regulated by ALDO/SALT in vivo and analyze ALDO-mediated miR-21 expression regulation in cardiac fibroblasts (CFs). Uninephrectomized male Sprague Dawley rats were treated with ALDO (0.75 µg/h) and 1.0% NaCl/0.3% KCl or vehicle for 2 weeks. Cardiomyocytes and CFs were differentially isolated, sorted using cell-specific markers and miR-21 expression quantified by qPCR. For in vitro studies, CFs were isolated from control rats, cultured, treated with increasing concentrations of ALDO (0.1-1,000 nM) for 24 h and miR-21 expression quantified by qPCR. In another set of experiments, ALDO-treated CFs were also subjected to TGFβ (1.2 pM) or stretching stimulation (20%, 1Hz) for 24 h and miR-21 expression quantified by qPCR.
ALDO/SALT treatment increased miR-21 expression only in the sorted CF cell fraction (CD90+, CD3-). In vitro treatment of CFs with ALDO, dose-dependently increased miR-21 expression reaching maximal stimulation at 10 nM ALDO. TGFβ treatment decreased miR-21 expression, while stretching increased miR-21 expression. However, both treatments abolished ALDO-mediated miR-21 upregulation.
In summary, these results suggest that CFs are a direct target of ALDO both in vitro and in vivo and that miR-21 expression regulation in CFs is subjected to complex interactions between ALDO, mechanical and humoral factors. Modulation of CF’s miR-21 levels may be a novel therapeutic approach to mitigate ALDO/SALT-mediated cardiac injury.
Nothing to Disclose: DGR, JPB, SB, LLY
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