Plasma aldosterone escape is found during long-term ACE inhibitor therapy of chronic heart failure. Evidence for aldosterone production in cardiovascular tissues raised the question of whether aldosterone escape occurs or not in these tissues. Rats with infarction-induced chronic heart failure were treated with enalapril (20 mg/kg/d) and losartan (15 mg/kg/d) for 20 weeks. Untreated chronic heart failure and sham-operated rats were used as positive and normal controls, respectively. Ex vivo mesenteric artery and heart perfusion, high performance liquid chromatography, and RIA for aldosterone were performed. Chronic heart failure due to myocardial infarction was associated with tissue-specific activation of cardiovascular aldosterone synthesis. In the mesenteric artery, enalapril significantly inhibited aldosterone production compared to untreated, chronic heart failure rats, and losartan lowered aldosterone production to that of sham rats. In myocardium, enalapril failed to significantly inhibit aldosterone production, and losartan significantly inhibited aldosterone production compared to untreated, chronic heart failure rats. These results provide the first evidence that long-term ACE inhibition therapy induces aldosterone escape in myocardium but not in mesenteric artery of chronic heart failure. The angiotensin II subtype 1 receptor blocker losartan tranquilized aldosterone levels in the cardiovascular tissues of chronic heart failure rats.
Background and Objective
Previous research has indicated that altered expression of microRNAs (miRNAs) is in connection with osteogenesis of human periodontal ligament‐derived stem cells (hPDLSCs). We investigated the mechanisms by which miR‐543 promotes osteogenic differentiation of hPDLSCs.
Material and Methods
First, the expression of miR‐543 in hPDLSCs cultured with or without an osteogenic inductive cocktail was explored. Then, the function of miR‐543 during osteogenesis of hPDLSCs was investigated by overexpressing and inhibiting miR‐543. Next, 3 databases were used to predict target genes of miR‐543 and a luciferase report was used to validate the direct regulation of miR‐543 on the target gene. Further, a rescue experiment using co‐transfection of miR‐543 mimic and target mimic was performed to evaluate whether overexpressing the target gene could partly rescue the efficiency of overexpressing miR‐543 on osteogenesis in hPDLSCs.
Results
miR‐543 was upregulated during osteogenic differentiation of hPDLSCs. Functional experiments showed that overexpressing miR‐543 could enhance osteogenesis, while inhibiting miR‐543 resulted in reduced formation of mineralized nodules. The transducer of ERBB2, 2 (TOB2) was identified as a target gene of miR‐543 and luciferase report revealed that miR‐543 interacts directly with the 3′‐untranslated repeat sequence of TOB2 mRNA. Overexpression of miR‐543 inhibited the expression of TOB2 in both mRNA and protein levels while inhibiting miR‐543 increased. Furthermore, the rescue experiment confirmed the promotional role of miR‐543 TOB2 expression could be abrogated by overexpressing TOB2, which also had the effect of reducing osteogenic differentiation.
Conclusion
Our research confirmed that miR‐543 is a promoter of osteogenesis in hPDLSCs, acting by inhibiting its target gene TOB2, which suggests that miR‐543 may be a potential therapy for bone loss in periodontitis.
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