The relationship between miRNA-26b and connective tissue growth factor in rat models of aortic banding and debanding

Abstract

Background/Aims: Connective tissue growth factor (CTGF) is a profibrotic factor implicated in pressure overload-mediated myocardial fibrosis. In this study, we determined the role of predicted CTGF-targeting microRNAs (miRNAs) in rat models of aortic stenosis and reverse cardiac remodeling. Methods: Minimally invasive ascending aortic banding was performed in 24 7-week-old male Sprague-Dawley rats, which were divided into three groups. The banding group consisted of eight rats that were sacrificed immediately after 6 weeks of aortic constriction. The debanding group underwent aortic constriction for 4 weeks and was sacrificed 2 weeks after band removal. The third group underwent sham surgery. We investigated the expression of CTGF, transforming growth factor-β1 (TGFβ1), and matrix metalloproteinase-2 using ELISA and examined miRNA-26b, miRNA-133a, and miRNA-19b as predicted CTGF-targeting miRNAs based on miRNA databases in 24-hour TGFβ-stimulated and TG-Fβ-washed fibroblasts and myocardial tissues from all subjects. Results: CTGF was elevated in 24-hour TGFβ-stimulated fibroblasts and decreased in 24-hour TGFβ-washed fibroblasts. miRNA-26b was significantly increased in TGFβ-washed fibroblasts compared with control and TGFβ-stimulated fibroblasts (p < 0.05). CTGF expression was significantly higher in the banding group than that in the sham and debanding groups. The relative expression levels of miRNA-26b were higher in the debanding group than in the banding group. Conclusions: The results of our study using models of aortic banding and debanding suggested that miRNA-26b was significantly increased after aortic debanding. The in vitro model yielded the same results: miRNA-26b was upregulated after removal of TGFβ from fibroblasts.

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery

“…Although technically challenging and with not insignificant mortality rates [ 66 ], rats can undergo aortic de-banding to investigate the antiremodeling effects of LV unloading which are accomplished by aortic valve replacement or ventricular assist devices in the clinical setting. After 6 to 9 weeks of aortic banding, LV unloading (i.e., de-banding) promotes the regression of hypertrophy and the recovery of diastolic function [ 73 ], supported by the restoration of mitochondrial energetics [ 74 ] and a reduction of pro-fibrotic factors [ 67 ]. Interestingly, aortic banding triggers significant systo-diastolic impairment and activation of prohypertrophic and profibrotic pathways also in the RV, which persist partially altered even after de-banding [ 63 ].…”

“…Surgical hypertensive models have been utilized to test reverse remodeling pharmacological strategies to treat HF, such as angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists [ 12 , 68 , 137 ] and, more recently, to guide targeted anti-fibrotic therapeutic molecules [ 67 ]. Interesting insights into the most appropriate timing to plan aortic valve replacement in the setting of asymptomatic aortic stenosis may be derived from these models in the future.…”