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MicroRNA-21 deteriorates left ventricular reverse remodeling by promoting cardiac fibrosis in non-ischemic cardiomyopathy
Authors : K Watanabe (Yamagata,JP), T Narumi (Yamagata,JP), T Watanabe (Yamagata,JP), T Aono (Yamagata,JP), J Goto (Yamagata,JP), T Sugai (Yamagata,JP), T Toshima (Yamagata,JP), S Kato (Yamagata,JP), H Tamura (Yamagata,JP), S Nishiyama (Yamagata,JP), H Takahashi (Yamagata,JP), T Arimoto (Yamagata,JP), T Shishido (Yamagata,JP), M Watanabe (Yamagata,JP)
K. Watanabe1
,
T. Narumi1
,
T. Watanabe1
,
T. Aono1
,
J. Goto1
,
T. Sugai1
,
T. Toshima1
,
S. Kato1
,
H. Tamura1
,
S. Nishiyama1
,
H. Takahashi1
,
T. Arimoto1
,
T. Shishido1
,
M. Watanabe1
,
1Yamagata University, Department of Cardiology, Pulmonology, and Nephrology - Yamagata - Japan
,
Background: Left ventricular reverse remodeling (LVRR) contributes to better outcomes in patients with non-ischemic cardiomyopathy (NICM). It is reported that LVRR is associated with progression of cardiac fibrosis. MicroRNAs (miRs) have emerged as powerful regulators of post-transcriptional gene expression. We focused on miR-21, which plays a key role in pathogenesis of fibrosis in multiple organs. The aim of this study was to clarify the effect of miR-21 on cardiac fibrosis and LVRR in patients with NICM.
Methods: We measured plasma miR-21 levels in 16 patients with NICM. LVRR was defined as increased LVEF by ≥10% and decreased LV end-diastolic diameter index by ≥10% from baseline data after optimal medication treatment at 1-year of follow-up. Further, we examined miR-21 expression and its potential role in cardiac fibrosis induced by transverse aortic constriction (TAC) in mice and angiotensin II (Ang II) stimulation in neonatal rat cardiomyocytes (NRCMs).
Results: There were 12 patients without LVRR and 4 patients with LVRR. Plasma miR-21 levels were significantly higher in patients without LVRR compared with those with LVRR. In TAC mice heart, miR-21 levels were significantly increased and programmed cell death 4 (PDCD4), a main target of miR-21, was decreased. In vitro, miR-21 levels were significantly increased and its upstream transcriptional factor, activator protein 1 (AP-1), was activated by Ang II stimulation in NRCMs. After transfection of miR-21 specific inhibitor, PDCD4 levels were upregulated. Furthermore, AP-1 activity, expression of collagen type I, and α-smooth muscle actin levels were significantly decreased after miR-21 inhibition.
Conclusions: These findings suggested that miR-21/PDCD4/AP-1 feedback loop pathway was involved in LVRR in patients with NICM by promoting cardiac fibrosis. MiR-21 can be the therapeutic target in NICM.