MicroRNA-410-5p exacerbates high-fat diet-induced cardiac remodeling in mice in an endocrine fashion

Tong Zou,Xue Yu,Li Xu,Lan-Qing Ma,Mei Zhu,Jiefu Yang,Fei Xiao,Yi-Cheng Ma,Jian-Zeng Dong

doi:10.1038/s41598-018-26646-4

Abstract

Metabolic disorders, such as obesity and type 2 diabetes, are associated with an increased risk of cardiomyopathy. To date, microRNA (miRNAs) functions in cardiac remodeling induced by obesity remain to be elucidated. We found that rats fed a high fat diet (HFD) manifested cardiac fibrosis and LV dysfunction. In the heart of rats fed HFD, the phosphorylation levels of Smad 2 and the expression of fibrotic genes, such as connective tissue growth factor, collagen-1α1 (Col1α1), Col3α1, and Col4α1, were up-regulated, which accompanied by an increase in Smad 7 protein levels, but not its mRNA levels. Using miRNA microarray analysis, we showed that the miRNA miR-410-5p inhibited the protein expression of Smad 7, thus increasing the phosphorylation levels of Smad 2. Overexpression of miR-410-5p promoted cardiac fibrosis in rats fed normal diet, whereas inhibition of miR-410-5p by way of miR-410-5p antimiR suppressed cardiac fibrosis in rats fed HFD. Finally, our data revealed that miR-410-5p from the kidney and adipose tissues was probably transferred to heart to induce cardiac fibrosis. Taken together, our study characterizes an endocrine mechanism in which adipose- or kidney-derived circulating miR-410-5p regulates metabolic disorders-mediated cardiac remodeling by activating the TGFβ/Smad signaling in heart.

Highlights

Obesity is a global health problem contributing to development of various metabolic-related disease states, including type 2 diabetes and dyslipidemia
We found that high fat diet (HFD) notably up-regulated the mRNA expressions of fibrotic markers, such as connective tissue growth factor (CTGF), collagen-1α1 (Col1α1), Col3α1, and Col4α1 (Fig. 1b)
We have demonstrated that miR-410-5p is involved in cardiac fibrosis, an important part of cardiac remodeling, in rats fed HFD. miR-410-5p probably derived from the kidney or adipose tissues negatively regulates the protein expression of Smad-7 in the heart through direct base pairing to the 3′ UTR of its mRNA (Fig. 8)

Summary

Introduction

Obesity is a global health problem contributing to development of various metabolic-related disease states, including type 2 diabetes and dyslipidemia. Transforming growth factor β (TGFβ) signaling pathway plays a major role in the development of cardiac fibrosis in rats with obesity, diabetes, and hypertension[6,8,9]. The activated Smad 2/3 bind to the Co-Smad, Smad 4 This trimeric complex is translocated from cytoplasm into nuclei to regulate transcription of fibrotic genes[10,11]. Inhibitory Smads (I-Samds), such as Smad 7, antagonizes the TGFβ signaling by blocking the association of the activated Smad 2/3 with Smad 4 or competitively inhibiting R-Smad phosphorylation by TGFβRI. It has been shown that the expression of TGFβ1 and the phosphorylated levels of Smad 2/3 are significantly up-regulated in myocardial tissues of mice or rats fed high fat diet (HFD)[6,8]. Aubin et al have reported that the amount of the TGFβ1 transcript is not altered in rats fed HFD13

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Results

Conclusion