MicroRNA-27 attenuates pressure overload-Induced cardiac hypertrophy and dysfunction by targeting galectin-3

https://doi.org/10.1016/j.abb.2020.108405Get rights and content

Abstract

Cardiac hypertrophy is an adaptive response to hemodynamic stress to compensate for cardiac dysfunction. MicroRNAs can regulate cardiac function and play a vital role in the regulation of cardiac hypertrophy. In the current study, in vivo and vitro hypertrophy models are established to explore the role of miR-27b and to elucidate the underlying mechanism in cardiac hypertrophy. Expression of miR-27b was down-regulated in mice with cardiac hypertrophy. The cardiac function of the mice with cardiac hypertrophy could be restored with the overexpression of miR-27b, this is observed in terms of decreasing LVEDd, LVESd, and increasing LVFS, LVEF. This study also predicted and confirmed that galectin-3 is a target gene of miR-27b. Depletion of galectin-3 significantly attenuated hypertrophy of hearts in both in vitro and in vivo tests. In conclusion, MiR-27b be used to exert a protective role against cardiac dysfunction and hypertrophy by decreasing the expression level of galectin-3. The methodology suggested in this study provides a novel therapeutic strategy against cardiac hypertrophy.

Introduction

Cardiac hypertrophy is an adaptive response to hemodynamic stress to compensate for cardiac dysfunction with an increase in the cardiomyocyte size, enhanced protein synthesis, and a higher organization of the sarcomere [1,2]. Hypertrophic response occurs as a response to an increased workload causing ventricular wall stress. In this scenario, hypertrophic response balances the changes in wall stress to maintain cardiac output. Primarily, cardiac hypertrophy is broadly divided into pathological or physiological hypertrophy [3]. Physiological cardiac hypertrophy maintains normal cardiac function and exhibits enhanced pumping capacity when engaging in activities such as systematic athletic training [4,5]. On the other hand, pathological cardiac hypertrophy is identified by a decreased cardiac function, which eventually leads to contractile dysfunction, ventricular dilation, and heart failure [6,7].

MicroRNAs (miRNAs) are a class of small (20–23 nucleotide) endogenous non-coding RNAs. They are capable of regulating the translation or directly degrade their target genes by binding to the base pairing regions [[8], [9], [10]]. Due to the capability of regulating massive target genes, miRNAs play a crucial role in cell processes such as cellular differentiation, proliferation, apoptosis, and development. There has been increasing evidence demonstrating that miRNAs play a role in the regulation of cardiac functions and the progression of heart failure. For instance, miR-146a suppresses SUMO1 expression and induces cardiac dysfunction during maladaptive hypertrophy [11]. Besides, cardiac myocyte miR-29 promotes pathological remodeling of the heart through the activation of Wnt signaling [12]. Moreover, miR-206 mediates YAP-induced cardiac hypertrophy and survival [13]. Lastly, it has also been shown that microRNA-451 exacerbates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy in mice through the suppression of the LKB1/AMPK pathway [14]. Apart from these studies, there has not been further research focusing on the role of miR-27b in hypertrophy.

In the current study, in vivo and in vitro hypertrophic models are established to explore the role of miR-27b and its underlying mechanism. It was found that miR-27b exerts a protective role against cardiac dysfunction and hypertrophy by reducing the expression level of galectin-3. These findings provided a novel therapeutic strategy against cardiac hypertrophy potentially.

Section snippets

The establishment of cardiac hypertrophy model in mice

Male C57BL/6 mice (8–10 weeks) were anesthetized with 2% isoflurane and subjected to thoracotomy. This made it possible to establish the cardiac hypertrophy model using transverse aortic constriction (TAC) method. A 6.0 silk suture was placed across the aorta with a 26G blunt needle to yield the aorta constriction with 0.46 mm in diameter. Mice in the control group were treated using the same surgical process, however, without ligation. All the experimental procedures involving animals were

Down-regulation of miR-27b were observed in mice with cardiac hypertrophy

To establish a cardiac hypertrophy model in vitro, cardiomyocytes were treated with Ang II. In contrast to the normal cells, the immunofluorescence with α-SMA displayed larger size in cardiomyocytes that were treated with ang II (Fig. 1 A). The levels of ANP, BNP and β-MHC are always useful for evaluating the extent of myocardial hypertrophy and the level in which the AngII treatment group were identified to be elevated (Fig. 1 B). HE staining revealed that TAC treated hearts had a larger size

Discussion

MiR-27b is a member of the highly conserved miR-23-27-24 family. It is located in the intergenic region of chromosome 19, and involvement in the occurrence, invasion, and metastasis of many types of cancer is well documented. It does so by regulating the expression of target genes such as, FOXO1, BTG2, PHB, and other cancer-related genes. Moreover, it was shown that miR-27b inhibits Th2 differentiation and promotes proinflammatory Th1 autoimmune responses by suppressing BMI1 expression [15].

Funding

This study was supported by Key Projects of Zhejiang Provincial Administration of Traditional Chinese Medicine (No. 2018ZZ001)

References (31)

  • D. Ma et al.

    Inhibition of myocardial hypertrophy by magnesium isoglycyrrhizinate through the TLR4/NF-kappaB signaling pathway in mice

    Int. Immunopharm.

    (2018)
  • N. Frey et al.

    Cardiac hypertrophy: the good, the bad, and the ugly

    Annu. Rev. Physiol.

    (2003)
  • J. Heineke et al.

    Downregulation of cytoskeletal muscle LIM protein by nitric oxide: impact on cardiac myocyte hypertrophy

    Circulation

    (2003)
  • W. Grossman et al.

    Wall stress and patterns of hypertrophy in the human left ventricle

    J. Clin. Invest.

    (1975)
  • B.J. Maron et al.

    The heart of trained athletes: cardiac remodeling and the risks of sports, including sudden death

    Circulation

    (2006)
  • Cited by (0)

    View full text