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