MicroRNA Let-7i Negatively Regulates Cardiac Inflammation and Fibrosis

Abstract

Abstract-Angiotensin II stimulates fibroblast proliferation and substantially alters gene expression patterns leading to cardiac remodeling, but the mechanisms for such differences are unknown. MicroRNAs are a novel mechanism for gene expression regulation. Herein, we tested the miRNA and mRNA expression patterns in mouse heart using microarray assay and investigated their role in angiotensin II-induced cardiac remodeling. We found that let-7i was dynamically downregulated in angiotensin II-infused heart at day 3 and 7 and had the most targets that were mainly associated with cardiac inflammation and fibrosis. Overexpression or knockdown of let-7i in cultured cardiac fibroblasts demonstrated that let-7i played an inhibitory effect on the expression of its targets interleukin-6 and collagens. Furthermore, delivery of let-7i to mouse significantly inhibited angiotensin II-induced cardiac inflammation and fibrosis in a dose-dependent manner. Conversely, knockdown of let-7i aggravated this effect. Together, our results clearly demonstrate that let-7i acts as a novel negative regulator of angiotensin II-induced cardiac inflammation and fibrosis by suppressing the expression of interleukin-6 and multiple collagens in the heart and may represent a new potential therapeutic target for treating hypertensive cardiac fibrosis. (Hypertension. 2015;66:776-785.

Hypertension: Update 2017

“…All six 2015 Top Paper Award articles, [1][2][3][4][5][6] published in 2015 and selected in 2016, were highly accessed by readers and clearly novel and have important clinical implications. The 2015 award winning articles span a wide variety of topics.…”

Let-7i

“…More recently, multiple let-7 family members have been associated with cardiovascular pathologies either as drivers, mediators, or markers of cardiac hypertrophy, fibrosis, endothelial-to-mesenchymal transition, myocardial infarction, heart failure, dilated cardiomyopathy, and angiogenesis. 4 However, our knowledge of the role of let-7i in cardiac health and disease is limited, highlighting the importance of the study by Wang et al 2 Wang et al 2 report that the time-dependent downregulation of let-7i in cardiac tissue by Ang II is paralleled by an upregulation of interleukin-6 (IL-6) and collagens (Col1a2, Col3a1, Col4a1, and Col5a2), markers of cardiac inflammation, and fibrosis, respectively. Besides let-7i, only another let-7 family member, let-7g, was regulated by Ang II in cardiac tissue in vivo.…”

“…In vitro studies by Wang et al 2 show that let-7i is preferentially expressed in neonatal rat cardiac fibroblasts, and Ang II time dependently downregulates let-7i expression. Furthermore, they elegantly show that let-7i mimics attenuate and let-7i inhibitors exacerbate Ang II-induced upregulation of IL-6 and collagens, although let-7i mimics do not completely abolish Ang II-induced effects (Figure).…”

“…This combinatorial effect may explain why even modest regulation of particular target mRNAs by a specific microRNA can still have strong phenotypic effects as evidenced in in vivo experiments in the accompanying article. Furthermore, through a combination of in silico and mRNA fusion reporter assays, Wang et al 2 show that let-7i has a direct effect on the mRNAs of IL-6 and collagens. Although direct experimental evidence through Argonaute cross-linking immunoprecipitation and its plethora of analytic modifications is needed to prove a physical interaction between let-7i and mRNAs of IL-6 and collagens mRNAs, these results strongly suggest that indeed these mRNAs are let-7i targets.…”

“…Although obviously not proposed as a therapeutic approach but still critically relevant to prove the role of let-7i in cardiac injury, the authors pharmacologically downregulated let-7i in vivo to show that indeed the reduction of let-7i exacerbates Ang II-mediated cardiac inflammation and fibrosis without significant effects on blood pressure or cardiac hypertrophy and function. 2 These complementary experimental approaches make the case that let-7i is a mediator of Ang II-induced cardiac inflammation and fibrosis in vivo (Figure).…”