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Angiotensin II regulates microRNA expression

Pia Lindgren Jeppesen


The angiotensin II type 1 receptor (AT1R) is a key regulator of blood pressure and cardiac contractility. The AT1R is profoundly involved in development of cardiovascular disease as illustrated by the widespread clinical use of AT1R blockers (ARBs). Since several microRNAs (miRNAs) have been implicated in cardiovascular disease, we asked whether miRNAs might be regulated by AT1R signaling in vitro. We first performed global miRNA microarray analysis of angiotensin II (Ang II)-mediated miRNA regulation in HEK293N cells over-expressing the AT1R, followed by verification with quantitative real time PCR in HEK293N cells and primary cultures of cardiac myocytes and fibroblasts. These experiments revealed that several candidate miRNAs (miR-29b, -129-3p, -132, and -212) were up-regulated by Ang II. We also showed that this Ang II-mediated regulation of miRNAs in HEK293N and fibroblasts depends on the Gαq/11 pathway with ERK1/2 as a central signaling molecule. 

To examine the in vivo miRNA regulation by Ang II signaling, we infused Ang II in the left femoral vein in adult Sprague-Dawley rats. All candidate miRNAs except miR-29b were significantly up-regulated in rat aortas after chronic Ang II infusion. In addition miR-7 was also upregulated. We extended these findings to human internal mammary arteries (IMA). We examined the expression of all candidate miRNAs in arteries from 16 patients treated with ARBs versus an age- and gender-matched control group. Remarkably, all candidate miRNAs, except miR-29b, showed a tendency for down-regulation with significance for miR-7 in patients treated with ARBs.  

Type 2 diabetes is associated with an increased risk of cardiovascular disease. Since treatment of diabetic patients with ARBs reduces the risk of cardiovascular complications, we speculated if miRNAs could be a molecular link in diabetes and cardiovascular disease. We found that miR-17 was up-regulated in rats infused with Ang II and showed tendency for down-regulation in patients treated with ARBs. In addition, miR-17 was up-regulated in arteries from diabetic men compared to an age -matched control group. Alterations in miR-17 expression values may be a common pathway for effects of diabetes and Ang II on the arterial wall. As such, changes in miR-17 expression may be part of the explanation for beneficial effects of AT1R blockade in patients with type II diabetes.  

We identified that miRNAs may be involved in Ang II-mediated cardiovascular biology and disease, and that ARBs affect the miRNA expression profile. This is important since recent advances in miRNA therapeutics are directed to work on the expression of miRNAs that contribute to disease. However, a greater understanding of the miRNA-mediated silencing of gene expression is needed before miRNA technologies may be applied in the clinic.