Mitochondrial Regulation of micro RNA synthesis in Vascular Smooth Muscle Cell Proliferation and Migration

Mitochondria can play an important role in the control of vascular smooth muscle (VSM) cell proliferation and Migration1. The mechanisms responsible for this control are not fully understood. Recently a small number of miRNA have been reported to be present within the mitochondrial matrix. These studies suggest that mitochondrial miRNA or nuclear miRNA which regulate mitochondrial function could be responsible for the mitochondrial mediated control of VSM Cell proliferation and migration2. Indeed several miRNAs have been found to play an important role in switching VSM cells from a contractile to a synthetic phenotype including miR-145. Moreover, miR-378 and miR-761 have been associated with the activation of VSM cell pro-mitogenic signalling pathways3 and regulation of a number of mitochondrial functions including fission4. Thus the aim of the current study was to investigate the potential role of mitochondria in regulating miRNA expression and possible influences on VSM cell proliferation and migration.

Cells were cultured in 10% foetal calf serum for 21 days to produce the phenotypically changed cells whereas mitochondrial-depleted cells were cultured in 10% foetal calf serum containing 50ng/ml Ethidium Bromide and supplemented with 50μg/ml Uri dine and 1mM sodium pyruvate.

Blocking mitochondrial fission using DRP-1 inhibitor MDivi-1 attenuated VSM Cell proliferation in response to PDGF by two folds (p < 0.05). Furthermore, addition of MDivi-1 resulted in a deactivation of Akt-mTOR signalling pathway followed by a cell cycle arrest at G2/M phase (p < 0.05) and a reduction in ROS level by almost one fold (p < 0.05). MiRNA profiling revealed a significant role for miR-21 and miR-145 in these processes, since miR-21 was up-regulated and miR-145 is down-regulated following stimulation with PDGF. In concordance with the effects of SMC proliferation, treatment with MDivi-1 attenuated the up-regulation of miR-21 and down regulation of miR-145 and restored their expression levels to the normal level seen in the differentiated cells.

These data highlight the potential important role of mitochondria in regulating the expression of miRNAs involved in the initiation of vascular smooth muscle cell proliferation and highlight a link between miRNA expression, mitochondrial function and VSM cell proliferation and migration.

1. Zuhair Al-Sulti, David Kingsmore, Paul Coats. Mitochondrial-dependent Signalling in Vascular Smooth Muscle Cell Proliferation. Heart (2014); 100:A97.

2. Barrey E, Saint-Auret G, Bonnamy B, Damas D, Boyer O, Gidrol X. Pre-microRNA and mature microRNA in human mitochondria. PLoS ONE 6 (2011): e20220.

3. Claudio Iaconetti, Clarice Gareri, Alberto Polimeni and Ciro Indolfi. Non-Coding RNAs: The “Dark Matter” of Cardiovascular Pathophysiology. Int. J. Mol. Sci. 14 (2013) 19987-20018.

4. Bo Long, Kun Wang, Iram Murtaza, Jing-Ying Xiao, Yuan-Yuan Fana, Cui-Yun Liu, Wen-Hui Li, Zheng Cheng, PeiFeng Li. miR-761 regulates the mitochondrial network by targeting mitochondrial fission factor. Free Radical Biology and Medicine 65 (2013) 371–379.