MicroRNA-21 Blocks Abdominal Aortic Aneurysm Development and Nicotine-Augmented Expansion

Abstract

Identification and treatment of abdominal aortic aneurysm (AAA) remains among the most prominent challenges in vascular medicine. MicroRNAs are crucial regulators of cardiovascular pathology and represent possible targets for the inhibition of AAA expansion. We identified microRNA-21 (miR-21) as a key modulator of proliferation and apoptosis of vascular wall smooth muscle cells during development of AAA in two established murine models. In both models (AAA induced by porcine pancreatic elastase or infusion of angiotensin II), miR-21 expression increased as AAA developed. Lentiviral overexpression of miR-21 induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion. miR-21 overexpression substantially decreased expression of the phosphatase and tensin homolog (PTEN) protein, leading to increased phosphorylation and activation of AKT, a component of a pro-proliferative and antiapoptotic pathway. Systemic injection of a locked nucleic acid–modified antagomir targeting miR-21 diminished the pro-proliferative impact of down-regulated PTEN, leading to a marked increase in the size of AAA. Similar results were seen in mice with AAA augmented by nicotine and in human aortic tissue samples from patients undergoing surgical repair of AAA (with more pronounced effects observed in smokers). Modulation of miR-21 expression shows potential as a new therapeutic option to limit AAA expansion and vascular disease progression.

Role of miR-195 in Aortic Aneurysmal Disease

“…4 Additionally, miR-21 was implicated as a modulator of proliferation and apoptosis of vascular SMCs during development of AAA. 28 The age-related increase of miR-29 expression was proposed to render the aorta susceptible to aneurysm development, whereas inhibition of miR-29b, by treatment with LNA-antimiR-29b, reduced aortic dilation after Ang II infusion in aged mice. 5 Similar results were obtained in a model of genetically induced aneurysms in Fibulin-4 R/R mice.…”

Recent Developments in Cardiovascular Genetics and Genomics

“…12,84,[92][93][94][95][96][97] Similarly, a large number of microRNAs are implicated in vascular phenotypes ranging from pulmonary hypertension to aortic aneurysm. 77,79,[98][99][100][101][102][103][104][105][106][107] For example, microRNA-145 was recently shown to be upregulated in the lung tissue of patients with pulmonary hypertension and might be a contributing factor to the pathogenesis of pulmonary hypertension. 108 MicroRNA-10, microRNA-15a, microRNA-16, microRNA-26a, microR-NA-223, and microRNA-663 are involved in angiogenesis and regulate vascular smooth muscle and endothelial cell phenotypes.…”

Unique Phenotypes of Endothelial Cells in Developing Arteries: A Lesson from the Ductus Arteriosus

“…For instance, a wire injury model is used for studying pathology of endothelial injury/dysfunction [5]; low-density lipoprotein receptor-deicient mice [6] and apolipoprotein E-deicient mice [7] are commonly used as atherosclerosis models; calcium chloride [8], elastase [9], angiotensin II [10], or microRNA-21 [11] are infused to create an abdominal aortic aneurysms model. Developing a disease model occupies a great deal of scientiic indings on pathophysiology, and so the existing models should always open to be reined.…”