An emerging role for the miR-26 family in cardiovascular disease

Abstract

In response to acute myocardial infarction (MI), a complex series of cellular and molecular signaling events orchestrate the myocardial remodeling that ensues weeks to months after injury. Clinical, epidemiological, and pathological studies demonstrate that inadequate or impaired angiogenesis after myocardial injury is often associated with decreased left ventricular (LV) function and clinical outcomes. The microRNA family, miR-26, plays diverse roles in regulating key aspects of cellular growth, development, and activation. Recent evidence supports a central role for the miR-26 family in cardiovascular disease by controlling critical signaling pathways, such as BMP/SMAD1 signaling, and targets relevant to endothelial cell growth, angiogenesis, and LV function post-MI. Emerging studies of the miR-26 family in other cell types including vascular smooth muscle cells, cardiac fibroblasts, and cardiomyocytes suggest that miR-26 may bear important implications for a range of cardiovascular repair mechanisms. This review examines the current knowledge of the miR-26 family's role in key cell types that critically control cardiovascular disease under pathological and physiological stimuli.

Figure 1. MiR-26 family members and their genomic locations

(A) MiR-26a-1 is localized on chromosome 3, miR-26a-2 is localized on chromosome 12, and miR-26b is localized on chromosome 2. The mature miRNA for miR-26a-1 and miR-26a-2 have the same sequence which differ by 2 nucleotides from the mature miR-26b sequence. (B) Mature sequences of miR-26 family members that arise from the 5′ arm of the precursors. (C) Mature sequences of miR-26 family members that arise from the 3′ arm of the precursors.

Figure 2. Mechanism leading to increased endothelial cell growth and angiogenesis

MiR-26a expression is decreased by pro-angiogenic stimuli such as VEGF, bFGF and TNF-α in endothelial cells (ECs). MiR-26a inhibits SMAD1 by binding to its 3’-UTR, an effect that decreases ID1 and increases the expression of cell growth arrest proteins p21^WAF1/CIP1 and p27 resulting in decreased endothelial cell growth and angiogenesis. Neutralization of miR-26a using LNA-antimiR-26a relieves the miR-26a-mediated repression of BMP/SMAD1 signaling and increases EC growth and angiogenesis.

Figure 3. Inhibition of miR-26a increases angiogenesis, decreases infarct size, and improves LV function and myocardial fibrosis in a mouse model of acute MI

After a single tail vein injection in mice of LNA-anti-miR-26a (MiR-26a_i) (24mg/kg) or scrambled non-specific control LNA-antimiRs (NS_i) (n = 11–12 per group) on day 0, mice underwent acute myocardial infarction consisting of 45 minutes of ischemia and reperfusion of the left anterior descending artery (LAD) and infusion of fluorescent microbubbles on day 1. (A) TTC staining (top) demonstrates areas of infarct in the left ventricle. Myocardial infarction size was normalized to the area at risk. *P < 0.05 compared to NS_i Angiogenesis was quantified by CD31 (B) or isolectin staining (C) in sections from the entire left ventricle on day 2. *P < 0.05 compared to NS_i Scale bars, 500μm (left) and 250μm (right) in (B) and 100μm (left) and 50μm (right) in (C). (D) Left ventricular ejection fraction was measured by echocardiography on days 2 and 8. *P < 0.05 compared to NS_i (E) Fibrosis was measured by Masson-Trichrome staining on day 8. *P < 0.05 compared to NS_i. Scale bar 250μm.