miR-21 Normalizes Vascular Smooth Muscle Proliferation and Improves Coronary Collateral Growth in Metabolic Syndrome
Inadequate cell proliferation is considered a major causative factor for impaired coronary collateral growth (CCG). Proangiogenic growth factors (GFs) stimulate cell proliferation, but their administration does not promote CCG in patients. These GFs are increased in patients with metabolic syndrome and in animal models, where CCG is impaired. Here, we investigated whether excessive cell proliferation underlies impaired CCG in metabolic syndrome. Normal [Sprague-Dawley (SD)] and metabolic syndrome [James C. Russell (JCR)] rats underwent repetitive ischemia (RI; transient, repetitive coronary artery occlusion and myocardial ischemia). We have shown that CCG was maximal at d 9 of RI in SD rats but did not occur in JCR rats. The increase in cell proliferation (PCNA, Ki-67, cyclin A, phospho- cdc2, p21Waf, p27Kip) was transient (∼4-fold, d 3 RI) in SD rats but greater and sustained in JCR rats (∼8- to 6-fold, d 3-9 RI). In JCR rats, this was associated with increased and sustained miR-21 expression and accumulation of proliferating synthetic vascular smooth muscle cells in the lumen of small arterioles, which failed to undergo outward expansion. Administration of anti-miR-21 blocked RI-induced cell proliferation and significantly improved CCG in JCR rats (∼60%). miR-21-dependent excessive cell proliferation in the later stages of collateral remodeling correlates with impaired CCG in metabolic syndrome.
Hutcheson, R., Chaplin, J., Hutcheson, B., Borthwick, F., Proctor, S., Gebb, S., et al. (2014). miR-21 normalizes vascular smooth muscle proliferation and improves coronary collateral growth in metabolic syndrome. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 28(9), 4088-4099. doi:10.1096/fj.14-251223
Originally published in FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.14-251223