miR-128-3p is a novel regulator of vascular smooth muscle cell phenotypic switch and vascular diseases

Rationale: microRNAs (miRNAs) are small non-coding RNAs that modulate gene expression by negatively regulating translation of target genes. While the role of several miRNAs in vascular smooth muscle cells (VSMCs) has been extensively characterized, the function of miR-128 is still unknown. Objective: To determine if miR-128 modulates VSMC phenotype, and to define the underlying mechanisms. Methods and results: We screened for miRNAs regulated by DNA methylation in VSMCs, and among those we selected miR-128. MiR-128 expression was then measured in tissues, isolated cells, and pathological murine and human vascular specimens. Through gain- and loss-of-function approaches, we determined that miR-128 affects VSMC proliferation, migration, and differentiation. These effects depend upon epigenetic regulation of key VSMC differentiation genes; Kruppel-like factor 4 was found to be a target of miR-128. In vivo lentiviral delivery of miR-128 prevented intimal hyperplasia in a mouse model of carotid restenosis. Conclusion: miR-128 is a critical modulator of VSMCs and is regulated by epigenetic modifications upon stress. Its modulation in the context of disease could be exploited for therapeutic purposes.