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OBJECTIVES: Stretch affects vascular smooth muscle cell proliferation and apoptosis, and several responsible genes have been proposed. We tested whether the expression of microRNA 21 (miR-21) is modulated by stretch and is involved in stretch-induced proliferation and apoptosis of human aortic smooth muscle cells (HASMCs). METHODS AND RESULTS: RT-PCR revealed that elevated stretch (16% elongation, 1 Hz) increased miR-21 expression in cultured HASMCs, and moderate stretch (10% elongation, 1 Hz) decreased the expression. BrdU incorporation assay and cell counting showed miR-21 involved in the proliferation of HASMCs mediated by stretch, likely by regulating the expression of p27 and phosphorylated retinoblastoma protein (p-Rb). FACS analysis revealed that the complex of miR-21 and programmed cell death protein 4 (PDCD4) participated in regulating apoptosis with stretch. Stretch increased the expression of primary miR-21 and pre-miR-21 in HASMCs. Electrophoretic mobility shift assay (EMSA) demonstrated that stretch increased NF-κB and AP-1 activities in HASMCs, and blockade of AP-1 activity by c-jun siRNA significantly suppressed stretch-induced miR-21 expression. CONCLUSIONS: Cyclic stretch modulates miR-21 expression in cultured HASMCs, and miR-21 plays important roles in regulating proliferation and apoptosis mediated by stretch. Stretch upregulates miR-21 expression at least in part at the transcription level and AP-1 is essential for stretch-induced miR-21 expression.