Our previous study showed that epigallocatechin‐3‐gallate (EGCG) inhibition of human aortic smooth muscle cell (HASMC) proliferation might be mediated via upregulation of mitofusin 2 (Mfn‐2). Studies on the mechanism of Mfn‐2 inhibition of cell proliferation have mainly focused on downstream signaling. However, it is still not clear how upstream signaling molecules regulate Mfn‐2. The promoter region of the Mfn‐2 gene contains cis‐acting elements of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) and estrogen‐related receptor‐α (ERR‐α), suggesting a possible link between EGCG, Mfn‐2, and PGC‐1α/ERR‐α. However, the effect of EGCG on PGC‐1α/ERR‐α remains unknown. In this study, we investigated the role of PGC‐1α/ERR‐α in the regulation of Mfn‐2 induced by EGCG and assessed the underlying mechanisms. The effects of EGCG on cell proliferation of cultured HASMCs were observed by a cell counting kit‐8 (CCK8) and 5‐ethynyl‐2‐deoxyuridine (EdU) incorporation assay. Mfn‐2, PGC‐1α, and ERR‐α gene and protein levels were determined by quantitative real‐time polymerase chain reaction (PCR) and Western blot analysis. PGC‐1α gene‐silencing (PGC‐1α small interfering RNA [siRNA]) was achieved by RNA interference and Mfn‐2 promoter and peroxisome proliferator response element (PPRE) functional activity was achieved by a luciferase transfection assay. The results showed that the ERR‐α‐specific antagonist XCT‐790 and PGC‐1α siRNA decreased the expression of Mfn‐2, thus antagonizing the inhibition of HASMC proliferation induced by EGCG. EGCG enhanced Mfn‐2 promoter (−352 to 459) activity, while XCT‐790 and PGC‐1α siRNA abrogated this effect. PGC‐1α stimulating Mfn‐2 expression was dependent on intact ERR‐α binding in the Mfn‐2 promoter. The transcriptional effect of PGC‐1α on the Mfn‐2 promoter required the integrity of the −432 to 459 region and supported that Mfn‐2 was a key target gene of PGC‐1α. These results imply that PGC‐1α/ERR‐α played important physiological roles in inhibiting the proliferation of HASMCs by modulating Mfn‐2 gene expression. Hence, EGCG regulated Mfn‐2 expression likely through the PGC‐1α/ERR‐α pathway.
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