永井 良三

ビグアナイドは近年糖尿病患者への効果が再評価されており, わが国でも使用頻度が増加してきている. しかし, 重大な副作用として乳酸アシドーシスが知られている. 症例は77歳, 男性, 腎機能が低下した糖尿病患者に塩酸ブホルミン増量後に著明な乳酸アシドーシスとショック状態を呈して当院へ救急搬送された. 入院後も複数臓器の虚血症状が続発し, 治療に難渋した.

Alteration in the differentiated state of smooth muscle cells (SMCs) is known to be integral to vascular development and the pathogenesis of vascular disease. However, it is still largely unknown how environmental cues translate into transcriptional control of SMC genes. We found that deltaEF1 is upregulated during SMC differentiation and selectively transactivates the promoters of SMC differentiation marker genes, SM alpha-actin and SM myosin heavy chain (SM-MHC). DeltaEF1 physically interacts with SRF and Smad3, resulting in a synergistic activation of SM alpha-actin promoter. Chromatin immunoprecipitation assays and knockdown experiments showed that deltaEF1 is involved in the control of the SMC differentiation programs induced by TGF-beta signaling. Overexpression of deltaEF1 inhibited neointima formation and promoted SMC differentiation, whereas heterozygous deltaEF1 knockout mice exhibited exaggerated neointima formation. It thus appears deltaEF1 mediates SMC differentiation via interaction with SRF and Smad3 during development and in vascular disease.