Branched-chain amino acid transaminase 1–mediated pathway promotes proline-dependent collagen production in cardiac myofibroblasts

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Abstract

Myofibroblasts are the cells responsible for collagen production, leading to tissue fibrosis. Because 20.5% of the total amino acids in collagen are proline, myofibroblasts must acquire a well-developed proline-producing mechanism during their differentiation. However, the detailed mechanism for myofibroblasts to acquire and keep the developed proline biosynthesis machinery remains obscure. Here, we show that branched-chain amino acid (BCAA) transaminase 1 (Bcat1) was upregulated in a substantial subset of Periostin (Postn)-expressing protomyofibroblast-like fibroblasts, which are transitional cells en route to fully differentiated myofibroblasts, as well as in myofibroblasts in the fibrotic hearts and livers of mice and humans, and promoted the production of proline. The production of BCAA by BCAT1 promoted SMAD3 phosphorylation via HDAC5 phosphorylation at Ser488, thereby enhancing SMAD3-dependent transcription of the proline biosynthesis–related genes Aldh18a1, Pycr1, and Eprs in protomyofibroblast-like fibroblasts and myofibroblasts. In BCAT1-deficient mice, expression of proline biosynthesis–related genes was significantly attenuated in their hearts after myocardial infarction (MI), resulting in decreased cardiac fibrosis. Moreover, mice with MI that were treated with a BCAT1 inhibitor had reduced cardiac fibrosis. Our results identified a BCAT1-mediated pathway that promoted collagen production via proline biosynthesis regulation in protomyofibroblast-like fibroblasts and myofibroblasts, which may provide a therapeutic target for cardiac fibrosis.

Authors

Noburo Takizawa, Takanori Hironaka, Hayato Watanabe, Haruna Suetsugu, Keisuke Yoshioka, Yuma Horii, Yuri Nagata, Hiroaki Matoba, Hidetaka Kosako, Kenji Hamase, Go Hirai, Michio Nakaya