The matrix protease ADAMTS1 is transcriptionally activated by KLF6 and contributes to cardiac fibrosis in non-ischemic cardiomyopathy

Aims

Aberrant cardiac fibrosis, defined as excessive production and deposition of extracellular matrix (ECM), is mediated by myofibroblasts. ECM-producing myofibroblasts are primarily derived from resident fibroblasts during cardiac fibrosis. The mechanism underlying fibroblast-myofibroblast transition is not fully understood.

Methods

Cardiac fibrosis was induced by transverse aortic constriction (TAC) or by angiotensin II (Ang II) infusion in C57B6/j mice. Cellular transcriptome was evaluated by RNA-seq and CUT&Tag-seq.

Results

Integrated transcriptomic screening revealed that a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) was a novel transcriptional target for Kruppel-like factor 6 (KLF6) in cardiac fibroblasts. Treatment with either TGF-β or Ang II up-regulated ADAMTS1 expression. KLF6 knockdown attenuated whereas KLF6 over-expression enhanced ADAMTS1 induction. ChIP assay and reporter assay showed that KLF6 was recruited to the ADAMTS1 promoter to activate its transcription. Consistently, ADAMTS1 knockdown suppressed fibroblast-myofibroblast transition in vitro. Importantly, myofibroblast-specific ADAMTS1 depletion attenuated cardiac fibrosis and normalized heart function in mice.

Significance

In conclusion, our data demonstrate that ADAMTS1, as a downstream target of KLF6, contributes to cardiac fibrosis by regulating fibroblast-myofibroblast transition.