Abstract
Angiotensin II (Ang II) plays a major role in the pathogenesis of cardiac fibrosis in hypertension. It is known that Ang II induces TGF-β1 expression. How transcription mediates Ang II-induced TGF-β1 expression, as well as its contribution to cardiac fibrosis, is unknown. We studied the role of Krüppel-like family transcription factors in Ang II-induced myofibroblast formation. We found that among the Krüppel-like family members, Krüppel-like factor 4 (Klf4) was the highest expressed form in isolated cardiac fibroblasts after Ang II treatment. Klf4 increased expression of α-SMA and collagen, as well as increased myofibroblast formation. ChIP assays showed that Klf4 specifically bound to the TGF-β1 promoter. Deletion and mutagenesis analysis showed that the sites at −184∼−180 bp and −45∼−41 bp in the TGF-β1 promoter were responsible for Klf4 transactivation of the TGF-β1 promoter. Our studies demonstrate that Klf4 plays a pivotal role in Ang II-induced cardiac myofibroblast differentiation and collagen synthesis through transcriptional upregulation of TGF-β1.
Highlights
A growing body of evidence supports that the renin-angiotensin system is a critical mediator of cardiac remodeling and dysfunction in various cardiovascular diseases [1,2]
To determine whether Kruppel-like factors (Klfs) family members are involved in angiotensin II (Ang II)-induced cardiac fibrosis, quantitative RT-PCR analyses were performed to examine the expression of Klf1-17 in hearts at day 7 after Ang II infusion
The dynamic expression of Kruppel-like factor 4 (Klf4) in cardiac fibroblasts may be involved in Ang II-induced cardiac remodeling
Summary
A growing body of evidence supports that the renin-angiotensin system is a critical mediator of cardiac remodeling and dysfunction in various cardiovascular diseases [1,2]. Under angiotensin II (Ang II) activated conditions, morphological fibroblast-to-myofibroblast differentiation enhances. Myofibroblast is a characteristic of tissue repair, remodeling and fibrosis, commonly identified by expression of a-smooth muscle actin (a-SMA) [3]. In hypertension the emergence and persistence of myofibroblast is thought to express a set of fibrotic genes that contribute to a progressive profibrotic state [4]. It is accepted that Ang II induces cardiac fibrosis by stimulating transforming growth factor-b1 (TGF-b1), becoming an essential molecule in fibroblast-to-myofibroblast differentiation [5]. TGF-b1, after binding to its receptors, activates downstream mediators that lead to classic Smads signaling and exerts its fibrotic effects by promoting myofibroblast differentiation as well as excessive synthesis and deposition of the extracellular matrix (ECM) [6,7]
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