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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
The zinc-finger transcription factor KLF6 regulates cardiac fibrosis
Nan Li1, Yujia Xue1, Chenghao Zhu2
1Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Human Anatomy, Nanjing Medical University, Nanjing, China.
Insights
Kruppel-like factor 6 (KLF6) drives cardiac fibrosis by promoting fibroblast-to-myofibroblast transition. Depleting KLF6 in myofibroblasts improved heart function in mouse models of heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Fibrosis Research
Background:
- Heart failure (HF) is a major cause of cardiovascular morbidity and mortality.
- Cardiac fibrosis, the excessive accumulation of extracellular matrix in the heart, is a hallmark of HF, leading to impaired cardiac function.
- The precise mechanisms underlying cardiac fibrosis and fibroblast activation remain incompletely understood.
Purpose of the Study:
- To investigate the role of transcription factors in cardiac fibrosis.
- To identify key regulators of fibroblast-to-myofibroblast transition in the context of heart failure.
Main Methods:
- Bioinformatic screening identified Kruppel-like factor 6 (KLF6) as a potential mediator.
- In vitro studies exposed fibroblasts to transforming growth factor-beta (TGF-β) to induce transition.
- In vivo studies utilized mouse models of heart failure induced by transverse aortic constriction (TAC) or Angiotensin II (Ang II) infusion.
Main Results:
- KLF6 was upregulated in cardiac fibroblasts from patients with non-ischemic cardiomyopathy.
- Nuclear factor kappa B (NF-κB) mediated KLF6 activation by pro-fibrogenic stimuli.
- KLF6 knockdown reduced TGF-β-induced fibroblast-myofibroblast transition in vitro.
- Myofibroblast-specific KLF6 depletion ameliorated cardiac fibrosis and improved heart function in mouse models.
Conclusions:
- KLF6 plays a significant role in mediating cardiac fibrosis.
- Targeting KLF6 may represent a novel therapeutic strategy for heart failure.
Aims:
Heart failure (HF) is one of the most devastating consequences of cardiovascular diseases. Regardless of etiology, cardiac fibrosis is present and promotes the loss of heart function in HF patients. Cardiac resident fibroblasts, in response to a host of pro-fibrogenic stimuli, trans-differentiate into myofibroblasts to mediate cardiac fibrosis, the underlying mechanism of which remains incompletely understood.
Methods:
Fibroblast-myofibroblast transition was induced in vitro by exposure to transforming growth factor (TGF-β). Cardiac fibrosis was induced in mice by either transverse aortic constriction (TAC) or by chronic infusion with angiotensin II (Ang II).
Results:
Through bioinformatic screening, we identified Kruppel-like factor 6 (KLF6) as a transcription factor preferentially up-regulated in cardiac fibroblasts from individuals with non-ischemic cardiomyopathy (NICM) compared to the healthy donors. Further analysis showed that nuclear factor kappa B (NF-κB) bound to the KLF6 promoter and mediated KLF6 trans-activation by pro-fibrogenic stimuli. KLF6 knockdown attenuated whereas KLF6 over-expression enhanced TGF-β induced fibroblast-myofibroblast transition in vitro. More importantly, myofibroblast-specific KLF6 depletion ameliorated cardiac fibrosis and rescued heart function in mice subjected to the TAC procedure or chronic Ang II infusion.
Significance:
In conclusion, our data support a role for KLF6 in cardiac fibrosis.
