Endothelial Klf2-Foxp1-TGFβ signal mediates the inhibitory effects of simvastatin on maladaptive cardiac remodeling

Hongda Li, Yanfang Wang, Jiwen Liu, Xiaoli Chen, Yunhao Duan, Xiaoyu Wang, Yajing Shen, Yashu Kuang, Tao Zhuang, Brain Tomlinson, Paul Chan, Zuoren Yu, Yu Cheng, Lin Zhang, Zhongmin Liu, Yuzhen Zhang, Zhenlin Zhao, Qi Zhang, Jie Liu

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Aims: Pathological cardiac fibrosis and hypertrophy are common features of left ventricular remodeling that often progress to heart failure (HF). Endothelial cells (ECs) are the most abundant non-myocyte cells in adult mouse heart. Simvastatin, a strong inducer of Krüppel-like Factor 2 (Klf2) in ECs, ameliorates pressure overload induced maladaptive cardiac remodeling and dysfunction. This study aims to explore the detailed molecular mechanisms of the anti-remodeling effects of simvastatin. Methods and Results: RGD-magnetic-nanoparticles were used to endothelial specific delivery of siRNA and we found absence of simvastatin’s protective effect on pressure overload induced maladaptive cardiac remodeling and dysfunction after in vivo inhibition of EC-Klf2. Mechanism studies showed that EC-Klf2 inhibition reversed the simvastatin-mediated reduction of fibroblast proliferation and myofibroblast formation, as well as cardiomyocyte size and cardiac hypertrophic genes, which suggested that EC-Klf2 might mediate the anti-fibrotic and anti-hypertrophy effects of simvastatin. Similar effects were observed after Klf2 inhibition in cultured ECs. Moreover, Klf2 regulated its direct target gene TGFβ1 in ECs and mediated the protective effects of simvastatin, and inhibition of EC-Klf2 increased the expression of EC-TGFβ1 leading to simvastatin losing its protective effects. Also, EC-Klf2 was found to regulate EC-Foxp1 and loss of EC-Foxp1 attenuated the protective effects of simvastatin similar to EC-Klf2 inhibition. Conclusions: We conclude that cardiac microvasculature ECs are important in the modulation of pressure overload induced maladaptive cardiac remodeling and dysfunction, and the endothelial Klf2-TGFβ1 or Klf2-Foxp1-TGFβ1 pathway mediates the preventive effects of simvastatin. This study demonstrates a novel mechanism of the non-cholesterol lowering effects of simvastatin for HF prevention.

Original languageEnglish
Pages (from-to)1609-1625
Number of pages17
JournalTheranostics
Volume11
Issue number4
DOIs
Publication statusPublished - Jan 1 2021

Keywords

  • Forkhead box P1 (Foxp1)
  • Heart failure (HF)
  • HMG-CoA reductase inhibitors
  • Krüppel-like factor 2 (Klf2)
  • Maladaptive cardiac remodeling (cardiac fibrosis and hypertrophy)
  • Simvastatin
  • Transforming growth factor-beta 1 (TGFβ1)
  • Vascular endothelial cells (ECs)

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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