Abstract
Inflammation is involved in cardiac remodeling. In response to pathological stimuli, activated cardiac fibroblasts (CFs) secreting inflammatory cytokines and chemokines play an important role in monocyte/macrophage recruitment. However, the precise mechanism of CF-mediated inflammatory response in hypertension-induced cardiac remodeling remains unclear. In the present study, we investigated the role of transcription factor Krüppel-like factor 15 (KLF15) in this process. We found that KLF15 expression decreased while chemokine CXCL1 and its receptor CXCR2 expression increased in the hearts of angiotensin II (Ang II)-infused mice. Compared to the wild-type mice, KLF15 knockout (KO) mice aggravated Ang II-induced cardiac hypertrophy and fibrosis. Deficiency of KLF15 promoted macrophage accumulation, increase of CXCL1 and CXCR2 expression, and mTOR, ERK1/2, NF-κB-p65 signaling activation in the hearts. Mechanistically, Ang II dose- dependently decreased KLF15 expression and increased CXCL1 secretion from cardiac fibroblasts but not cardiac myoblasts. Loss- or gain-of-function studies have shown that KLF15 negatively regulated CXCL1 expression through its transactivation domain (TAD). Intriguingly, the adenovirus-mediated full length of KLF15—but not KLF15 with TAD deletion overexpression—markedly prevented pathological change in Ang II-infused mice. Notably, the administration of CXCR2 inhibitor SB265610 reversed KLF15 knockout-mediated aggravation of cardiac dysfunction, remodeling, and inflammation induced by Ang II. In conclusion, our study identifies that KLF15 in cardiac fibroblasts negatively regulates CXCL1/CXCR2 axis-mediated inflammatory response and subsequent cardiac remodeling in hypertension.
Highlights
Hypertensive heart failure is a terrible disease with high morbidity and mortality characterized by cardiac remodeling including left ventricular hypertrophy and interstitial fibrosis (Katz and Rolett, 2016)
Inspired by the RNA-seq results that identified several Krüppel-like factor 15 (KLF15)-regulated chemokines expression in smooth muscle cells (Sasse et al, 2017), we found that angiotensin II (Ang II) increased cardiac CXCL1 expression (Figure 1D), which showed an opposite trend compared with cardiac KLF15 expression
CXCR2, the receptor of CXCL1, was significantly increased after Ang II infusion (Figure 1E). These findings suggested that Ang II may induce CXCL1/CXCR2-associated inflammatory response via suppressing KLF15 expression
Summary
Hypertensive heart failure is a terrible disease with high morbidity and mortality characterized by cardiac remodeling including left ventricular hypertrophy and interstitial fibrosis (Katz and Rolett, 2016). Clinical and experimental studies reported that deregulated Ang II, the major effector in the renin-angiotensin system, plays an important role in the pathogenesis of cardiac remodeling (Kurdi and Booz, 2011). Ang II induces the infiltration of inflammatory cells, especially monocytes/macrophages in the heart and promotes the development of heart failure (McMaster et al, 2015; Wang et al, 2018). These studies suggest that a multifaceted crosstalk between cardiac cells and non-cardiac cells contributes to cardiac remodeling. Investigation of the critical molecule that promotes these cells’ interaction in the heart after hypertensive stress may provide new therapeutic strategies for cardiac remodeling
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