Th17/Treg imbalance modulates rat myocardial fibrosis and heart failure by regulating LOX expression.

Abstract

The imbalance of T helper (Th) 17/T regulatory (Treg) is involved in chronic heart failure (HF). The enzyme lysyl oxidase (LOX) contributes to myocardial fibrosis. This study was designed to decipher the regulatory mechanism of Th17/Treg on LOX expression and to validate whether Th17/Treg imbalance regulates myocardial fibrosis by modulating LOX expression. Human cardiac fibroblasts (HCFs) were treated with angiotensin II (Ang II) and co-cultured with Th17 cells and Tregs which were polarized from control naïve CD4+ T cells. Th17 cells and Tregs were adoptively transferred into abdominal aortic coarctation-induced chronic HF rats to investigate the efficacy of Th17 and Treg infusions on myocardial fibrosis and HF. Th17/Treg imbalance (increased Th17 cells and decreased Tregs) was observed in HF patients. Th17 cells/Tregs aggravated/attenuated Ang II-induced upregulation of LOX and fibrosis-related indicators (MMP-2/9 and collagen I/III) in HCFs in vitro and abdominal aortic coarctation-induced myocardial fibrosis and HF in rats, by promoting/inhibiting LOX expression. Mechanistically, Th17 cells promoted LOX expression by activating the IL-17/ERK1/2-AP-1 pathway, while Tregs inhibited LOX expression by activating the IL-10/JAK1-STAT3 pathway. Increased Th17 cells and decreased Tregs aggravate myocardial fibrosis and HF by inducing LOX expression.