Abstract
Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), known to be independently associated with cardiovascular diseases. However, the effect of IH on cardiac fibrosis and molecular events involved in this process are unclear. Here, we tested IH in angiotensin II (Ang II)-induced cardiac fibrosis and signaling linked to fibroblast activation. IH triggered cardiac fibrosis and aggravated Ang II-induced cardiac dysfunction in mice. Plasma thrombospondin-1 (TSP1) content was upregulated in both IH-exposed mice and OSA patients. Moreover, both in vivo and in vitro results showed IH-induced cardiac fibroblast activation and increased TSP1 expression in cardiac fibroblasts. Mechanistically, phosphorylation of STAT3 at Tyr705 mediated the IH-induced TSP1 expression and fibroblast activation. Finally, STAT3 inhibitor S3I-201 or AAV9 carrying a periostin promoter driving the expression of shRNA targeting Stat3 significantly attenuated the synergistic effects of IH and Ang II on cardiac fibrosis in mice. This work suggests a potential therapeutic strategy for OSA-related fibrotic heart disease.
Highlights
The prevalence of sleep apnea is high in patients with cardiovascular disease, which could be caused by multiple risk factors including respiratory instability, obesity and upper airway dysfunction (Javaheri et al, 2017; Kasai et al, 2012)
We found that TSP1 activated transforming growth factor b (TGFb) signaling, which subsequently promoted the transformation of cardiac fibroblasts (CFs) to myofibroblasts, dependent on STAT3 Tyr705 phosphorylation
TSP1 belongs to the thrombospondin family, a conserved family of extracellular, oligomeric, multidomain, calcium-binding glycoproteins that can be secreted by various cell types (Crawford et al, 1998; Adams and Lawler, 2011; Hugo et al, 1998)
Summary
The prevalence of sleep apnea is high in patients with cardiovascular disease, which could be caused by multiple risk factors including respiratory instability, obesity and upper airway dysfunction (Javaheri et al, 2017; Kasai et al, 2012). As a member of the signal transducer and activator of transcription (STAT) protein family, STAT3 was originally identified as an interleukin-6–activated transcription factor It can be phosphorylated by receptor-associated Janus kinase (JAK) in response to growth factor and hemodynamic stress, acting as a regulator in fundamental cellular processes including inflammation, cell growth, proliferation, differentiation, migration, and apoptosis (Wei et al, 2003; Chakraborty et al, 2017; He et al, 2018). Given the integrated function of STAT3 activation in inflammation and fibrosis, we hypothesized that IH-induced STAT3 activation might play a crucial role in CF activation and cardiac fibrosis by increasing TSP1 expression. TSP1 expression induced by IH in CFs, mediated by phosphorylation of STAT3 at Tyr705, was involved in CF activation and cardiac fibrosis. Pharmacological or genetic inhibition of STAT3 restrained IH-induced CF activation and cardiac fibrosis and ameliorated IH-induced cardiac dysfunction
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