Abstract
BackgroundChronic low-grade inflammation and oxidative stress play important roles in the development of obesity-induced cardiac hypertrophy. Here, we investigated the role of Fibronectin type III domain containing 5 (FNDC5) in cardiac inflammation and oxidative stress in obesity-induced cardiac hypertrophy.MethodsMale wild-type and FNDC5−/− mice were fed normal chow or high fat diet (HFD) for 20 weeks to induce obesity, and primary cardiomyocytes and H9c2 cells treated with palmitate (PA) were used as in vitro model. The therapeutic effects of lentiviral vector-mediated FNDC5 overexpression were also examined in HFD-induced cardiac hypertrophy.ResultsHigh fat diet manifested significant increases in body weight and cardiac hypertrophy marker genes expression, while FNDC5 deficiency aggravated cardiac hypertrophy evidenced by increased Nppa, Nppb and Myh7 mRNA level and cardiomyocytes area, in association with enhanced cardiac inflammatory cytokines expression, oxidative stress level and JAK2/STAT3 activation in HFD-fed mice. FNDC5 deficiency in primary cardiomyocytes or FNDC5 knockdown in H9c2 cells enhanced PA-induced inflammatory responses and NOX4 expression. Exogenous FNDC5 pretreatment attenuated PA-induced cardiomyocytes hypertrophy, inflammatory cytokines up-regulation and oxidative stress in primary cardiomyocytes and H9c2 cells. FNDC5 overexpression attenuated cardiac hypertrophy as well as cardiac inflammation and oxidative stress in HFD-fed mice.ConclusionsFNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3 associated-cardiac inflammation and oxidative stress. The cardio-protective role of FNDC5 shed light on future therapeutic interventions in obesity and related cardiovascular complications.
Highlights
Chronic low-grade inflammation and oxidative stress play important roles in the development of obe‐ sity-induced cardiac hypertrophy
We have identified the efficiency of Fibronectin type III domain containing 5 (FNDC5) deficiency in our recent study, and we further confirmed that FNDC5 was deleted in heart of mice in the present study (Fig. 1a)
Echocardiographic analysis showed that, despite lack of an obvious difference in left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) among HFDfed WT and F NDC5−/− mice, FNDC5 deficiency significantly augmented left ventricular hypertrophy evidenced by increased IVSd and LVPWd and cardiac hypertrophy markers (Nppa, natriuretic peptide type B (Nppb), Myh7) mRNA expression as well as LVW/BW (Table 1, Fig. 1c, d) after high fat diet (HFD) treatment
Summary
Chronic low-grade inflammation and oxidative stress play important roles in the development of obe‐ sity-induced cardiac hypertrophy. Despite an increasing understanding toward the pathophysiological process of cardiac hypertrophy, Geng et al J Transl Med (2019) 17:107 in the pathogenesis of obesity-related complications. It has been demonstrated both in vitro and in vivo that the increased free fatty acids in obesity can activate the nuclear factor-kappaB (NF-kB) pathway, subsequently increasing the expression of several pro-inflammatory cytokines and inducing cellular oxidative stress [8]. Irisin improves glucose homoeostasis by reducing gluconeogenesis and increasing glycogenesis via PI3K/Akt pathway in HepG2 cells [12] These findings of our previous studies confirmed the beneficial effects of FNDC5/irisin in metabolic diseases. As an up-regulated myokine after exercise, the exact role of FNDC5 in cardiomyocytes remains unclear
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