Irisin inhibits high glucose‐induced endothelial‐to‐mesenchymal transition and exerts a dose‐dependent bidirectional effect on diabetic cardiomyopathy

Abstract

Emerging evidence indicates that irisin provides beneficial effects in diabetes. However, whether irisin influences the development of diabetic cardiomyopathy (DCM) remains unclear. Therefore, we investigated the potential role and mechanism of action of irisin in diabetes‐induced myocardial dysfunction in mice. Type 1 diabetes was induced in mice by injecting streptozotocin, and the diabetic mice were administered recombinant r‐irisin (low or high dose: 0.5 or 1.5 μg/g body weight/day, I.P.) or PBS for 16 weeks. Irisin treatment did not alter blood glucose levels in the diabetic mice. However, the results of echocardiographical and histopathological assays indicated that low‐dose irisin treatment alleviated cardiac fibrosis and left ventricular function in the diabetic mice, whereas high‐dose irisin failed to mitigate the ventricular function impairment and increased collagen deposition. The potential mechanism underlying the effect of low‐dose irisin involved irisin‐mediated inhibition of high glucose‐induced endothelial‐to‐mesenchymal transition (EndMT); conversely, high‐dose irisin treatment enhanced high glucose‐induced MMP expression by stimulating MAPK (p38 and ERK) signalling and cardiac fibroblast proliferation and migration. Low‐dose irisin alleviated DCM development by inhibiting high glucose‐induced EndMT. By contrast, high‐dose irisin disrupted normal MMP expression and induced cardiac fibroblast proliferation and migration, which results in excess collagen deposition. Thus, irisin can inhibit high glucose‐induced EndMT and exert a dose‐dependent bidirectional effect on DCM.

FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

“…In addition, several researches have proved that FNDC5/Irisin played a pivotal role in protecting the heart against ischemia/reperfusion injury and could be a potentially candidate marker for myocardial infarction [23,53,54]. Irisin supplementation could also attenuate collagen deposition and ventricular function impairment in diabetic hearts [55]. Recently, results from Li et al suggested that irisin alleviated pressure overloadinduced cardiac hypertrophy in mice [24].…”

Endothelial to Mesenchymal Transition Represents a Key Link in the Interaction between Inflammation and Endothelial Dysfunction

“…It was shown that high-glucose-induced EndMT occurs through positive regulators, such as Smad2/3, Snail, Rho-associated kinase 1 (ROCK1), serum response factor (SRF), nucleotide-binding oligomerization domain-containing protein 2 (NOD2), and ERK in glomerular ECs ( 57 – 60 ). In human aortic ECs (HAECs) and HUVECs, high glucose also induces EndMT through positive regulators, such as angiotensin II, poly (ADP-ribose) polymerase 1 (PARP-1), endothelin 1 (ET-1), Smad, Akt, p38, and ERK, contributing to diabetic cardiomyopathy ( 55 , 56 , 61 – 63 ). It has also been shown that oxidized low-density lipoprotein (ox-LDL) accelerates radiation-induced EndMT in HAECs and contributes to radiation-induced atherosclerosis ( 64 ), whereas high-density lipoprotein (HDL) inhibits TGFβ1-induced EndMT in HAECs suggesting anti-fibrotic effects of HDL (Figure 2 ) ( 65 ).…”

“…Several studies have shown that EndMT contributes to diabetic nephropathy, while inhibition of EndMT by lovastatin, fasudil, and CCG-1423 could ameliorate diabetic nephropathy in streptozotocin (STZ)-induced diabetic animal models ( 57 – 59 ). In addition, inhibition of EndMT by Irbesartan, glucagon-like peptide-1 analog, ET-1 inhibition and low-dose irisin could prevent diabetic cardiomyopathy in diabetic animal models ( 55 , 61 – 63 ).…”

Nur77 deficiency exacerbates cardiac fibrosis after myocardial infarction by promoting endothelial‐to‐mesenchymal transition

“…Previous studies have shown that pathological EndMT participate in cardiac fibrosis induced by pressure overload, diabetes, and MI (Gong, Lyu, Wang, Hu, & Zhang, 2017; X. Liu et al, 2018). By cell lineage tracing, Aisagbonhi et al (2011), for the first time, proved that MI triggered EndMT.…”