Irisin ameliorates doxorubicin-induced cardiac perivascular fibrosis through inhibiting endothelial-to-mesenchymal transition by regulating ROS accumulation and autophagy disorder in endothelial cells

Abstract

The dose-dependent toxicity to cardiomyocytes has been well recognized as a central characteristic of doxorubicin (DOX)-induced cardiotoxicity (DIC), however, the pathogenesis of DIC in the cardiac microenvironment remains elusive. Irisin is a new hormone-like myokine released into the circulation in response to exercise with distinct functions in regulating apoptosis, inflammation, and oxidative stress. Recent advances revealed the role of irisin as a novel therapeutic method and an important mediator of the beneficial effects of exercise in cardioprotection. Here, by using a low-dose long-term mouse DIC model, we found that the perivascular fibrosis was involved in its myocardial toxicity with the underlying mechanism of endothelial-to-mesenchymal transition (EndMT). Irisin treatment could partially reverse DOX-induced perivascular fibrosis and cardiotoxicity compared to endurance exercise. Mechanistically, DOX stimulation led to excessive accumulation of ROS, which activated the NF-κB-Snail pathway and resulted in EndMT. Besides, dysregulation of autophagy was also found in DOX-treated endothelial cells. Restoring autophagy flux could ameliorate EndMT and eliminate ROS. Irisin treatment significantly alleviated ROS accumulation, autophagy disorder, NF-κB-Snail pathway activation as well as the phenotype of EndMT by targeting uncoupling protein 2 (UCP2). Our results also initially found that irisin was mainly secreted by cardiomyocytes in the cardiac microenvironment, which was significantly reduced by DOX intervention, and had a protective effect on endothelial cells in a paracrine manner. In summary, our study indicated that DOX-induced ROS accumulation and autophagy disorders caused an EndMT in CMECs, which played a role in the perivascular fibrosis of DIC. Irisin treatment could partially reverse this phenomenon by regulating UCP2. Cardiomyocytes were the main source of irisin in the cardiac microenvironment. The current study provides a novel perspective elucidating the pathogenesis and the potential treatment of DIC.

Secretion of miRNA-326-3p by senescent adipose exacerbates myocardial metabolism in diabetic mice

“…Neonatal mouse ventricular myocytes (NMVMs) were isolated from one-day old C57BL/6 J pups as previously described [ 27 ]. More than 95% of cardiomyocytes are typically present in cell preparations.…”

Endothelial Autophagy in Coronary Microvascular Dysfunction and Cardiovascular Disease

“…Although activated fibroblasts, named myofibroblasts, are regarded as the predominant regulator for fibrosis, the contribution of EndMT to the initiation and progression of fibrosis has been gradually appreciated [164,165]. Recent research suggests that the inhibition of autophagy to EndMT serves as a critical cardioprotective mechanism in ameliorating cardiac fibrosis [149,150,[166][167][168]. According to Ke's study, restoring the TFEB-mediated autophagic flux could inhibit the transforming growth factor-β (TGF-β)-meditated EndMT and promote angiogenesis in HCAECs by triggering TFEB nucleus translocation [166].…”

“…In addition, the upregulation of autophagy was reported to prevent hypoxia-induced EndMT and cell apoptosis, while enhancing angiogenesis by inhibiting the NF-κB-Snail signaling pathway in human CMECs [149,150]. Furthermore, Pan et al identified that irisin (a new hormone-like myokine, primarily secreted by cardiomyocytes) treatment significantly alleviated doxorubicin-initiated cardiac perivascular fibrosis by restraining EndMT via restoring autophagy in ECs, resulting in reduced ROS accumulation and inhibited NF-κB-Snail pathway [168]. However, some researchers found that in certain conditions, the activation of autophagy could induce EndMT and contribute to cardiac fibrosis [169,170].…”

“…The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/cells11132081/s1, Table S1: Mechanistic studies implicating endothelial autophagy or mitophagy in cardiovascular diseases [93,105,106,[108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][130][131][132][133][149][150][151][152][153][154][155][156][157][158][159][160][166][167][168][169][170]181,[184][185][186][187]…”

Irisin is an Effector Molecule in Exercise Rehabilitation Following Myocardial Infarction (Review)

“…Mice transverse aortic constriction (TAC)-induced cardiac hypertrophy model reported irisin treatment attenuates pressure overload-induced cardiac hypertrophy and fibrosis mainly through regulating AMPK-mTOR signaling or inhibiting NOD-like receptor protein 3 (NLRP3) -mediated pyroptosis activation (Yu et al, 2019;Yue et al, 2021). A recent study revealed that irisin as a mediator of the beneficial effects of exercise in cardioprotection like ameliorate EndMT through inhibiting activation of NF-κB-Snail pathway due to excessive accumulation of UCP2 and ROS and regulating the autophagy disorders (Pan et al, 2021). In summary, these findings show that irisin (including exercise-induced irisin secretion) exerts a myocardial protective role through its anti-inflammation activity, antioxidant stress effect, and anti-apoptosis properties, as well as improving mitochondrial function, promoting angiogenesis and fibrotic remodeling.…”