Irisin promotes cardiac progenitor cell‐induced myocardial repair and functional improvement in infarcted heart

Abstract

Irisin, a newly identified hormone and cardiokine, is critical for modulating body metabolism. New evidence indicates that irisin protects the heart against myocardial ischemic injury. However, whether irisin enhances cardiac progenitor cell (CPC)-induced cardiac repair remains unknown. This study examines the effect of irisin on CPC-induced cardiac repair when these cells are introduced into the infarcted myocardium. Nkx2.5 CPC stable cells were isolated from mouse embryonic stem cells. Nkx2.5 CPCs (0.5 × 10 ) were reintroduced into the infarcted myocardium using PEGlylated fibrin delivery. The mouse myocardial infarction model was created by permanent ligation of the left anterior descending (LAD) artery. Nkx2.5 CPCs were pretreated with irisin at a concentration of 5 ng/ml in vitro for 24 hr before transplantation. Myocardial functions were evaluated by echocardiographic measurement. Eight weeks after engraftment, Nkx2.5 CPCs improved ventricular function as evident by an increase in ejection fraction and fractional shortening. These findings are concomitant with the suppression of cardiac hypertrophy and attenuation of myocardial interstitial fibrosis. Transplantation of Nkx2.5 CPCs promoted cardiac regeneration and neovascularization, which were increased with the pretreatment of Nkx2.5 CPCs with irisin. Furthermore, irisin treatment promoted myocyte proliferation as indicated by proliferative markers Ki67 and phosphorylated histone 3 and decreased apoptosis. Additionally, irisin resulted in a marked reduction of histone deacetylase 4 and increased p38 acetylation in cultured CPCs. These results indicate that irisin promoted Nkx2.5 CPC-induced cardiac regeneration and functional improvement and that irisin serves as a novel therapeutic approach for stem cells in cardiac repair.

Irisin exerts a therapeutic effect against myocardial infarction via promoting angiogenesis

“…In addition, irisin protects cardiomyocytes against hypoxia and reoxygenation injury and the heart against ischemiareperfusion (I/R) injury [7]. Irisin generated a protective effect against myocardial I/R injury by suppressing the opening of the mitochondrial permeability transition pore [8] through a SOD2dependent mitochondria mechanism [9]. The protective effects of irisin have also been found in endothelial cells.…”

Integrin-Ligand Interactions in Inflammation, Cancer, and Metabolic Disease: Insights Into the Multifaceted Roles of an Emerging Ligand Irisin

“…Treatment with recombinant irisin significantly increases phosphorylated p38 and phosphorylated ERK in both primary rat and 3T3-L1 adipocytes, while cotreatment with an inhibitor of either p38 or ERK or both abolishes the irisin-induced upregulation of UCP1 expression (Zhang et al, 2014). Irisin has been shown to promote Nkx2.5positive cardiac progenitor cell-induced cardiac regeneration, neovascularization and functional improvements in the ischemic heart (Zhao et al, 2019). Moreover, administration of irisin promotes the proliferation of human umbilical vein endothelial cells and cord formation via the ERK pathway (Wu et al, 2015), suggesting that irisin plays a role in guarding against cardiovascular diseases.…”

Novel Mechanisms of Exercise-Induced Cardioprotective Factors in Myocardial Infarction

“…Recently, irisin has been found to protect against the pathologic process of MI via its anti-apoptotic, pro-angiogenetic, and cardiac regenerative functions Liao et al, 2019;Zhao et al, 2019). showed that irisin treatment induced remarkable improvements in ventricular functional recovery and reduction of infarct size in the Langendorff perfused ischemia/reperfusion (I/R) injury heart of mice via suppressing the opening of mitochondrial permeability transition pore, which results in mitochondrial swelling, and protecting mitochondrial function to reduce cardiomyocyte apoptosis.…”

“…Liao et al (2019) reported that treatment with irisin for 2 weeks significantly reduced infarct size and fibrosis in MI mice, significantly increased angiogenesis in the ischemic area, and decreased cardiomyocyte apoptosis via activating the ERK signaling pathway. Besides, it has been recently reported that irisin can induce cardiac regeneration and functional improvement of MI mice via promoting the function of cardiac progenitor cells (CPCs) (Zhao et al, 2019). Thus, irisin is a key exercise-induced cardioprotective factor exerting multiple functions in MI.…”